Hypopigmentation

Hypopigmentation

Edited by
Electra Nicolaidou, MD, PhD
Associate Professor of Dermatology and Venereology
1st Department of Dermatology and Venereology
National and Kapodistrian University of Athens
“Andreas Sygros” Hospital for Skin and Venereal Diseases
Athens, Greece

Clio Dessinioti, MD, MSc, PhD

Clinical Fellow
1st Department of Dermatology and Venereology
National and Kapodistrian University of Athens
“Andreas Sygros” Hospital for Skin and Venereal Diseases
Athens, Greece

Andreas D. Katsambas, MD, PhD

Emeritus Professor of Dermatology and Venereology
National and Kapodistrian University of Athens
Head
Dermatology Clinic
Hygeia Hospital
Athens, Greece
CRC Press
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Library of Congress Cataloging-in-Publication Data

Names: Nicolaidou, Electra, editor. | Dessinioti, Clio, editor. | Katsambas, A. D. (Andreas D.), 1944- editor.
Title: Hypopigmentation / [edited by] Electra Nicolaidou, Clio Dessinioti, Andreas Katsambas.
Description: New York, NY : CRC Press/Taylor & Francis Group, [2020] |
Includes bibliographical references and index.
Identifiers: LCCN 2019015583| ISBN 9781138505230 (hardback : alk. paper) | ISBN 9781315146454 (ebook)
Subjects: | MESH: Hypopigmentation | Vitiligo | Skin Diseases
Classification: LCC RL790 | NLM WR 265 | DDC 616.5/5--dc23
LC record available at https://lccn.loc.gov/2019015583

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Contents

Preface vii
Contributors ix

1 Basic concepts on melanocyte biology 1

Mauro Picardo and Daniela Kovacs
2 Approach to hypopigmentation 13
Clio Dessinioti and Andreas D. Katsambas
3 Historical review of vitiligo 21
Maja Kovacevic, Nika Franceschi, Mirna Situm, Andy Goren, Andrija Stanimirovic, Yan Valle, and Torello Lotti
4 Epidemiology and classification of vitiligo 27
Serena Gianfaldoni and Torello Lotti
5 Pathophysiology of vitiligo 35
Alexandra Miniati
6 Segmental vitiligo 39
Christina Bergqvist and Khaled Ezzedine
7 Childhood versus post-childhood vitiligo 43
Electra Nicolaidou and Styliani Mastraftsi
8 Pharmacological therapy of vitiligo 49
Ivana Binić and Andrija Stanimirović
9 Surgical treatment of vitiligo 69
Muhammed Razmi T., T. P. Afra, and Davinder Parsad
10 Phototherapy and lasers in the treatment of vitiligo 79
Viktoria Eleftheriadou
11 Emerging treatments for vitiligo 85
Angelo Massimiliano D’Erme and Giovanni Bagnoni
12 Tuberous sclerosis complex 89
Vesna Pljakoska, Katerina Damevska, and Natasa Teovska Mitrevska
13 Oculocutaneous albinism 93
Mira Kadurina, Anastasiya A. Chokoeva, and Torello Lotti
14 Hermansky-Pudlak syndrome, Chediak-Chigasi syndrome, and Griscelli syndrome 97
Vesna Pljakoska, Silvija Duma, and Andrej Petrov
15 Piebaldism 101
Jovan Lalošević and Miloš Nikolić
16 Waardenburg syndrome 107
Carmen Maria Salavastru, Stefana Cretu, and George Sorin Tiplica
17 Alezzandrini syndrome, Margolis syndrome, Cross syndrome, and other rare genetic disorders 113
Athanasios I. Pavlidis and Andreas D. Katsambas
18 Mosaic hypopigmentation 117
Irene Latour-Álvarez and Antonio Torrelo
19 Skin disorders causing post-inflammatory hypopigmentation 127
Polytimi Sidiropoulou, Dimitrios Sgouros, and Dimitris Rigopoulos
20 Infectious and parasitic causes of hypopigmentation 133
Serena Gianfaldoni, Aleksandra Vojvodic, Nooshin Bagherani, Bruce R. Smoller, Balachandra Ankad, Leon Gilad,
Arieh Ingber, Fabrizio Guarneri, Uwe Wollina, and Torello Lotti
21 Melanoma leukoderma 145
Alexander J. Stratigos, Polytimi Sidiropoulou, and Dorothea Polydorou
22 Halo nevi 149
Christina Stefanaki
23 Drug-induced hypopigmentation 153
Katerina Damevska, Suzana Nikolovska, Razvigor Darlenski, Ljubica Suturkova, and Torello Lotti

v
vi Contents

24 Hypopigmentation from chemical and physical agents 159

Katerina Damevska, Igor Peev, Ranthilaka R. Ranawaka, and Viktor Simeonovski
25 Guttate hypomelanosis and progressive hypomelanosis of the trunk (progressive macular hypomelanosis) 165
Alexander Katoulis and Efthymia Soura

Index177
Preface

The skin is the most visible organ, and dyschromias This comprehensive illustrated text from
and disorders of pigmentation may be a common international experts aims to enable clinicians
cause of significant psychological burden in to diagnose and treat the full range of these
affected individuals. Hypopigmentation of the conditions in children and in adults by discussing
skin is characterized clinically by areas of “off- detailed clinical clues and presenting signs and
white” color that is lighter compared to the explaining the approach to management.
surrounding normal skin, or by areas of complete We want to thank all our co-authors for their
loss of pigmentation characterized by absolute work and CRC Press/Taylor & Francis and Robert
white color. Hypopigmentation may reflect Peden, for their support.
cutaneous diseases such as vitiligo or mosaic
This book is dedicated by all three of us to
or post-inflammatory hypopigmentation, or be
our families for their patience, support, and
a marker of underlying systemic disorders and thoughtfulness.
complex genetic syndromes including tuberous
sclerosis, albinism, piebaldism, Waardenburg Electra Nicolaidou
syndrome, and other rare disorders. Moreover,
Clio Dessinioti
hypopigmentation may be a sign of cutaneous
T-cell lymphoma or be induced by drugs, including Andreas D. Katsambas
cancer immunotherapy such as anti-PD-1 agents. Athens, Greece

vii
Contributors

T. P. Afra Razvigor Darlenski

Department of Dermatology Department of Dermatology and Venereology
IQRAA International Hospital and Research Centre Trakia University
Calicut, India Stara Zagora, Bulgaria
and
Balachandra Ankad
Department of Dermatology and Venereology
Rajiv Gandhi University of Health Sciences
Acibadem City Clinic Tokuda Hospital
Bengaluru, India
Sofia, Bulgaria
Nooshin Bagherani
Angelo Massimiliano D’Erme
Dermatologist and Lawyer
Unit of Dermatology
Nooshin Bagherani’ Office
Melanoma & Skin Cancer Unit—AVNO
Arak, Iran
Livorno Hospital
and Livorno, Italy

Department of Molecular Medicine Clio Dessinioti

Tehran University of Medical Sciences 1st Department of Dermatology and Venereology
Tehran, Iran National and Kapodistrian University of Athens
“Andreas Sygros” Hospital for Skin and Venereal Diseases
Giovanni Bagnoni Athens, Greece
Unit of Dermatology
Melanoma & Skin Cancer Unit—AVNO Silvija Duma
Livorno Hospital University Clinic of Dermatology
Livorno, Italy St. Cyril and Methodius University
Skopje, Republic of North Macedonia
Christina Bergqvist
Department of Dermatology Viktoria Eleftheriadou
University Hospital Henri Mondor Dermatology
Créteil, France Leicester Royal Infirmary
Leicester, United Kingdom
Ivana Binić
Khaled Ezzedine
University Clinical Centre
Department of Dermatology
Medical School University of Niš
University Hospital Henri Mondor
Niš, Serbia
Créteil, France
Anastasiya A. Chokoeva Nika Franceschi
”Pro Art “—Clinic for Dermatology Department of Dermatology and Venereology
and Aesthetics University Hospital Center Sestre Milosrdnice
Plovdiv, Bulgaria Zagreb, Croatia

Stefana Cretu Serena Gianfaldoni

Second Clinic of Dermatology Department of Dermatology
“Colentina” Clinical Hospital Guglielmo Marconi University
Bucharest, Romania Rome, Italy

Katerina Damevska Leon Gilad

University Clinic of Dermatology Department of Dermatology
St. Cyril and Methodius University Hebrew University of Jerusalem
Skopje, Republic of North Macedonia Jerusalem, Israel

ix
x Contributors

Andy Goren Irene Latour-Álvarez

Department of Dermatology and Venereology Department of Dermatology
Guglielmo Marconi University University Children’s Hospital Niño Jesús
Rome, Italy Madrid, Spain

Fabrizio Guarneri Torello Lotti

Department of Clinical and Experimental Department of Dermatology and Venereology
Medicine—Dermatology and
University of Messina Department of Education Sciences
Messina, Italy Guglielmo Marconi University
Rome, Italy
Arieh Ingber
Department of Dermatology Styliani Mastraftsi
Hadassah University Hospital 1st Department of Dermatology and Venereology
Hebrew University of Jerusalem National and Kapodistrian University of Athens
Jerusalem, Israel “Andreas Sygros” Hospital for Skin and Venereal
Diseases
Mira Kadurina Athens, Greece
Department of Dermatology
Guglielmo Marconi University Alexandra Miniati
Rome, Italy Department of Adult Internal Medicine
Lowell General Hospital
Alexander Katoulis Lowell, Massachusetts
2nd Department of Dermatology and Venereology
National and Kapodistrian University of Athens Natasa Teovska Mitrevska
“Attikon” University General Hospital Department of Dermatology and Venereology
Athens, Greece ReMedika Hospital
Skopje, Republic of North Macedonia
Andreas D. Katsambas
Dermatology and Venereology Electra Nicolaidou
National and Kapodistrian University of Athens 1st Department of Dermatology and Venereology
Head National and Kapodistrian University of Athens
Dermatology Clinic “Andreas Sygros” Hospital for Skin and Venereal
Hygeia Hospital Diseases
Athens, Greece Athens, Greece

Maja Kovacevic Miloš Nikolić

Department of Dermatology and Venereology Department of Dermatovenereology
University Hospital Center Sestre Milosrdnice University of Belgrade School of Medicine
Zagreb, Croatia Belgrade, Serbia

Daniela Kovacs Suzana Nikolovska

Cutaneous Physiopathology and Integrated University Clinic of Dermatology
Center of Metabolomics Research St. Cyril and Methodius University
San Gallicano Dermatological Institute Skopje, Republic of North Macedonia
IRCCS
Rome, Italy Davinder Parsad
Department of Dermatology, Venereology,
Jovan Lalošević and Leprology
Clinic of Dermatovenereology Postgraduate Institute of Medical Education
Clinical Center of Serbia and Research
Belgrade, Serbia Chandigarh, India
 Contributors xi

Athanasios I. Pavlidis Dimitrios Sgouros

Department of Dermatology 1st Department of Dermatology and Venereology
Errikos Dunant Hospital Center National and Kapodistrian University of Athens
Athens, Greece “Andreas Sygros” Hospital for Skin and Venereal Diseases
Athens, Greece
Igor Peev
University Clinic of Plastic and Reconstructive Surgery Polytimi Sidiropoulou
St. Cyril and Methodius University 1st Department of Dermatology and Venereology
Skopje, Republic of North Macedonia National and Kapodistrian University of Athens
“Andreas Sygros” Hospital for Skin and Venereal
Andrej Petrov Diseases
Department of Dermatology and Venereology Athens, Greece
Acibadem Sistina Hospital
Skopje, Republic of North Macedonia Viktor Simeonovski
University Clinic of Dermatology
and St. Cyril and Methodius University
Faculty of Medicine Skopje, Republic of North Macedonia
Goce Delcev University
Mirna Situm
Shtip, Republic of North Macedonia
Department of Dermatology and Venereology
Mauro Picardo University Hospital Center Sestre Milosrdnice
Cutaneous Physiopathology and Integrated Center of Zagreb, Croatia
Metabolomics Research
San Gallicano Dermatological Institute Bruce R. Smoller
IRCCS Department of Pathology
Rome, Italy and
Department of Dermatology
Vesna Pljakoska University of Rochester
Department of Dermatology and Venereology Rochester, New York
Acibadem Sistina Hospital
Skopje, Republic of North Macedonia Efthymia Soura
1st Department of Dermatology and Venereology
Dorothea Polydorou
National and Kapodistrian University of Athens
Department of Dermatology and Venereology
“Andreas Sygros” Hospital for Skin and Venereal Diseases
“Andreas Sygros” Hospital for Skin and Venereal Diseases
Athens, Greece
Athens, Greece
Andrija Stanimirovic
Ranthilaka R. Ranawaka
Department of Clinical Medicine
Dermatology Clinic
University of Applied Health Sciences
General Hospital Kalutara
Zagreb, Croatia
Sri Lanka
Christina Stefanaki
Muhammed Razmi T. 1st Department of Dermatology and Venereology
Department of Dermatology National and Kapodistrian University of Athens
IQRAA International Hospital and Research Centre “Andreas Sygros” Hospital for Skin and Venereal Diseases
Calicut, India Athens, Greece

Dimitris Rigopoulos Alexander J. Stratigos

1st Department of Dermatology and Venereology 1st Department of Dermatology and Venereology
National and Kapodistrian University of Athens National and Kapodistrian University of Athens
“Andreas Sygros” Hospital for Skin and Venereal Diseases “Andreas Sygros” Hospital for Skin and Venereal Diseases
Athens, Greece Athens, Greece

Carmen Maria Salavastru Ljubica Suturkova

Paediatric Dermatology Discipline Faculty of Pharmacy
“Carol Davila” University of Medicine and Pharmacy St. Cyril and Methodius University
Bucharest, Romania Skopje, Republic of North Macedonia
xii Contributors

George Sorin Tiplica Yan Valle

Second Clinic of Dermatology Vitiligo Research Foundation
“Colentina” Clinical Hospital New York, New York
and
Second Dermatology Discipline Aleksandra Vojvodic
“Carol Davila” University of Medicine Department of Dermatology and Venereology
and Pharmacy Military Medical Academy
Bucharest, Romania Belgrade, Serbia

Antonio Torrelo Uwe Wollina

Department of Dermatology Department of Dermatology and Venereology
University Children’s Hospital Niño Jesús Stadtisches Klinicum Dresden
Madrid, Spain Dresden, Germany
Basic concepts on melanocyte biology
MAURO PICARDO and DANIELA KOVACS
1
CONTENTS
Evolution/adaptation of human pigmentation and Extracellular matrix microenvironment
its heterogeneity 1 and melanocyte homeostasis 9
Melanocytes and melanin synthesis 3 Concluding remarks 9
Melanosome transport inside melanocytes and References 9
melanosome transfer to keratinocytes 4
Cell–cell crosstalk in the control of melanocyte
functionality 7

EVOLUTION/ADAPTATION OF HUMAN PIGMENTATION to promote photoprotection near the equator (stimulating

AND ITS HETEROGENEITY the dark constitutive pigmentation) and on the other to
Melanocytes participate as the major performers in the promote the ultraviolet B (UVB)-induced photosynthesis
complex scenario of biological components regulating the of vitamin D at the poles (stimulating light constitutive
process of pigmentation. These cells are specialized in the pigmentation).1–3 On the other hand, the evolution of
synthesis of melanin pigments inside membrane-bound epidermal pigmentation has been also proposed as a
organelles, the melanosomes. Along with hemoglobin and protective strategy against UV-mediated damages to the
carotenoids, melanin is the main pigment responsible for skin permeability barrier and as a defense against the high
the color variations of our skin and hair. Differences in skin water loss occurring in dessicating external environments
and hair color are considered to be adaptive responses and to such as the sub-Saharan African regions. In support of
be highly related to ultraviolet (UV) exposure and latitude. this hypothesis, in comparison to lightly pigmented
During evolution, human ancestors living in equatorial individuals, darkly skinned people show a more acidic pH
Africa were probably characterized by light pigmentation of the stratum corneum, which is further acidified by the
of the body, which was, however, covered by dark hair. slow and delayed degradation/extrusion of melanin. It has
The gradual loss of body hair paralleled the increase in the been also theorized that the melanocytes of darkly skinned
epidermal and stratum corneum thickness and in dark- people secrete paracrine mediators able to stimulate
photoprotective eumelanin pigmentation to prevent the epidermal differentiation and the production of lipids
damages of ultraviolet radiation (UVR) near the equator. positively involved in the constitution of the skin barrier,
Under intense UVR exposure, dark skin developed as a thus efficiently improving barrier competence in dark
protective mechanism to limit destruction of cutaneous skin. Moreover, a pigmented epidermis displays enhanced
and systemic folate. Folate regulates important biological antimicrobial defense, a property strictly co-regulated and
processes such as DNA synthesis, repair, methylation, interconnected with permeability barrier homeostasis.4–6
and maintenance of active spermatogenesis, as well as Melanocytes originate from neural crest multipotent
melanin production. Folate deficiency has been linked to precursors and after steps of migration, proliferation,
pregnancy complications and severe fetal abnormalities and differentiation finally settle into epidermis and hair
in neural tube development. The sensitivity of folate follicles as well as extracutaneous sites, for example,
and of its main serum form, 5-methyltetrahydrofolate, mucosa, cardiovascular system, adipose tissue, cochlea,
to be degraded by UVR and reactive oxygen species and choroid.7–9 In the skin, they differentiate into dentritic
(ROS) supports the hypothesis according to which the pigment-producing melanocytes (Figure 1.1) and are
increased pigmentation occurring in high UVR-exposed distributed among keratinocytes of the epidermal basal
terrestrial areas evolved to prevent fertility reduction layer and in hair follicles (Figure 1.2). Synthesized melanin
caused by folate photodegradation. As hominins gradually primarily aims at protecting from the harmful effects of
moved outside of tropical latitudes, toward Eurasia, the UV radiation derived from sunlight as well as, nowadays,
Americas, and nonequatorial Africa, the intensity and from indoor tanning apparatuses, thanks to its ability to
duration patterns of UV exposure decreased together absorb UVR and damaging free radicals. The tanning
with a reduced potential for vitamin D production, thus response and the resulting promotion of pigmentation
favoring the promotion of depigmentation. Therefore, constitute the main protective mechanisms activated
the wide array of pigmentation characterizing modern following acute and chronic UV exposure by melanocytes
humans seems to be guided on the one hand by the need and the skin in its entirety.

1
2 Basic concepts on melanocyte biology

(a)
Phase contrast

(b)

DOPA staining

Figure 1.1 (a) Phase contrast microscopic analysis of primary cultures of normal human melanocytes showing the typical dendritic
shape. (b) DOPA staining of human primary melanocytes displaying the cellular brown/black appearance due to the activity of
tyrosinase on DOPA substrate. Scale bar: a, b: 50 µm.

Melanocytes actively interact with both epidermal are two main types of melanin synthesized through the
and dermal compartments. Each melanocyte, through multistep process of melanogenesis: red/yellow pheomelanin
its dendrites, is in mutual connection with about 30–40 and brown/black or dark eumelanin, which are both
keratinocytes, constituting the epidermal melanin unit produced in different ratios. In light-skinned people, the
(Figure 1.3), and with dermal fibroblasts, thus establishing predominant melanin type is usually pheomelanin, the
a finely balanced network of cell–cell crosstalk, ultimately melanosomes are smaller and less condensed, and they
influencing the color of the skin. Differentiated melanocytes are transferred to keratinocytes grouped in membrane-
display a low growth rate and elevated resistance to apoptosis bound clusters containing four to eight melanosomes.11,12
as a result of their high intrinsic expression of the anti- As light keratinocytes terminally differentiate, melanosome
apoptotic protein Bcl-2.10 Despite variations in the density of structures are fully degraded in the upper epidermal layers.11
melanocytic cells in diverse body areas, their overall number Differently, in dark-skinned people, eumelanin is the main
appears constant among human populations. Differences in produced melanin type, and melanosomes are larger and
ethnic color are rather related to the type and quantity of more copious but singularly packaged and transferred into
produced melanin and to its transfer, distribution pattern, the surrounding keratinocytes, where their degradation and
and degradation into neighboring keratinocytes. There disappearance are slower13 (Figure 1.4).
 Melanocytes and melanin synthesis 3

(a)

MART1

(b)

MITF

Figure 1.2 Serial sections of a skin specimen showing the presence of melanocytes identified using the melanocyte markers
MART1 (melanoma antigen recognized by T cells 1) (melanosome structural protein) (a), and MITF (microphtalmia-associated
transcription factor) (b). Nuclei are counterstained with hematoxylin. Right panels represent higher-magnification images of the
black boxed areas. Scale bar: Left panels: 50 µm; higher-magnification images on the right panels: 20 µm.

MELANOCYTES AND MELANIN SYNTHESIS constituents. Progressing to stage II, they assemble into
A decisive aspect in determining skin color is the type elongated fibrillar organelles containing structural (e.g.,
of melanin synthesized by melanocytes. Melanin Pmel17—melanosomal matrix protein 17, also known as
synthesis occurs within specialized membrane-bound PMEL, SILV, gp100) and enzymatic proteins (tyrosinase),
organelles, the melanosomes, through four stages of but they still lack pigment. Then, melanin synthesis
maturation. Melanin arrangement inside melanosomes begins and the produced pigment is placed on internal
guarantees the protection of other cell compartments fibrils (stage III). At stage IV, melanosomes are mature
from oxidative stress produced during pigment synthesis and fully melanized. They are deprived of tyrosinase
and, at the same time, condensates melanin for its activity and are transferred along dendrites and then to
transfer to kertinocytes.14 While maturing, melanosomes the surrounding keratinocytes.12 Within melanosomes,
progressively acquire structural and enzymatic melanin synthesis occurs through a sequence of reactions
proteins, allowing them to produce pigment. At stage I, guided by the coordinate actions of crucial enzymes,
melanosomes appear as round vesicles without structural namely tyrosinase, tyrosinase-related protein 1 (TYRP-1),

Epidermal-melanin unit: 1 melanocyte/30-40 keratinocytes

Keratinocytes

Melanocyte

Figure 1.3 The epidermal-melanin unit showing the interactions between melanocytes and the surrounding keratinocytes.
Left panel: Detection of melanocytes on a section of a skin specimen by immunohistochemical analysis of the expression of MART1.
Scale bar: 50 µm.
4 Basic concepts on melanocyte biology

(a) (b)

Dark skin Light skin

Melanocytes

Melanocytes

Figure 1.4 Pigmentation in dark and light skin. In dark-skinned people (left panel, a), melanosomes are large, abundant, and
transferred to keratinocytes as singly packaged organelles. In light-skinned individuals (right panel, b), melanosomes are small, less
matured, and transferred to keratinocytes as clusters in membrane-bound organelles, encompassing more melanosomes. Insert in a:
immunohistochemical analysis of the expression of the melanocyte marker MITF in a darkly pigmented skin specimen. Arrows indicate
stained melanocytes. Melanin pigment is observable inside basal and suprabasal keratinocytes. Insert in b: immunohistochemical
analysis of the expression of the melanocyte marker MITF in a lightly pigmented skin specimen. Arrows indicate stained melanocytes.

and tyrosinase-related protein 2/dopachrome tautomerase DHICA oxidation and polymerization, leading to light-
(TYRP-2, DCT). The cooperation of these three enzymes brown, fairly soluble DHICA eumelanin15 (Figures 1.5 and
leads to the production of two main melanin-type 1.6). Eumelanin is prevalent in dark-skinned/black-haired
biopolymers: red-yellow pheomelanin and brown- individuals and protects from UV damage. Pheomelanin,
black eumelanin. Melanogenic enzyme functionality which is higher in people with fair skin and red hair,
and substrate obtainability drive the type of melanins generates an increased amount of free radicals, thus
produced. Tyrosinase governs the initial synthesis steps, inducing more harmful effects. Several genes involved
hydroxylating l-tyrosine to l-3,4-dihydroxyphenylalanine in melanin synthesis and melanosome formation, as
(l-DOPA) (the earliest melanogenesis rate restricting step) well as in pigment trafficking inside melanocytes and
and subsequently oxidizing DOPA to DOPAquinone. At melanin transfer to keratinocytes, decisively influence
this point, when sulfhydryl groups such as l-cysteine the variations in pigmentation observed among human
are available, dopaquinone reacts with them, forming populations. Multiple genes are known to directly or
cysteinylDOPA isomers, including 5-S-cysteinylDOPA indirectly impact pigmentation, and mutations of many
and 2-S-cysteinylDOPA. They are hence oxidized and of these genes may lead to pigmentary disorders, either as
polymerize, producing pheomelanins via benzothiazine hyper- or hypopigmentation.16,17
intermediates. As sulfhydryl groups are not available,
dopaquinone is spontaneously subjected to cyclization MELANOSOME TRANSPORT INSIDE MELANOCYTES
and rearrangement to DOPAchrome. DOPAchrome AND MELANOSOME TRANSFER TO KERATINOCYTES
spontaneously decarboxylates into 5, 6 dihydroxyindole As melanosomes differentiate, they progressively move
(DHI), forming, by rapid oxidation and polymerization, from the melanocyte perinuclear area to the dendrite
dark brown-black insoluble DHI-melanin. In the presence tips. Melanosome intracellular movement occurs both
of the enzymatic protein dopachrome tautomerase antero- and retrogradely, toward microtubule proteins
(TYRP2, DCT), dopachrome will generate DHI-2- belonging to the kinesin and dynein/dynein-associated
carboxylic-acid (DHICA). TYRP1 catalyzes further protein superfamilies, respectively. In the dendrites,
 Melanosome transport inside melanocytes and melanosome transfer to keratinocytes 5

(a)

Keratinocyte
Stage IV
Melanocyte
Stage I Stage II

Stage III Melanosome

Melanosomes Nucleus
transfer

(b)

NKI/beteb (gp100) Tyrosinase

DAPI DAPI

Tyrosinase-related protein 1 Tyrosinase-related protein 2

DAPI DAPI

Figure 1.5 (a) Cartoon depicting the four stages of melanosome maturation within melanocytes. While maturing, melanosomes
acquire the structural and enzymatic components necessary to produce melanin. (b) Immunofluorescence analysis of the expression
of the structural melanosome-associated protein NKIbeteb/gp100 and of the enzymatic proteins tyrosinase, tyrosinase-related protein
1, and tyrosinase-related protein 2 in human primary melanocytes. Nuclei are counterstained with 4′,6′-diamidino-2 phenylindole
(DAPI). Scale bar: 20 µm.

Melanosome L-tyrosine

Tyrosinase
3,4-dihydroxyphenylalanine (L-DOPA)
Tyrosinase
DOPAquinone Lack of cysteine
+ cysteine
DOPAchrome
2-S-Cysteinyldopa 5-S-Cysteinyldopa Tyrosinase-related
protein 2
5,6-dihydroxyindole-2-carboxylic acid
CysteinyIDOPA-quinones (DHICA)
tyrosinase-related 5,6-dihydroxyindole (DHI)
protein 1 Tyrosinase
Benzothiazine
intermediates Indole-5,6-quinone-2-carboxylic acid Indole-5,6-quinone
(DHICA melanin) (DHI melanin)
Pheomelanins
Eumelanins

Figure 1.6 Melanin biosynthetic pathway. Two major melanin forms are synthesized within melanosomes: red-yellow pheomelanin
and brown-black eumelanin.
6 Basic concepts on melanocyte biology

melanosomes are then connected with peripheral actin fusion of melanocyte-keratinocyte plasma membranes.
filaments by a tripartite complex composed of the small Melanosome transfer by the fusion model has been also
GTPase Rab27a, its effector protein melanophillin, and suggested to occur via melanocyte filopodia united with
the actin motor myosin Va, allowing their detachment keratinocyte plasma membrane to form a tubular structure
from the microtubules and their settling close to the of actin filaments. (iv) Transfer through membrane-
plasma membrane.18,19 From the tips of the dendrites, bound vesicles: melanocytes release membrane vesicles
fully melanized melanosomes are transferred to the containing melanosomes, which are then phagocytosed
neighboring keratinocytes, where they distribute as by keratinocytes.20–22
a supra-nuclear cap, aiming at protecting cell nuclei Keratinocytes, for their part, actively participate in
from the damaging effects of UV. Based on in vitro and regulating the process of melanosome uptake. The expression
ultrastructural studies, different models of melanosome of specific receptors on keratinocytes, but not on melanocytes,
intercellular transfer, which are not incompatible with positively controls melanosome internalization. Among
each other, have been hypothesized: (i) Exocytosis them, the G-protein-coupled protease-activated receptor 2
of naked melanin (also referred to as melanocore) (PAR-2) is decisive in melanosome uptake by stimulating
into the extracellular areas through the fusion of the the process of phagocytosis. PAR-2 receptors are activated
melanocyte plasma- and melanosome membranes. The by proteolytic cleavage of their extracellular N-terminal
pigment particles are then taken up by the surrounding domain via serine proteases. The cleavage discloses
keratinocytes via phagocytosis. (ii) Cytophagocytosis: tethered ligands that bind the receptor, thus inducing its
keratinocytes internalize melanocyte dendrite tips activation. Once activated, PAR-2 increases melanosome
via phagocytosis. Subsequent fusion of lysosomes and internalization by a Rho-dependent mechanism.23,24 PAR-2
dissolution of the melanosome membrane lead to the expression and activity are upregulated following UV25 and
formation of phagolysosomes. The latter are then gradually are also correlated with skin color, showing more elevated
degraded in vesicles containing melanin granules levels with respect to lightly pigmented skin.26 Melanosome
spread in the cytoplasm of keratinocytes. Filopodial transfer is also stimulated by the expression and activation
phagocytosis, in which melanocyte filopodia containing of the keratinocyte growth factor receptor (KGFR) in early
melanosomes are phagocitosed by keratinocytes, has differentiated keratinocytes, where the levels of the receptor
been also reported. (iii) Membrane fusion: melanosomes are increased. KGFR directly promotes the phagocytic
proceed via a thin, transient channel derived from the process27,28 (Figure 1.7).

(a) (b)
NKI/beteb cytokeratin DAPI

Figure 1.7 Double immunofluorescence staining of human primary melanocyte-keratinocyte co-cultures with anti-NKI-beteb
antibody (green signal) to stain melanosomes and with anti-cytokeratin antibody (red signal) to detect keratinocytes. Intracytoplasmic
dots positively stained for NKI-beteb are detectable in keratinocytes (white arrows), evidencing melanosome transfer. The images in
(b) represent higher magnification of the boxed areas in (a). Scale bar: 50 µm.
 Cell–cell crosstalk in the control of melanocyte functionality 7

CELL–CELL CROSSTALK IN THE CONTROL characterized by a prevalence of pheomelanin, a feeble

OF MELANOCYTE FUNCTIONALITY potential for tanning, and increased risk for melanoma
Melanocyte homeostasis is guided by the active signaling and nonmelanoma skin cancers. 30 Upon UV exposure,
crosstalk established with the surrounding epidermal direct transcriptional activation of POMC/alpha-MSH
and dermal microenvironment via secreted factors and occurs in keratinocytes by the tumor-suppressor protein
intercellular connections. p53, 31 thus promoting melanocyte functions. Besides its
central role in regulating pigmentation, MC1R influences
Melanocyte-keratinocyte interactions several other processes, not only in melanocytes but also
Keratinocytes impact melanocyte functions through in the skin microenvironment in its entirety, maintaining
adhesion molecules and an inter/intracellular network genomic integrity, controlling oxidative stress, and
of paracrine/autocrine bioactive messengers, whose promoting the antioxidant defense system.32 Recently, a
physiological release is upregulated in response to external connection between MC1R and nuclear receptor activation
triggers, first UV exposure and/or also inflammatory has been described, further underlying the multitude of
stimuli. Binding to their specific receptors, keratinocyte- functions guided by MC1R in cells and tissues. α-MSH has
derived mediators activate intracellular signaling pathways been shown to activate the nuclear receptor peroxisome
controlling the growth, survival, differentiation, and proliferator-activated receptor-γ (PPAR-γ) through the
pigment synthesis of melanocytic cells. induction of the phosphatidylinositol [PI(4,5)P2/PLCβ]
Among these growth factor/receptor axes, the pro- signal pathway, demonstrating how MC1R has a role in
opiomelanocortin (POMC) cleavage peptides alpha- controlling extrapigmentary functions such as proliferation
melanocyte stimulating hormone (α-MSH) and via lipid mediators.32,33
adrenocorticotropic hormone (ACTH), via signaling Many other melanocyte mitogen and melanogen
through the G protein-coupled receptor melanocortin 1 factors are produced by keratinocytes, for example, stem
receptor (MC1R), are key players in the induction of cell factor (SCF), endothelin-1 (ET-1), basic fibroblast
melanocyte differentiation and melanin synthesis. growth factor (bFGF/FGF2), granulocyte-macrophage
Activation of MC1R through cAMP-dependent colony-stimulating factor (GM-CSF), and hepatocyte
signaling promotes the upregulation of the transcription growth factor (HGF). As for α-MSH, the synthesis of
factor microphtalmia-associated transcription factor most of them is significantly increased following UV
(MITF). MITF is considered a crucial transcription irradiation. ET-1 acts, binding to endothelin receptor
factor for melanocyte functions (Figure 1.8), regulating type B (EDNRB), promoting melanocyte growth
the transcription of pigmentation-related genes (e.g., and melanogenesis. 34 The SCF/c-kit tyrosine kinase
tyrosinase, TYRP-1, TYRP-2, PMEL, MART1), thus receptor axis favors melanocyte survival and melanin
promoting melanocyte differentiation, as well as genes production. 35 Comparable to POMC, the transcription
linked to survival (e.g., Bcl-2), cell cycle, and metabolism and synthesis of both ET-1 and SCF are stimulated by
(e.g., CDK2). 29 Through the induction of MITF and, p53.36 Along with growth factors, other mediators released
consequently, the pigmentation-related genes, MC1R by keratinocytes in the course of biological processes
regulates the production of eu- versus pheomelanin. such as inflammation or wound healing may function as
Activating the receptor by agonists such as α-MSH activators of melanocytes. Among them, the arachidonic
or ACTH, the production of eumelanin is stimulated. acid–derived lipid molecules prostaglandins E2 and F2a
Differently, the action of an antagonist, for example, stimulate melanocyte dendricity and melanogenesis. 37
Agouti signaling protein, may lead to the synthesis of Keratinocytes secrete also nerve growth factor (NGF),
pheomelanin. MC1R variants with a weak functionality which is implicated in melanocyte dendrite formation
are observed in fair-skinned/red-haired people, who are and melanin synthesis, survival, and migration. 38 In

MITF MITF DAPI

Figure 1.8 Immunofluorescence analysis of MITF expression (white arrows) in primary cultures of human melanocytes. Nuclei
are counterstained with DAPI. Scale bar: 20 µm.
8 Basic concepts on melanocyte biology

the finely balanced crosstalk between keratinocytes and (a) Keratinocyte-melanocyte interactions
melanocytes, alongside messengers acting as positive
inducers of the functionality of the latter, keratinocytes HGF
BMP-6
also release some inhibiting factors. TGF-β inhibits Melanocytes
BMP-4
melanocyte proliferation, differentiation, and melanin α-MSH/ACTH
TNF-α ET-1
synthesis. The production of TGF-β in keratinocytes TGF-β
SCF
is suppressed upon UV exposure, and such an event NGF
GM-CSF
IFN-γ IL-6
allows the upregulation of the transcription factor SOX3 IL-1α bFGF
PGE2/PGF2a
in melanocytes, thus stimulating the pigmentation Inhibiting mediators
Activating mediators
process. 39 Keratinocytes, as well as melanocytes Keratinocytes
themselves, express bone morphogenic proteins
(BMPs), signaling molecules belonging to the TGFβ1
superfamily. Among them, BMP-4 is able to inhibit
melanogenesis, decreasing tyrosinase expression. On the Fibroblast-melanocyte interactions
(b)
contrary, BMP-6 acts in the opposite way, stimulating
melanin synthesis through the induction of tyrosinase bFGF
expression and activity, together with melanin transfer Melanocytes
from melanocytes to keratinocytes. 40,41 Following UV KGF
HGF
exposure, keratinocytes are also stimulated to synthesize Neuregulin-1
TGF-β
the cytokine interferon gamma (IFN-γ), which exerts DKK1 SCF
an inhibitory effect on pigmentation, decreasing the sFRP2
Inhibiting mediators
expression of enzymes deputed to melanin biosynthesis, Activating mediators
thus impeding melanosome maturation. 42 Additional
Fibroblasts
keratinocyte-derived cytokines with downregulating
effects on melanization and melanocyte proliferation
are interleukin 6 (IL-6), interleukin 1 alpha (IL-1α), and
Endothelial cell-melanocyte interactions
tumor necrosis factor alpha (TNF-α)43 (Figure 1.9a). (c)

Melanocyte-fibroblast interactions Melanocytes

Dermal fibroblasts play an active role in modulating
melanocyte homeostasis through the secretion of growth SCF
TGF-β1 Clusterin ET-1
factors and cytokines, which act both in a synergistic
and sometimes overlapping fashion with respect to the Inhibiting mediators Activating mediators
keratinocyte-mediated signaling network. Additionally, Endothelial cell
some paracrine messengers released by fibroblasts can
indirectly target melanocyte functions, inducing the
production of biofactors able to either block or stimulate
melanocyte activities in keratinocytes. Similar to growth Figure 1.9 Summary of the stimulating and inhibiting
factors and cytokines synthesized by keratinocytes, in bioactive mediators involved in the regulation of melanocyte
this intricate epithelial-mesenchymal interaction, some functionalities. (a) Keratinocyte-derived messengers.
fibroblastic bioactive messengers act as melanocyte (b) Fibroblast-derived messengers. (c) Endothelial cell-derived
activators, others as inhibitors. The physiological messengers.
hypopigmented phenotype of the palms and soles has
been attributed to increased expression of the Wnt
pathway antagonist dickkopf1 (DKK1) in these body others are exclusively of fibroblastic origin. Among the
areas. This site-specific fibroblast-derived factor exerts a latter, neuregulin-1 has been demonstrated to be highly
dual action: on the one hand, it suppresses melanocyte expressed in fibroblasts of type VI skin, where it positively
growth and melanin synthesis, and on the other, it participates in the regulation of constitutive pigmentation
acts on keratinocytes, decreasing the expression of the of darker skin.45 Keratinocyte growth factor (KGF) belongs
proteinase-activated receptor 2 actively involved in the to the family of fibroblast growth factors and represents a
process of melanosome transfer.44 Furthermore, fibroblasts further mesenchymal-specific pro-pigmenting paracrine
share with keratinocytes the production of TGF-β, with mediator. KGF directly promotes melanosome transfer
repressive properties on melanocytes. 39 However, the via activation of its receptor KGFR in keratinocytes.
largest number of fibroblast-derived messengers exert a Additionally, it upregulates the synthesis and release of SCF
positive action on melanocyte activities, acting on their from keratinocytes, thus indirectly promoting melanocyte
growth, survival, migration, and pigment production. pro-pigmenting and pro-growing activities. It has been
Some of these pro-pigmenting mediators are also produced also demonstrated that the treatment with KGF alone or in
by epidermal cells, for example, SCF, HGF, and bFGF; combination with IL-1α increases melanin production and
 References 9

deposition in pigmented epidermal equivalents and human CONCLUDING REMARKS

skin explants.27,46,47 The Wnt modulator secreted frizzled- Despite the relatively low number of melanocytes
related protein 2 (sFRP2) has been recently discovered as distributed throughout the epidermis in comparison to
a further fibroblast-secreted stimulating factor, thanks to their neighboring keratinocytes, these cells represent
its ability to increase the expression levels of MITF and intriguing and master players in the control of a multitude
tyrosinase through beta catenin signaling48 (Figure 1.9b). of cutaneous biological functions. Melanocyte homeostasis
has been guided, over time, by both intrinsic and extrinsic
Melanocyte-endothelial cell interactions
factors (above all, UV exposure) that have contributed and
In the complex scenario of the epidermal-dermal are still contributing to the development and evolution
interactions emerging as crucially involved in mediating of the pigmentary system. All these influences create an
melanocyte homeostasis under both physiological and intricate and finely balanced signaling crosstalk, in which
pathological conditions, several reports have now been melanocytes exert a central and dynamic role in controlling
focused on the epithelial/endothelial cell–cell interplay. the equilibrium and protection of the skin in its entirety.
However, contradictory effects are reported in the On the other hand, the network of bioactive messengers
literature, showing both positive and negative regulatory acts bidirectionally to and from the melanocytes toward
abilities of vascular endothelial cells on the process of the other dermal and epidermal cells. As a result, this
pigmentation. A stimulatory effect of endothelial cell- mutual interaction confers on the whole cutaneous
derived ET-1 on melanogenesis, via the signaling pathway microenvironment the ability to strongly influence
of the EDNRB on melanocytes, has been reported.49 On melanocytes themselves and therefore to contribute to
the other hand, subsequent studies demonstrated the both constitutive pigmentation and, whenever altered, to
ability of endothelial cells to inhibit pigmentation via the the onset and persistence of pigmentary disorders.
secretion of high amounts of TGF-β1 and/or clusterin,
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Approach to hypopigmentation
CLIO DESSINIOTI and ANDREAS D. KATSAMBAS
2
CONTENTS
Introduction 13 Congenital hypopigmentation 14
Diagnostic approach to hypopigmentation 13 Noncongenital hypopigmentation 17
Congenital hypopigmentation or not? 14 References 19
Special considerations based on the distribution of
hypopigmentation 14

INTRODUCTION hypopigmented lesions. The characteristic primary

Cutaneous pigmentation is a complex human trait, or secondary lesions of these skin diseases are also
influenced by melanin, capillary blood flow, cutaneous usually present to guide the diagnosis. Morphea,
chromophores (lycopene, carotene), and collagen in discoid lupus, lichen sclerosus, and scleroderma
the dermis. The synthesis and type of melanin and its may present hypopigmented/depigmented lesions
distribution within melanosomes are genetically regulated with concomitant induration or epidermal atrophy
by a number of genes, such as MC1R, TYR, OCA2, SLC24A5, that will guide correct diagnosis.4
MATP, and ASIP.1 3. The use of systemic drugs or topical agents should be
Disorders of hypopigmentation may be linked to a investigated as a possible cause of hypopigmentation/
variety of causal factors, including genetic defects or depigmentation.
acquired conditions such as vitiligo or contact with topical 4. Ask about traveling to endemic regions for endemic
environmental agents, as a sequel to another inflammatory treponematosis.
skin disease, or due to systemic drug intake leading to
hypopigmentation.
• History of hypopigmentation: Age at onset (congenital or
later in life), stable or increasing in size
DIAGNOSTIC APPROACH TO HYPOPIGMENTATION • Complete physical examination: Distribution and extent
of hypopigmentation (widespread or circumscribed),
The diagnostic approach to patients with cutaneous presence of hair hypopigmentation, other skin lesions,
hypopigmentation requires an understanding of the palpation of lymph nodes
types of hypopigmentation disorders. Hypopigmentation
disorders are classified as hypomelanotic/amelanotic
• Wood’s light examination:
• Accentuates (increases contrast) depigmented
and hypomelanocytic/amelanocytic, which are due to (chalk-white) skin and may differentiate from
melanin deficiency and reduction or absence of melanocyte hypopigmented (off-white) skin. In depigmented
number, respectively. For the diagnostic approach, a further skin, there is absence of epidermal melanin, and the
categorization that distinguishes cutaneous hypopigmentation underlying fluorescent compounds of the skin give
disorders into congenital or acquired, and circumscribed, a characteristic chalky bluish-white appearance.
mixed, or generalized may be extremely helpful.2,3 On the contrary, hypopigmented skin shows an off-
The approach to the patient presenting with white accentuation without fluorescence.4
hypopigmentation is based on a thorough understanding
• Punctiform red to orange f luorescence may
of the possible causes of hypopigmentation and the clinical be seen in the follicles in progressive macular
presentation of each condition. A diagnostic approach hypomelanosis of the trunk.5
includes:
• Further evaluations depending on suspected condition
• Family history of hypopigmentation may include:
• Medical history to ask the patient for: • For tuberous sclerosis complex (TSC): Genetic
1. A known history of other skin diseases that may testing, renal ultrasound, cardiac echocardiogram,
result in temporary hypopigmentation during the ophthalmologic evaluation, neuroimaging
resolution of their primary lesions, such as psoriasis. • For suspected hypopigmentation due to gene defects
The characteristic primary or secondary lesions of in the pigmentation pathway: Hearing screening,
these skin diseases may also be present. ophthalmologic evaluation
2. Infectious or parasitic skin diseases (leprosy, • For hypopigmented mycosis fungoides, sarcoidosis,
treponematoses), sarcoidosis, and mycosis leprosy: Cutaneous biopsy and histopathologic
fungoides may present with hypopigmentation or examination to establish diagnosis

13
14 Approach to hypopigmentation

Congenital

Yes No

Generalized Circumscribed
Vitiligo
Albinism Piebaldism Infectious causes
Hermansky- Waardenburg syndrome Pityriasis versicolor
Pudlak (depending on type) Progressive hypomelanosis of the trunk
Nevus depigmentosus Post-inflammatory hypopigmentation
Tuberous sclerosis Pityriasis alba
Ito hypomelanosis Due to chemicals or drugs
Halo nevus
MM-leukoderma
Incontinentia pigmenti
Ito hypomelanosis

Figure 2.1 Diagnostic approach to hypopigmentation. (Hypopigmented lesions of Ito hypomelanosis may be recognized at birth
or become visible during the neonatal period or early childhood.)

CONGENITAL HYPOPIGMENTATION OR NOT? • Conditions with discrete hypopigmented macules:

An important step in the diagnostic ladder of Tuberous sclerosis complex, idiopathic guttate
hypopigmentation is answering the question of whether hypomelanosis, post-inflammatory hypopigmentation
the hypopigmentation is congenital (i.e., present at birth) • Conditions with discrete depigmented macules: Vitiligo,
(Figure 2.1). A basic classification of hypopigmentation is drug- or chemical-induced leukoderma
summarized below:
a. Congenital hypopigmentation CONGENITAL HYPOPIGMENTATION
•
Due to defects in the pigmentation pathway: Human congenital disorders of hypopigmentation may
widespread or circumscribed originate from mutations affecting the complex pathway
•
Nevus depigmentosus of melanocyte development and function. The distinction
•
Ito hypomelanosis
•
Tuberous sclerosis
b. Not congenital hypopigmentation
•
Incontinentia pigmenti
•
Acquired hypopigmentation Congenital
• Vitiligo circumscribed
• Pityriasis versicolor
• Progressive hypomelanosis of the trunk
• Pityriasis alba
• Post-inflammatory hypopigmentation
• Melanoma leukoderma
• Due to chemicals or drugs Acquired Congenital
generalized generalized
SPECIAL CONSIDERATIONS BASED ON THE
DISTRIBUTION OF HYPOPIGMENTATION
The distribution of hypopigmentation may assist in
the diagnostic approach (Figure 2.2). Examples of
characteristic distribution in disorders of hypopigmentation Acquired
include: circumscribed

• Following Blaschko lines: Incontinentia pigmenti, linear

hypomelanosis (congenital, stable)
• Bilateral, symmetric distribution of white patches that
may progress over time: Nonsegmental vitiligo Figure 2.2 The distribution of hypopigmentation assists in
• Segmental: Vitiligo the diagnostic approach.
 Congenital hypopigmentation 15

of a genetic disorder of hypopigmentation is important, 1. Melanoblast migration from the neural crest to the
as genetic defects in the migration of melanoblasts, or the skin (Waardenburg syndrome type 1–4/WS1-WS4,
formation of melanin pathways or melanosome formation piebaldism, Tietz syndrome). Melanoblasts, the
and transfer, as presented above, are not expected to precursors of melanocytes, migrate, proliferate, and
improve/repigment with systemic or topical treatments or differentiate on their way to the basal epitheium of the
phototherapy. epidermis and hair bulbs of the skin, the uveal tract of
Further disorders of hypopigmentation that may be the eye, the stria vascularis, the vestibular organ and the
congenital (i.e., present at birth), but are not caused by endolymphatic sac of the ear, and the leptomeninges of
specific gene defects, are Ito hypomelanosis and nevus the brain.8 So, genetic disorders of hypopigmentation
depigmentosus, which are due to cutaneous mosaicism. due to genetic defects of melanoblast migration may
Also, tuberous sclerosis complex is a multisystem disease be accompanied by extracutaneous findings such as
that may present with characteristic hypopigmented deafness and eye disorders.
lesions. It may be familial or sporadic. Among sporadic 2. Melanin synthesis in the melanosome (oculocutaneous
cases, most (over 70%) are due to defects in the tuberous albinism type 1–4/OCA1-4).
sclerosis complex genes TSC1 and TSC2. However, these 3. Melanosome formation in the melanocytes (Hermansky-
genes do not regulate in the pigmentation pathway, but are Pudlak syndrome type 1–7/HPS1-7, Chediak-Higashi
involved in cell growth and proliferation.6 There are cases syndrome/CHS1).
of hypopigmented lesions, such as nevus depigmentosus 4. Mature melanosome transfer to the tips of the dendrites
or hypopigmented lesions of tuberous sclerosis, that may (Griscelli syndrome type 1–3/GS1-3).
be congenital but are not noticed until infancy when
The basic differentiating characteristics of congenital
the child is exposed to the sun, especially in very light-
disorders of hypopigmentation caused by gene defects in
colored skin.
the pigmentation pathway are summarized in Table 2.1.
Disorders of hypopigmentation due to gene defects Piebaldism and Waardenburg and Tietz syndromes
in the pigmentation pathway represent disorders of melanoblast migration or
proliferation during embryonic development and are
Genetic disorders of hypopigmentation are typically
characterized by stable congenital white patches of the skin
present at birth. They are caused by an inherited
(leukoderma) and hair (poliosis or white forelock).1
genetic defect in a particular step in the pigmentation
pathway. The cutaneous pigmentation is a multistep Piebaldism: Rare autosomal dominant disorder with
process regulated by various signaling pathways and congenital depigmented patches of the midforehead, chest,
transcription factors and includes the following major abdomen, and extremities, where no melanocytes are found.
steps (Figure 2.3)1,7: These patches may sometimes contain hyperpigmented
macules. Cutaneous depigmentation ranges from only a

Neural tube Melanoblast Eumelanin Melanosome

Neural Keratinocyte
Melanocyte

crest
cells

Pheomelanin

Melanoblast Melanoblast Melanin Melanosome Transfer of

development migration to the synthesis formation pigment
skin granules to
keratinocyte
PAX3 Endothelins 1,3 Tyr HPS1 -8
SOX10 E-cadherin P gene DTNBP1 MYO5A
MITF HGF TRP-1 BLOC1S3 RAB27A
KIT FGF MATP CHS1/LYST MLPH
EDN3 TRP2
EDNRB (DCT)

Figure 2.3 Biologic function of melanocytes and genes that control the pigmentary pathway. MATP, membrane-associated
transporter protein; MITF, microphthalmia transcription factor; TRP, tyrosinase-related protein; BLOC3, biogenesis of lysosome-related
organelle complex; HPS, Hermansky-Pudlak syndrome; CHS, Chediak-Higashi syndrome; MYO5A, myosin 5A; MLPH, melanophilin;
DCT, dopachrome tautomerase; EDN3, endothelin 3; EDNRB, endothelin receptor B. (From Dessinioti C et al. Exp Dermatol 2009;18:741–
749, with permission.)
Table 2.1 Basic useful characteristics for the differential diagnosis of disorders of depigmentation caused by gene defects in the pigmentation pathway
Hermansky-Pudlak Waardenburg
Albinism syndrome Chediak-Higashi syndrome Griscelli syndrome Piebaldism syndrome
16 Approach to hypopigmentation

Etiology Genetic Genetic Genetic Genetic Genetic Genetic

Inherited or sporadic Inherited Inherited Inherited Inherited Inherited Inherited
Age at onset of Congenital Congenital Congenital Congenital Congenital Congenital
depigmentation
Distribution of Generalized Generalized or Generalized Pigmentary dilution Circumscribed Circumscribed
depigmentation circumscribed Silvery sheen to the hair and skin of skin, hair
Type of disorder of Normal melanocytes, Normal melanocytes, no Disorder of melanosome Disorder of No melanocytes in white No melanocytes in
depigmentation no melanin melanin formation and transfer melanosome lesions white lesions
formation and
transfer
Clinical findings Depending on type Depending on type Decreased iris pigmentation, Depending on type White forelock Depending on type
Skin, hair, eyes Ocular/cutaneous strabismus, nystagmus, severe Immune defects, White patches may White patches of skin
Photophobia, albinism immunodeficiency, neurological contain and hair
nystagmus, Platelet disorders: pancytopenia, bleeding, manifestations hyperpigmented Heterochromia irides,
decreased visual bleeding diathesis, bruising, hepatosplenomegaly, macules dystopia canthorum,
acuity, cutaneous ceroid storage disease neurological disorders congenital deafness,
sensitivity to UVR, resulting in pulmonary limb anomalies,
increased risk for fibrosis, kidney failure, Hirschsprung disease
NMSC granulomatous colitis
Course of Stable Stable Stable Stable Stable Stable
depigmentation
 Noncongenital hypopigmentation 17

white forelock with minimal ventral depigmentation to (SV).16 NSV presents with amelanotic lesions on various
almost entire body and hair depigmentation.9,10 body areas with a bilateral and symmetrical distribution
Waardenburg syndrome (WS): Autosomal dominant that may spread or repigment over time, showing an
genetic disorder characterized by piebaldism and unpredictable course. SV is characterized by an early age
sensorineural deafness. The disease is commonly classified of onset; rapid stabilization; and unilateral, segmental
into four clinical types with possible extracutaneous distribution (Table 2.2).3
findings.1,11,12 Acquired diseases that may present with hypopigmented
Tietz syndrome: Rare autosomal dominant disorder, skin lesions include sarcoidosis, pityriasis versicolor, leprosy,
characterized by generalized depigmentation, blue eyes, syphilis (leukoderma syphiliticum), and hypopigmented
and congenital deafness.13 mycosis fungoides.5,10
Most forms of congenital hypopigmentation that Furthermore, post-inflammatory hypopigmentation
are caused by defects in melanin synthesis are types of may be caused by various skin diseases during the
oculocutaneous albinism (OCA) and affect ocular as well resolution of their primary skin lesions, as is the case with
as cutaneous melanocytes.1 psoriasis. A thorough medical history is essential for the
Hermansky-Pudlak syndrome: Rare, albinism with diagnostic approach to the patient, as hypopigmentation
extrapigmentary disorders. Platelet storage pool may be due to topical agents or systemic drug intake.
deficiency resulting in bleeding diathesis, ceroid storage Melanoma-associated leukoderma may appear in patients
disease resulting in pulmonary fibrosis, kidney failure, with melanoma treated with immunotherapy and is a
granulomatous colitis.14 reported marker of favorable prognosis.4,17
Chediak-Higashi syndrome: Rare autosomal recessive Idiopathic guttate hypomelanosis presents with sharply
disorder characterized by oculocutaneous albinism, demarcated, hypopigmented to depigmented macules, mainly
neutropenia, recurrent infections, thrombocytopenia, in adults of more advanced age, and shows a predilection for
bleeding diathesis, neurologic defects. Fatal in the first the lower, or more rarely, the upper extremities.5
decade of life from infections or bleeding.6 Most cases are Progressive macular hypomelanosis of the trunk
fatal unless treated by bone marrow transplantation. presents with hypopigmented macules or patches on the
Griscelli syndrome (GS): Rare autosomal recessive trunk. There is characteristic punctiform red to orange
disorder characterized by oculocutaneous albinism, severe fluorescence in the follicles under Wood’s lamp light.5
immunodeficiency, neurologic defects.1
Tuberous sclerosis complex
NONCONGENITAL HYPOPIGMENTATION Tuberous sclerosis complex is a genetic disease that may
The basic differentiating characteristics of disorders with be caused by inherited or sporadic mutations and leads
hypopigmentation/depigmentation that typically appear to hamartomatous lesions in many organs that appear
later in life are summarized in Table 2.2. in different periods of life.6 Patients with TSC often seek
Incontinentia pigmenti (IP) is a rare, hereditary, X-linked medical attention due to skin lesions or for seizures. TSC
dominant disorder that may present with hypopigmentation may be diagnosed by positive genetic testing and with
in adult life. IP is usually lethal in males, so female clinical diagnostic criteria (two major or one major with
patients are almost exclusively recognized (92%). IKBKG two or more minor for definite diagnosis, and either
(previously NEMO) is the gene known to be associated one major or two or more minor for possible diagnosis).
with IP.15 Stages of skin changes in IP include stage 1 Negative genetic testing does not exclude TSC diagnosis.18
(vesiculo-bullous stage), stage 2 (verrucous stage), and A complete skin examination should be performed to
stage 3 (hyperpigmented stage). The fourth stage (atrophic/ evaluate for the number of hypopigmented macules;
hypopigmented stage) may present in approximately 13% the presence of angiofibromas on the face; “confetti”
of patients with IP. Hypopigmentation presents as swirls of skin lesions; and a shagreen patch, most commonly on
atrophic hypopigmented or depigmented bands of streaks the lower back, that may present from an early age. The
along the Blaschko lines, which are also hypohydrotic and characteristic hypopigmented macules (ash leaf) were
hairless. Reduction of melanin in the epidermis has been first described by Fitzpatrick in 1968.19 They may appear
described. The hypopigmented lesions present in adult life. at birth or present within the first few years of life.19,20
Extracutaneous abnormalities are frequent3 (Table 2.2). Wood’s lamp examination to accentuate hypomelanotic
Diagnostic criteria have been proposed.15 macules is beneficial in the detection of these macules
in infants (Table 2.2). The number of melanocytes is not
Acquired disorders of hypopigmentation decreased in TSC hypopigmented lesions, in contrast with
Vitiligo is a common disorder of hypopigmentation.3 It may the lesions of vitiligo.21 There is decreased melanization of
appear at any age, but usually presents during childhood or melanosomes.3 In older patients, dental pits and ungual
young adulthood, while it is rarely described in newborns fibromas may be clinically detected. Clinical suspicion
and infants.3 Vitiligo may be classified on the basis of the of TSC will prompt further evaluations and follow-up.18
extension and distribution of lesions into nonsegmental Improvement of hypomelanotic macules has been reported
vitiligo (NSV, including acrofacial, mucosal, generalized, with topical rapamycin in a small number of patients21–23
universal, mixed, and rare variants) and segmental vitiligo and with topical sirolimus in a patient with TSC.24
 18

Table 2.2 Basic useful characteristics for the differential diagnosis of disorders of hypopigmentation/depigmentation
Vitiligo Ito hypomelanosis Nevus depigmentosus Incontinentia pigmenti Tuberous sclerosis
Approach to hypopigmentation

Etiology Acquired Cutaneous mosaicism Cutaneous mosaicism Genetic Genetic

Inherited or sporadic Sporadic or familial (heritable) Sporadic or inherited Nonhereditary Inherited Sporadic or inherited
Age at onset of Any age Congenital Congenital, rarely early Usually only females Hypopigmented (off-white)
hypopigmentation Childhood or young adulthood Neonatal childhood Adults macules may be present at birth
Very rarely congenital Early infancy or within the first years of life
Distribution of Generalized or circumscribed Circumscribed Unilateral off-white Circumscribed, following Discrete hypopigmented macules
hypopigmentation Symmetrical lesions
Unilateral or bilateral, following Blaschko lines
Blaschko lines May be solitary
Type of disorder of Normal melanocytes, no Decreased number of Normal number of Reduction of melanin in the Decreased melanization of
hypopigmentation melanin melanocytes melanocytes, decrease epidermis melanosomes
of melanin
Clinical findings White, depigmented patches Linear whorled hypomelanosis Hypomelanotic lesion, In 13%, whorled hypomelanosis. Hypopigmented off-white skin
of skin and hair Disorders of central nervous does not cross the Linear, atrophic, hypohidrotic macules
Chalky bluish-white system, eyes, teeth midline hypomelanosis Confetti-like macules
appearance with Wood’s light Off-white with Wood’s Loss of hair in lesions Epilepsy, angiofibromas, retinal
lamp Disorders of central nervous hamartomas, renal
system, eyes, teeth, hair angiomyolipoma, cardiac
rhabdomyoma (diagnostic criteria
apply)
Course of Unpredictable for NSV. May Stable Stable Stable Repigmentation with treatment
hypopigmentation progress or repigment with has been reported in a small
treatment number of patients
 References 19

REFERENCES 14. Wei ML. Hermansky-Pudlak syndrome: A disease of

1. Dessinioti C, Stratigos AJ, Rigopoulos D, protein trafficking and organelle function. Pigm Cell
Katsambas AD. A review of genetic disorders of Res. 2006;19(1):19–42.
hypopigmentation: Lessons learned from the biology 15. Minic S, Trpinac D, Obradovic M. Incontinentia
of melanocytes. Exp Dermatol. 2009;18(9):741–749. pigmenti diagnostic criteria update. Clin Genet.
2. Mollet I, Ongenae K, Naeyaert JM. Origin, clinical 2014;85(6):536–542.
presentation, and diagnosis of hypomelanotic skin 16. Ezzedine K, Lim HW, Suzuki T et al. Revised classi­
disorders. Dermatol Clin. 2007;25(3):363–371, ix. fication/nomenclature of vitiligo and related issues: The
3. Ortonne JP, Bahadoran P, Fitzaptrick TB et al. Vitiligo Global Issues Consensus Conference. Pigment
Hypomelanoses and hypermelanoses. In: Freedberg Cell Melanoma Res. 2012;25(3):E1–E13.
IM, Eisen AZ, Woff K. et al., eds. Fitzpatrick’s 17. Gogas H, Ioannovich J, Dafni U et al. Prognostic
Dermatology in General Medicine. New York: significance of autoimmunity during treatment
McGraw-Hill; 2003:836–881. of melanoma with interferon. N Engl J Med.
4. Saleem MD, Oussedik E, Schoch JJ, Berger AC, 2006;354(7):709–718.
Picardo M. Acquired disorders with depigmentation: 18. Northrup H, Krueger DA, International Tuberous
A systematic approach to vitiliginoid conditions. J Sclerosis Complex Consensus Group. Tuberous
Am Acad Dermatol. 2018. sclerosis complex diagnostic criteria update:
5. Saleem MD, Oussedik E, Picardo M, Schoch JJ. Recommendations of the 2012 International
Acquired disorders with hypopigmentation: A Tuberous Sclerosis Complex Consensus Conference.
clinical approach to diagnosis and treatment. J Am Pediatr Neurol. 2013;49(4):243–254.
Acad Dermatol. 2018. 19. Fitzpatrick TB, Szabo G, Hori Y, Simone AA, Reed
6. Narayanan V. Tuberous sclerosis complex: Genetics WB, Greenberg MH. White leaf-shaped macules.
to pathogenesis. Pediatr Neurol. 2003;29(5):404–409. Earliest visible sign of tuberous sclerosis. Arch
7. Tomita Y, Suzuki T. Genetics of pigmentary Dermatol. 1968;98(1):1–6.
disorders. Am J Med Genet C Semin Med Genet. 20. Teng JM, Cowen EW, Wataya-Kaneda M et al.
2004;131C(1):75–81. Dermatologic and dental aspects of the 2012
8. Lin JY, Fisher DE. Melanocyte biology and skin International Tuberous Sclerosis Complex Consensus
pigmentation. Nature. 2007;445(7130):843–850. statements. JAMA Dermatol. 2014;150(10):1095–1101.
9. Giebel LB, Spritz RA. Mutation of the KIT (mast/ 21. Arbiser JL. Efficacy of rapamycin in tuberous
stem cell growth factor receptor) protooncogene sclerosis-associated hypopigmented macules: Back
in human piebaldism. Proc Natl Acad Sci USA. to the future. JAMA Dermatol. 2015;151(7):703–704.
1991;88(19):8696–8699. 22. Wataya-Kaneda M, Tanaka M, Yang L et al. Clinical
10. Dessinioti C, Stratigos AJ. Piebaldism. https://www. and histologic analysis of the efficacy of topical
dermatologyadvisor.com/dermatology/piebaldism/ rapamycin therapy against hypomelanotic macules
article/691421/. Accessed January 2, 2019. in tuberous sclerosis complex. JAMA Dermatol.
11. Zazo Seco C, Serrao de Castro L, van Nierop JW et al. 2015;151(7):722–730.
Allelic mutations of KITLG, encoding KIT ligand, 23. Jozwiak S, Sadowski K, Kotulska K, Schwartz RA.
cause asymmetric and unilateral hearing loss and Topical use of mammalian target of rapamycin
Waardenburg syndrome type 2. Am J Hum Genet. (mTOR) inhibitors in tuberous sclerosis complex-A
2015;97(5):647–660. comprehensive review of the literature. Pediatr
12. Liu XZ, Newton VE, Read AP. Waardenburg Neurol. 2016;61:21–27.
syndrome type II: Phenotypic findings and diagnostic 24. Malissen N, Vergely L, Simon M, Roubertie A,
criteria. Am J Med Genet. 1995;55(1):95–100. Malinge MC, Bessis D. Long-term treatment of
13. Smith SD, Kelley PM, Kenyon JB, Hoover D. cutaneous manifestations of tuberous sclerosis
Tietz syndrome (hypopigmentation/deafness) complex with topical 1% sirolimus cream: A
caused by mutation of MITF. J Med Genet. prospective study of 25 patients. J Am Acad Dermatol.
2000;37(6):446–448. 2017;77(3):​464–472. e463.
Historical review of vitiligo
MAJA KOVACEVIC, NIKA FRANCESCHI, MIRNA SITUM, ANDY GOREN,
3
ANDRIJA STANIMIROVIC, YAN VALLE, and TORELLO LOTTI

CONTENTS
Introduction 21 Treatment of vitiligo through the ages 22
Perception of vitiligo from ancient times to the Prognosis 24
modern period 21 References 24
Social stigmatization of patients from ancient times
to the modern period 22

INTRODUCTION disease. White skin was also mentioned in literature from

Vitiligo, as well as other pigmentation disorders, has the Far East dating from 1200 bc, in prayers known as
been observed throughout history. These disorders Makatominoharai where the “shira bito” or white man
causing white, light, or dark spots have caused distress is described (Kopera). In his book Clio, Greek historian
and rejection and have led to the isolation of affected Herodotus (484–425 bc) notices white spots on foreigners
people for thousands of years. Until the invention of the and considers them a sign of sin against the sun.7
microscope and biopsy and the discovery of histochemical Several religious books also mention vitiligo. In the Old
stains, skin color was a mystery and the mechanism for Testament of the Holy Bible, the Hebrew word “Zora’at”
skin color production was based on myths, folklore, and includes five groups of depigmenting disorders combined
religious theories.1 Over the years, various theories have with other entities such as inflammation, scaling, atrophy,
been proposed regarding the etiology of vitiligo, while the white hairs, and “white spots” per se, interpreted as vitiligo
most accepted theories include the genetic, autoimmune, or post-inflammatory leukoderma.6 In the Greek version of
neurogenic, and melanocyte self-destruction hypotheses.2 the Bible, Leviticus 13, the word “Zora’at” was translated as
Treatments for this disorder have been investigated since “white leprosy,” which enhanced the prejudices toward the
ancient times and various remedies have been suggested in disease. In the Koran, the Arabic name for vitiligo, “alabras,”
medical literature over the years. Although great progress is mentioned and was also translated as “leprosy” in several
has recently been achieved regarding this depigmentation languages. Taking into consideration all mistranslations,
disorder, a long history of difficult management and it is not surprising that even Hippocrates (460–355 bc)
the still perplexing etiology of the disease, as well as ill included vitiligo, leprosy, lichen, and psoriasis in the same
treatment of patients suffering from this disorder, indicate category of diseases.
the importance of further scientific research, along with The term “vitiligo” was most probably first used by
education of the public and patients concerning this Celsus in the first century bc in his medical publication De
disease. First, however, as Hippocrates declared, “The Medicina and may have been derived from the Latin word
physician must know what his predecessors have known “vitium” meaning defect or blemish, or “vitulum” meaning
if he does not wish to deceive both himself and others.”3 small blemish.8 Others, however, suggest that the term may
have been derived from the Latin word “vitelius,” meaning
PERCEPTION OF VITILIGO FROM ANCIENT TIMES calf, referring to the skin of this animal.8
TO THE MODERN PERIOD European descriptions of vitiligo date from the Early
From ancient times, depigmenting disorders altered the Modern age. In the sixteenth century, Italian physician
quality of a patient’s life. The earliest descriptions of Hieronymus Mercurialis elucidated the pathogenesis of
these disorders were found in Iranian literature, Tarkh- vitiligo in his book De morbus cutaneis (Mercurialis).
e-Tibble, in 2200 bc, 4 while the Ebers Papyrus from According to his explanation, accumulated phlegm
1500 bc observes two types of disorders that affect skin under the skin results in the appearance of leukoderma,
color, probably both vitiligo and leprosy. 5 Various terms and as a confirmation of his theory, he uses the
describing white spots such as “Kilas,” “Palita,” “Sveta ancient writings of the Greek philosopher Plato.1 In
Khista,” and “Charak” were found in Indian sacred the seventeenth century, Korean authors described
books, Atharva Veda (1400 bc), and the Buddhist sacred certain hypopigmented and depigmented entities such
book Vinay Pitak (224–544 bc).6 Some of the terms, such as vitiligo, naevus depigmentosus, tinea versicolor,
as “Sveta Khista,” were used to describe leprosy, so it is naevus anemicus, and albinism in Doney Bogam,
not surprising that vitiligo was often confused with this Eastern medical writing from the Yi dynasty.9 Proposed

21
22 Historical review of vitiligo

therapeutic options included arsenic, mercury, and the unfortunate victims of vitiligo is striking, and scarcely
sulfur ointments. The importance of the disease was fails to evoke a feeling of horror and pity for the afflicted.
further emphasized by the portrait of an eminent The picture of otherwise dark person, marked with spots
official of the Korean Yi dynasty whose face was painted perfectly white, even to eyes familiarized to the sight,
with vitiligo lesions.10 Interestingly, with this artwork, appears repugnant.”15
Korean society showed acceptance of the patients and Due to the long-lasting misleading association of
not discrimination, contrary to many other civilizations contagion with vitiligo, stigmatization of vitiligo patients
at that time and also today. is still present nowadays. Modern life dictates perfection in
In the nineteenth century, Louis Brocq introduced the different contexts; imperfection in skin appearance due to
term “dyschromy,” defined by the lack of pigmentation evident contrast of depigmented patches causes emotional
(achromy) in vitiliginous skin combined with an devastation in many patients. Any condition that impairs
increase of pigmentation at the periphery of the lesion skin appearance might have different consequences in
(hyperchromy).11 In the same century, histopathologic the sense of normal social life, work opportunities, and
characteristics of vitiligo were described by Moritz Kaposi emotional bonding as well. Despite global progress in
as lack of pigment granules in deep rete cells and increase modern times, vitiligo still remains a disease that leads to
of pigmentation on the periphery.12 The etiology of the low self-esteem, depression, self-consciousness, isolation,
disease remained questionable from ancient times to the and stigmatization in many countries worldwide.
modern period. From the nineteenth century, the role of
triggering factors has been suggested in vitiligo onset, TREATMENT OF VITILIGO THROUGH THE AGES
with emotional stress and stimulation of the nervous Treatment of white spots or vitiligo has been sought since
system being predominant.11 A definition of vitiligo was the disorder was first observed, attesting to the significance
finally established in the twentieth century: “Vitiligo can of the disease in all cultures and societies. In Table 3.1, a
be described as an acquired, primary, usually progressive, partial list of treatment modalities tried throughout history
melanocyte loss of still mysterious etiology, clinically is presented.
characterized by circumscribed achromic macules often The Ebers Papyrus (c. 1550 bc), the Atharva Veda,
associated with leucotrichia, and progressive disappearance (c. 1400 bc), other Indian and Buddhist medical literature
of melanocytes in the involved skin.”6,13 (c. 200 ac), and Chinese literature from the Sung period
(c. 700 ac) mention herbal remedies for the treatment of
SOCIAL STIGMATIZATION OF PATIENTS FROM ANCIENT vitiligo.6
TIMES TO THE MODERN PERIOD According to Indian medical literature, “Malapu” (Ficus
Social stigmatization of patients with vitiligo has been hispida) and “Babchi” (Psoralea corylifolia) administered
described alongside the first writings about the disease orally or topically were the most effective remedies.16
itself. Buddhist literature indicates that patients with In the “Charaka Samhita,” juice of the fruit “Malapu”
Kilasa were not able to become priests, while Indian is recommended followed by exposure to sunlight.
Rigveda literature considers patients with Switra, as well Subsequently developed blisters should be ruptured, after
as their offspring, unsuitable for marriage. 6 Herodotus which repigmentation occurs. Other recommendations
believed that vitiligo patients were sinners against the sun, for curing “Svitra” in the “Charaka Samhita” include
and, interestingly, his hypothesis included animals as well, preparations with seeds of radish and Babchi seeds rubbed in
mainly white pigeons. In Leviticus (13:34), descriptions of cow’s urine; a plaster prepared of redwood fig, Babchi seeds,
patients with white spots include torn clothes, untidy hair, and white flowered leadwort in cow’s urine; red arsenic
and covering of their upper lip due to the belief that they prepared with peacock’s bile; seeds of Babchi, lac, or ox-bile;
are unclean and have sinned against the God.14 In order and extracts of Indian berberry, antimony, long pepper, and
to reduce social stigmatization of vitiligo patients, the iron powder.17,18 Psoralea corylifolia, called “Pu Ku Chih,” is
Catholic church added in 1943 the following note with also mentioned in the ancient Chinese literature as a method
reference to Leviticus 13: “Various kinds of skin blemishes for treating leukoderma.19 It was later established that both
are treated here, which were not contagious but simply of these herbs, “Malapu” and “Babchi,” contain psoralens,
disqualified their subjects from associations with others, demonstrating that photochemotherapy was also practiced
until they were declared ritually clean. The Hebrew term in ancient times.17 The Atharva Veda mentions two drugs,
used does not refer to Hansen disease, currently called “asikni” and “shyama,” that lead to repigmentation of the
leprosy.”6 skin when applied topically. These medicines were praised
According to Islamic theologians, if the husband or wife in poems in an attempt to even skin color.16
had baras, it was a legitimate reason for divorce. Harrith Seeds of the plant Ammi majus that grows as a weed
bin Hilliza, an Arabic poet, states that vitiligo patients were in the Nile Delta were used by Egyptians. The Arabic
able to receive emperors’ messages only if they were behind pharmaceutical encyclopedia Mofradat Al Adwiya (The
a screen, in order to avoid direct contact. Stigmatization Book of Medicinal and Nutritional Terms) written by Ibn
and disfigurement of vitiligo patients were also present El-Bitar (c. 1200 bc) first documented the use of Ammi
in the nineteenth century. In his writings, Brito describes majus. Exposure to sunlight followed the administration
the disfigurement of vitiligo patients: “The appearance of of the remedy. The usefulness of this plant was also known
 Treatment of vitiligo through the ages 23

Table 3.1 Partial list of treatments for vitiligo throughout Table 3.1 (Continued) Partial list of treatments for
history vitiligo throughout history
Topical and oral • Rose-flavored honey • Lithium salts
treatments • Bitter almonds in vinegar • Pentoxifylline
• Babchi seeds • Minoxidil
• Bergamot • Monoamine oxidase inhibitors
• Ginkgo biloba • Monobenzyl ether of hydroquinone
• Anapsos • Vesicants
• Agaric • Escharotics
• Turpeth • Corrosive sublimate
• Colocynth • Cantharidin
• Khellin • Byzantine syrup
• Tincture of nux vomica • Crude coal tar
• Syrup of betony • Anthralin
• Oxymel • Anapsos
• Mustard Procedures and • Cryotherapy
• Copper phototherapy • Dermabrasion
• Iron • Surgical excision
• Zinc • Minigrafting autografts
• Manganese • Thermal and caustic blistering
• Nickel • Vibrapuncture
• Cobalt • Finsen lamp
• Calcium • Phenylalanine-UVA
• Arsenic • Psoralens + sunlight
• Silver nitrate • Psoralen + UVA
• Dopa • Narrowband UVB
• ACTH Other • Cosmetics
• Metharmon-F • Diets
• α-MSH • Tattooing
• Melagenina
Source: Adapted from Montes LF. Vitiligo: Current Knowledge and
• Vitamins: B6, B12, C, D, E Nutritional Therapy. 3rd ed. Buenos Aires: Westhoven Press;
• Prostaglandin analogue 2006; Sehgal VN, Srivastava G. J Dermatolog Treat. 2006;​
• Ascorbic acid 17(5):262–275.
• Folic acid
• Hydrochloric acid to a Berberian tribe living in northwestern Africa under
• Hydrogen peroxide the name Aatrillal.6,17
• Pseudocatalase In ancient Korea, sulfur and various arsenic or mercury
• Steroids ointments were applied locally following exposure to
• Calcineurin inhibitors sunlight. Another topically applied remedy combined the
• Methotrexate juice of fig fruit and leaves, unripe walnut shells, moss,
• Levamisole Japanese parsley, buttercups, and rice bran followed by
• Tretinoin exposure to sunlight. However, patients were frequently
• Carmustine (BCNU) overexposed to sunlight, resulting in extreme sunburn
• Clofazimine and worsening of depigmented lesions. Other methods
• Antimalarials: Chloroquine, quinacrine, included the use of garlic, ginger, or vinegar to induce
mefloquine skin irritation. Herbal remedies containing ginseng,
• Thiambutosine black sesame, white peony, sweet flag plant, barberry
• Cyclosporine root, and chaulmoogra seeds were administered orally
• Dapsone and depended on the type of vitiligo. It was suggested
• Fluorouracil that they normalized the immune imbalance of the body.
• Fluphenazine enanthate Medicine consisting of parsley and angelica induced
• Mechlorethamine photosensitization following exposure to sunlight, as
• Aspirin they contain furocoumarins. Other treatments included
• Isoprinosine acupuncture along with topically applied herbs, while red
• Cyclophosphamide bean powder was used as cosmetic camouflage.9
• Resorcin paste In the beginning of the nineteenth century, systemic
(Continued) application of bromides, iodides, valerianates, mercury,
24 Historical review of vitiligo

antimony, and arsenic was used, as well as subcutaneous Topical calcineurin inhibitors
injection of pilocarpine, saline, or bromoiodic baths. In 2002, the first studies with tacrolimus ointment 0.03%
Different mixtures containing croton oil, iodine, and 0.1% were conducted in patients with vitiligo. Findings
sublimate, and naphtol have been suggested for topical showed that tacrolimus ointment was an effective and
use; however, all these recommendations showed limited safe treatment modality.41–43 A case report involving a
to no effect.20 In his work, Brito listed possible treatment 19-year-old patient with vitiligo on the face treated with
options such as the use of silver nitrate; excision, which pimecrolimus cream followed.44
may be succeeded by grafts; dermal injections of silver
nitrate solutions followed by exposure to sunlight; PROGNOSIS
tattooing; and internal administration of silver salts for The prognosis of vitiligo has also been documented in
treating vitiligo.15 ancient literature. In a compilation of ancient Indian
Photo(chemo)therapy medicine, Ashtanga Hridaya (600 ad), written by
Vagbhata, “Svitra can be cured if the hair over these
In the beginning of the twentieth century, Nils Ryberg patches has not turned white; if the patches are not
Finsen, the founder of modern phototherapy, developed numerous; if the patches are not connected with each
the Finsen light, a source of short ultraviolet (UV) waves other; if the patches have freshly occurred; and if the
produced by a carbon or mercury arc. Finsen was awarded patches are not caused by burns.” The condition termed
the Nobel Prize in Medicine in 1903 for his contribution “kilása,” a variety of leukoderma, was regarded as being
to the treatment of lupus vulgaris with concentrated “incurable if the patches were present in the genital
light radiation, starting a whole new era in the treatment and anal regions, palms and lips, even if these patches
of dermatologic diseases. Subsequently, patients with were fresh. Such patients should never be treated if the
vitiligo were exposed to such UV light and, in certain physician desired to have success in life.”17,45 In the work
patients, visible improvement was seen after a series of “Prognostic,” Hippocrates also made similar observations
treatments.20,21 that “these complaints (vitiligo) are the more easily cured
The basis for future development of phototherapy the more recent they are, and the younger the patients,
occurred in the 1940s when the active ingredients and the more the soft and fleshy the parts of the body in
of Ammi majus, 8-methoxypsoralen (8-MOP) and which they occur.”14,17
5-methoxypsoralen (5-MOP), were isolated. The first
studies with 8-MOP followed by sun exposure were
performed in vitiligo patients by the Egyptian physician REFERENCES
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good safety profile and efficacy of these psoralens.25,26 2. Koranne RV, Sachdeva KG. Vitiligo. Int J Dermatol.
In the 1970s, ultraviolet irradiators emitting high-intensity December 1988;27(10):676–681.
ultraviolet A (UVA) radiation were invented that were 3. Adams, F. (Trans.-Ed.). The Genuine Works of
designed for oral psoralen photochemotherapy to deliver Hippocrates. London: The Sydenham Society, 1848.
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was much more effective and represented the real start of Teheran, Iran: Shamsi, 1934.
psoralen plus ultraviolet A (PUVA) photochemotherapy, 5. Ebbel B. The Papyrus Ebers. Copenhagen: Levin and
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became the treatment of choice for a wide variety of skin 6. Gauthier Y, Benzekri L. Historical aspects. In:
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Topical corticosteroids 8. Panda AK. The medicohistorical perspective of
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in flexible collodion by Kandil, applied once daily on Korea. Int J Dermatol 1997;36:313–315.
localized vitiligo macules with more or less satisfactory 10. Lee S. Vitiligo auf einem historischen Portrait.
results, depending on the duration of the disease and Hautarzt 1982;33:335–336.
disease stage. 33 Other studies involving betamethasone 11. Brocq L, ed. Traitment des Maladies de la Peau. Paris:
17-valerate soon followed. 34,35 Additionally, studies Doin, 1892:853–855.
involving clobetasol propionate 0.05% cream 36–39 and 12. Kaposi M, ed. Pathologie and Therapie der
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conducted.40 Schwarzenberg, 1st ed, 1879:703–707.
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13. Prasad PV, Bhatnagar VK. Medico-historical study 31. Scherschun L, Kim JJ, Lim HW. Narrow-band
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disorder. Bull Ind Inst Hist Med 2003;33:113–127. treatment for vitiligo. J Am Acad Dermatol.
14. Goldman L, Richard S, Moraites R. White spots in 2001;44(6):999–1003.
biblical times. Arch Derm 1966;93:744–753. 32. Whitton ME, Pinart M, Batchelor J, Leonardi-Bee
15. Brito PS. On leucoderma, vitiligo, ven kuttam (Tamil) J, González U, Jiyad Z, Eleftheriadou V, Ezzedine K.
or cabbare (Singhalese), and several new methods of Interventions for vitiligo. Cochrane Database Syst
treatment. Br Med J 1885;1(1269):834–835. Rev. 2015;(2):CD003263.
16. Singh G, Ansari Z, Dwivedi RN. Letter: Vitiligo 33. Kandil E. Vitiligo: Response to 0.2% betamethasone
in ancient Indian medicine. Arch Dermatol. 1974;​ 17-valerate in flexible collodion. Dermatologica.
109(6):913. 1970;141:277–81.
17. Nair BK. Vitiligo—A retrospect. Int J Dermatol. 34. Kandil E. Treatment of vitiligo with 0.1%
1978;17(9):755–917. betamethasone 17-valerate in isopropyl alcohol: A
18. Shree Gulabkunverba Ayurvedic Society, ed. Charaka double blind trial. Br J Dermatol. 1974;91:457–460.
Samhita. Jamnagar, India: Shree Gulabkunverba 35. Koopmans-van DB, Goedhart-van DB, Neering H, van
Ayurvedic Society, 1949. Dijk E. The treatment of vitiligo by local application
19. Khushboo PS, Jadhav VM, Kadam VJ, Sathe of betamethasone 17-valerate in a dimethyl sulfoxide
NS. Psoralea corylifolia Linn.—“Kushtanashini.” cream base. Dermatologica. 1973;146:310–314.
Pharmacogn Rev. 2010;4(7):69–76. 36. Bleehen SS. The treatment of vitiligo with
20. Hann SK, Nordlund JJ, editors. Vitiligo: A Monograph topical corticosteroids. Light and electro­n micro­
on the Basic and Clinical Science. New York: John scopic studies. Br J Dermatol. March 1976;94​(Suppl
Wiley & Sons, 2008. 12):​43–50.
21. Menon AN. Ultra-violet therapy in cases of 37. Clayton R. A double-blind trial of 0%–05% clobetasol
leucoderma. Ind Med Gaz 1945;80:612–614. proprionate in the treatment of vitiligo. Br J Dermatol.
22. Fahmy IR, Abu-Shady H, Schönberg AA. Crys­ 1977;96(1):71–73.
talline principle from Ammi majus L., Nature 38. Kumari J. Vitiligo treated with topical clobetasol
1947;160(4066):468. propionate. Arch Dermatol. 1984;120(5):631–635.
23. Fahmy IR, Abu-Shady H. Ammi majus Linn: The 39. Liu XQ, Shao CG, Jin PY, Wang HQ, Ye GY, Yawalkar
isolation and properties of ammoidin, ammidin S. Treatment of localized vitiligo with ulobetasol
and majudin, and their effect in the treatment of cream. Int J Dermatol. May 1990;29(4):295–297.
leukoderma. QJ Pharm Pharmacol. 1948;21(4):​ 40. Westerhof W, Nieuweboer-Krobotova L, Mulder PG,
499–503. Glazenburg EJ. Left-right comparison study of the
24. El-Mofty AM. A preliminary clinical report on the combination of fluticasone propionate and UV-A
treatment of leukoderma with Ammi majus Linn, vs. either fluticasone propionate or UV-A alone for
J Egypt Med Assoc. 1948;31:651–665. the long-term treatment of vitiligo. Arch Dermatol.
25. Lerner AB, Denton CR, Fitzpatrick TB. Clinical and 1999;135(9):1061–1066.
experimental studies with 8-methoxypsoralen in 41. Grimes PE, Soriano T, Dytoc MT. Topical tacrolimus
vitiligo. J Invest Dermatol. 1953;20(4):299–314. for repigmentation of vitiligo. J Am Acad Dermatol.
26. Pathak MA, Mosher DB, Fitzpatrick TB. Safety and 2002;47(5):789–791.
therapeutic effectiveness of 8-methoxypsoralen, 42. Smith DA, Tofte SJ, Hanifin JM. Repigmentation
4,5′,8-trimethylpsoralen, and psoralen in vitiligo. of vitiligo with topical tacrolimus. Dermatology.
Natl Cancer Inst Monogr. 1984;66:165–173. 2002;205(3):301–303.
27. Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak 43. Grimes PE, Morris R, Avaniss-Aghajani E, Soriano T,
MA. Photochemotherapy of psoriasis with oral Meraz M, Metzger A. Topical tacrolimus therapy for
methoxsalen and longwave ultraviolet light. N Engl vitiligo: Therapeutic responses and skin messenger
J Med. 1974;291(23):1207–1211. RNA expression of proinflammatory cytokines. J Am
28. Pathak MA, Fitzpatrick TB. The evolution of Acad Dermatol. 2004;51(1):52–61.
photochemotherapy with psoralens and UVA 44. Mayoral FA, Gonzalez C, Shah NS, Arciniegas C.
(PUVA): 2000 bc to 1992 ad. J Photochem Photobiol Repigmentation of vitiligo with pimecrolimus cream:
B. 1992;30(14):3–22. A case report. Dermatology. 2003;207(3):322–323.
29. Parsad D, Kanwar AJ, Kumar B. Psoralen-ultraviolet 45. Dash B, Kashyap L, eds. Diagnosis and Treatment of
A vs. narrow-band ultraviolet B phototherapy for the Diseases in Ayurveda, Volume 5. New Delhi, India:
treatment of vitiligo. J Eur Acad Dermatol Venereol. Concept Publishing Company, 1991.
2006;20(2):175–177.
30. Westerhof W, Nieuweboer-Krobotova L. Treatment
of vitiligo with UV-B radiation vs topical psoralen
plus UV-A. Arch Dermatol. 1997;133(12):1525–1528.
Epidemiology and classification
of vitiligo
4
SERENA GIANFALDONI and TORELLO LOTTI

CONTENTS
Introduction 27 Classification and clinical features 28
Epidemiology 27 References 32

INTRODUCTION different races.8,9 It is possible that the major color contrast

Vitiligo is an acquired, chronic, pigmentary disorder between healthy pigmented skin and vitiliginous skin
characterized by the progressive loss and dysfunction of the (leopard-like skin appearance) observed in dark-skinned
melanocytes from epidermis and epidermal appendages, people leads to a deep stigma and forces patients to seek
which results in hypopigmented cutaneous areas that dermatological consultation.5
progressively become amelanotic. Males and females are equally affected.10,11 Only two
In the last decades, several theories about its studies report a higher prevalence of vitiligo in males
etiopathogenesis (e.g., genetic, neuronal, autoimmune, than in females, with a ratio of about 1.6:1.12,13 In contrast,
biochemical hypotheses), have been proposed, but none other epidemiological studies record that females are
of them is strongly supported (Table 4.1) and the exact more affected than males. However, this result seems to
nature of the disease is still unclear.1 Nevertheless, recent be related only to a greater negative psychological effect of
data indicate that vitiligo is a T-cell–mediated autoimmune the disease in women than in men, so that they present for
disorder, maybe triggered by oxidative stress, associated treatment more frequently.14
with an underlying genetic predisposition.2 Vitiligo may develop at all ages, but it is rarely described
in newborns and infants. 5 Most patients (79%–80%)
EPIDEMIOLOGY present the disease before 30 years of age.6,15,16 Childhood-
Vitiligo is a quite common skin disease. Its worldwide onset vitiligo (before age 12 years) is common, affecting
prevalence has been estimated to be 0.5%–1.0%.3 However, about 32%–37% of all patients.16,17 Recent studies underline
a recent review of vitiligo’s epidemiology, conducted by how vitiligo prevalence progressively increases with age.4,18
Krüger and Schallreuter on more than 50 studies, reports a It is well known that the prevalence of the disease varies in
greater general prevalence, ranging between 0.5% and 2.0%.4 different countries and races.12 Apart from differences due to
The incidence of vitiligo varies in different countries, nonunified methods in collecting epidemiological data, it is
ranging from 0.1% to over 8.8%. 5 The highest rates of clear that vitiligo incidence has fluctuations that seem to be
incidence have been recorded in India, Mexico, and Japan,6 related to both genetic and environmental factors.
while the lowest rates are reported in Caucasians of Finland, Nowadays, vitiligo is considered to be inherited in a non-
England, and Denmark.4–5,7 Apart from a real difference Mendelian, multifactorial, and polygenic pattern.2,20 Its
in vitiligo’s incidence, the data are partially conditioned heritability ranges from 46% to 16%21; close relatives of vitiligo
by the different modalities in collecting data, sometimes patients have increased risk of vitiligo and other autoimmune
limited to a small sample of the population,4 and by the diseases, which are about 6–18-fold elevated.22,23
different psychological impact of the disease in patients of To date, more than 30 loci for vitiligo susceptibility
have been identified. Among these, only 10% of genes
encode for molecules relevant to normal melanogenesis
Table 4.1 Etiopathophysiological theories for vitiligo
(e.g., TYR, which encodes for tyrosinase, and MC1R,
• Autocytotoxic theory which encodes for melanocortin receptor and regulates
• Autoimmune theory melanogenesis), while 90% of them encode for HLA
• Biochemical theory haplotypes (e.g., HLAs-A2, -DR4, -DR7, -DQB1*0303) and
• Inflammatory theory other immunoregulatory proteins, which are implicated in
• Melanocytorrhagy theory both cellular and humoral immunity (Table 4.2).21,24,25
• Neurohumoral theory From genetic studies on vitiligo, two interesting data
• Oxidative stress theory points have emerged. The first is that genetic alterations
• Theory of decreased melanocyte lifespan in vitiligo patients may lead to the onset of comorbidities

27
28 Epidemiology and classification of vitiligo

Table 4.2 Some of the genes that may be implicated in vitiligo pathogenesis
Gene Protein Function
BACH2 BTB and CNC homology 1, basic leucine zipper B-cell transcriptional repressor
CCR6 Chemokine receptor type 6 Regulation of B-cell differentiation
CD 44 CD44 antigen T-cell regulator
CD80 B-cell activation antigen B7-1 T-cell priming by B cells, T cells, and dendritic cells
CLNK Mast cell immunoreceptor signal transducer Immunoreceptor signaling
CTLA4B Cytotoxic T lymphocytes antigen 4 Inhibition of T cells
FOXD3 Forkhead box D3 Transcriptional regulator of neuronal crest
FOXP1 Forkhead box P1 Regulation of lymphoid cell development
FOXP3 Forkhead box p3 Transcriptional regulator of T reg cell function and
development
GZMB Granzyme B Mediator of T-cell and NK apoptosis
HLA A-B-C Leukocyte antigen B or C α chain Presentation of peptide antigen
HLA-A Leukocyte antigen A α chain Presentation of peptide antigen
HLA-DRB1-DQA1 Major histocompatibility complex class II Presentation of peptide antigen
IFIH1 Interferon-induced RNA helicase Regulation of innate antiviral immune responses
IL2RA Interleukin 2 receptor Regulation of lymphocyte response to bacteria
PTPN22 Lymphoid-specific protein tyrosinase Regulation of T-cell receptor signaling
phosphatase nonreceptor 22
RERE Atrophin-like protein 1 Regulation of apoptosis
TG/SLA Tyroglobulin SRC-like adaptor isoform C Regulation of antigen receptor signaling in T and B cells
TICAM1 Toll-like receptor adaptor molecule 1 Innate antiviral immune responses
TSLP Thymic stromal lymphoprotein Regulation of T-cell and DC maturation
UBASH3A Ubiquitin associated and SH3 domain containing Regulation of T-cell signaling
XBP1 X-box binding protein 1 Transcriptional regulator of MHC class II

(Table 4.3), such as autoimmune and endocrine diseases.26

Table 4.3 Examples of genetic alterations detected in
Among these, the association with autoimmune thyroid
vitiligo patients with comorbidities
disorders is the more commonly described. 27 Other
endocrinological disorders that may be associated with Gene Protein Comorbidities
vitiligo are hypoparathyroidism, Addison’s disease, PTPN22 Lymphoid-specific Type 1 DM, Graves’
polyglandular syndrome type I and type II, and diabetes protein tyrosinase disease, RA, Addison
mellitus. Vitiligo has been also described in association phosphatase disease, psoriasis, IBD
with numerous autoimmune diseases, such as hematologic nonreceptor 22
disorders and several skin diseases (Table 4.4), 28,29 and, CTLA4B Cytotoxic T Type 1 DM, Graves’
more recently, with systemic inflammatory disorders like lymphocytes disease, Hashimoto
obesity and metabolic syndrome.30 antigen 4 thyroiditis, IBD, SLE
Another interesting finding is the correlation between
CCR6 Chemokine receptor IBD, AR, Graves’
vitiligo and melanoma. Some of the genes expressed by
type 6 disease
melanocytes in vitiligo have been observed to be involved
IL2RA Interleukin 2 receptor Type 1 DM, Graves’
in susceptibility to malignant melanoma with an opposite
disease, RA, multiple
role. The development of depigmentary disorders in
sclerosis, SLE
melanoma patients seems to lead to a more favorable
prognosis, maybe as sign of an active immune response
directed against melanocytes.31 in monozygotic twins is approximately 23%.23 Although
Apart from a genetic background, many data support the exact mechanism of action of the different trigger
the important role of environmental trigger factors in the factors is still unclear, their role in vitiligo pathobiology is
development of vitiligo32 (Table 4.5). First, there is evidence well known, such as the importance of recognizing them to
of a variable prevalence of the disease in different countries. limit the incidence and progression of the disease.
Also suggestive are the data about the incidence of vitiligo
among families. In fact, while up to 20% of patients have an CLASSIFICATION AND CLINICAL FEATURES
affected relative, the majority of vitiligo cases are sporadic. Clinically, vitiligo is characterized by asymptomatic, milk-
Finally, the incidence of concordance of pigmentary disease white macules and patches, with well-defined borders
 Classification and clinical features 29

Table 4.4 Common autoimmune diseases associated with

vitiligo
• Alopecia areata
• Atopic dermatitis
• Autoimmune hemolytic anemia
• Autoimmune thyroid disease
• Diabetes mellitus
• Guillain-Barré syndrome
• Inflammatory bowel disease
• Myasthenia gravis
• Morphea
• Multiple sclerosis
• Pemphigus vulgaris
• Pernicious anemia
• Psoriasis
• Rheumatoid arthritis
• Sjögren syndrome
• Systemic lupus erythematosus
• Others

Table 4.5 Trigger factors that may be involved in vitiligo

onset Figure 4.1 White macules of vitiligo. (Courtesy Dermatologic
• Physical stress: major illness, surgical operations, accidents Clinic, University of Parma.)
• Intercurrent infections and repeated antibiotic intake
• UVR and sunburns
• Chemical factors: thiols, phenols, catechols,
Table 4.6 Clinical variants of vitiligo
mercaptoamines, quinones and their derivatives Type of vitiligo Characteristics
• Endocrine factors: pregnancy
Punctata vitiligo Small, punctuate-like, depigmented
• Malnutrition: malnutritional habits; intake of preserved,
macules
stale, or junk food
Follicular vitiligo Vitiligo involving the follicular
• Psychosocial insecurity/shocks
reservoir with poor cutaneous lesions
Inflammatory vitiligo Erythematous halo surrounding the
(Figure 4.1). Lesions may vary in number, form, and white patches
distribution, and may affect skin, mucous membranes, and Trichrome vitiligo Hypopigmented area between the
hair. Characteristic is Koebner’s phenomenon, consisting central amelanotic zone and the
of the development of new lesions at sites of skin trauma. peripheral normal skin
In some cases, vitiligo patients may also show different Quadrichrome Variant of trichrome vitiligo with foci
clinical variants of the disease (Table 4.6)33,34 and vitiligo of repigmentation at the follicular osti
abnormalities of the melanocytes localized in different Pentachrome vitiligo Lesions show the occurrence of five
organs (e.g., eyes and ears).35,36 Not rarely, nail abnormalities shades of color, white to black
(e.g., longitudinal ridging, leukonychia, absent lunula, Blue vitiligo Bluish appearance of skin color
onycholysis, and others) may also be detected.37
Classically, vitiligo may be classified, on the basis of the
extension of the disease, into localized, generalized, or which amelanotic lesions usually involve different parts
universalis forms (Table 4.7). of the body with a bilateral and symmetrical distribution.
More recently, the Vitiligo Global Issues Consensus Typical of all the types are the unpredictable course and
Conference proposed another classification for the disease, the possible association with comorbidities. In NSV, the
which is based on the clinical features and natural history most commonly described type is generalized vitiligo
of vitiligo (Table 4.8).38 The new classification recognizes (also known as vitiligo vulgaris), characterized by
three main types of vitiligo: nonsegmental vitiligo (NSV), multiple lesions that usually involve the face, trunk, and
segmental vitiligo (SV), and indeterminate forms. upper and lower limbs, especially on trauma-exposed
NSV is the most commonly described. Even if it can areas (Figures 4.2 and 4.3). Another common type of NSV
occur at any age, it usually develops in young people is acrofacial, characterized by white patches limited to the
between the ages of 10 and 30 years. Clinically, it is face and distal end of extremities, but it can later progress
characterized by a heterogeneous group of types, in to widespread forms.
30 Epidemiology and classification of vitiligo

Table 4.7 Classification of vitiligo on the basis of the extent of the disease
Localized Generalized Universalis
• Focal: One or more macules in one area but not • Vulgaris: Scattered patches that are • Complete or nearly
clearly in a segmental distribution widely distributed complete depigmentation
• Unilateral/segmental: One or more macules • Acrofacialis: White patches on the distal
involving a unilateral segment of the body— extremities and face
lesions stop abruptly at the midline • Mixed: Vitiligo acrofacialis and vulgaris
• Mucosal: Lesions limited to mucous membranes

Table 4.8 Classification of vitiligo based on the clinical features and natural history of the disease
Types Characteristics Subtypes
Segmental vitiligo (SV) One or more vitiliginous patches, in a linear or Unisegmental
flag-like pattern of mosaicism, with a unilateral Bisegmental
dermatomal distribution Multisegmental
Nonsegmental vitiligo (NSV) Heterogeneous group of clinical subtypes with Acrofacial
multifocal localization, usually in a symmetric Mucosal (more than one site affected)
pattern Generalized
Universal
Mixed (associated with segmental vitiligo)
Rare forms
Unclassified or indeterminate Focal
Mucosal (only one site)

In some cases, mixed vitiligo may be also be described. described. It consists of segmental and nonsegmental
Clinically, it is characterized by the combination of vitiligo following Blaschko lines.40
segmental and nonsegmental vitiliginous lesions. 39 Rarer variants of NSV are universal and mucosal
Recently, a particular subtype of mixed vitiligo has been vitiligo. The first consists of complete or nearly complete
skin depigmentation (80%–90% of the body’s surface),
often associated with mucosal and scalp hair involvement.
The second is characterized by acromic lesions localized
on the oral and genital mucosa, sometimes associated with
more common cutaneous lesions.
Finally, there are rarer variants of NSV: punctata, minor,
and follicular. The first is characterized by punctuate-like,
depigmented macules; the second by a partial defect in
pigmentation, which seems to be limited to dark-skinned
individuals; and the third by poor cutaneous lesions
involving the follicular reservoir.
SV is less common than nonsegmental vitiligo,
representing about 5%–16% of overall vitiligo cases.41
Differently from NSV, SV is characterized by an early age
of onset, rapid stabilization, and less common association
with comorbidities.19
Clinically, it is characterized by one or more vitiliginous
macules, with a typical unilateral and segmental or band-
shaped distribution, usually respecting the midline
(Figure 4.4). On the basis of the lesions’ localization, SV
may be further classified as unisegmental, bisegmental, or
multisegmental. Among these, the unisegmental type is
the most commonly described.
Figure 4.2 Generalized nonsegmental vitiligo. (Courtesy A particular manifestation of SV is poliosis, which is
Dermatologic Clinic, University of Parma.) characterized by a patch of white hair.1
 Classification and clinical features 31

Figure 4.3 (a–e) Generalized nonsegmental vitiligo. (Courtesy Dermatologic Clinic, University of Parma.)

Finally, there is indeterminate vitiligo, which comprises Despite the possibility of classifying vitiligo on the
forms with isolated mucosal involvement and focal forms. basis of different parameters (e.g., morphology, extension,
While the first is characterized by lesions affecting only natural history), the classification of the disease remains
one mucosa, focal vitiligo is characterized by small isolated a challenging endeavor and each patient should be
macules without segmental distribution, which does not considered individually for proper management and
evolve to NSV after a period of at least 2 years. treatment.42
32 Epidemiology and classification of vitiligo

10. Handa S, Kaur I. Vitiligo: Clinical findings in 1436

patients. J Dermatol. 1999;26:653–657.
11. Lotti TM, Berti SF, Hercogova J et al. Vitiligo: Recent
insights and new therapeutic approaches. G Ital
Dermatol Venereol. 2012;147(6):637–647.
12. Wang X, Du J, Tinglin Wang T et al. Prevalence and
clinical profile of vitiligo in China: A community
based study in six cities. Acta Derm Venereol.
2013;93:62–65.
13. McBurney E. Vitiligo: Clinical picture and
pathogenesis. Arch Intern Med. 1979;139:1295–1297.
14. Alikhan A, Felsten LM, Daly M et al. Vitiligo:
A comprehensive overview Part I. Introduction,
epidemiology, quality of life, diagnosis, differential
diagnosis, associations, histopathology, etiology, and
work-up. J Am Acad Dermatol. 2011;65:473–491.
15. Behl PN, Kotia A, Sawal P. Vitiligo: Age group related
trigger factor and morphological variants. Indian
J Dermatol Venereol Lepr. 1994;60:275–279.
16. Nicolaidou E, Antoniou C, Miniati A et al. Childhood-
and later-onset vitiligo have diverse epidemiologic
and clinical characteristics. J Am Acad Dermatol.
2012;66:954–958.
Figure 4.4 Segmental vitiligo. (Courtesy Dermatologic
17. Ezzedine K, Diallo A, Léauté-Labrèze C et al. Pre-
Clinic, University of Parma.)
vs. post-pubertal onset of vitiligo: Multivariate
analysis indicates atopic diathesis association
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1. Lotti T, Hautmann G, Hercogovà J. Vitiligo: Disease 2012;167:490–495.
or symptom? From the confusion of the past to 18. Al-Refu K. Vitiligo in children: A clinical-
current doubts. In: Lotti T, Hercogovà J, eds. Vitiligo. epidemiologic study in Jordan. Pediatr Dermatol.
Problems and Solutions. New York: Marcel Dekker; 2012;29:114–115.
2004:1–14. 19. van Geel N, Mollet I, Brochez L et al. New insights in
2. Lee BW, Schwartz RA, Hercogová J, Valle Y, Lotti segmental vitiligo: Case report and review of theories.
TM. Vitiligo road map. Dermatol Ther. 2012;25(Suppl Br J Dermatol. 2012;166:240–246.
C):S44–S56. 20. Sun XK, Xu AE, Meng W et al. Study on genetic
3. Taïeb A, Picardo M; VETF Members. The definition epidemiology on 815 patients with vitiligo in the
and assessment of vitiligo: A consensus report of Zhejiang area. Zhonghua Liu Xing Bing Xue Za Zhi.
the Vitiligo European Task Force. Pigment Cell Res. 2005;26:911–914.
2007;20:27–35. 21. Spritz RA. Modern vitiligo genetics sheds new
4. Krüger C, Schallreuter KU. A review of the worldwide light on an ancient disease. J Dermatol. 2013;40(5):​
prevalence of vitiligo in children/adolescents and doi:10.1111/1346-8138.12147.
adults. Int J Dermatol 2012;51:1206–1212. 22. Laberge G, Mailloux CM, Gowan K et al. Early
5. Alzolibani AA, Robaee AA, Zedan K. Genetic disease onset and increased risk of other autoimmune
epidemiology and heritability of vitiligo. In: Dr. Hwa diseases in familial generalized vitiligo. Pigment Cell
Park KK. ed. Vitiligo—Management and Therapy. Res. 2005;18:300–305.
2011. 23. Alkhateeb A, Fain PR, Thody A et al. Epidemiology
6. Sehgal VN, Srivastava G. Vitiligo: Compendium of of vitiligo and associated autoimmune diseases in
clinico-epidemiological features. Indian J Dermatol Caucasian probands and their families. Pigment Cell
Venereol Leprol. 2007;73:149–156. Res. 2003;16:208–214.
7. Howitz J, Brodthagen H, Schwartz M et al. Prevalence 24. Jin Y, Ferrara T, Gowan K et al. Next-generation DNA
of vitiligo. Epidemiological survey on the Isle of re-sequencing identifies common variants of TYR
Bornholm, Denmark. Arch Dermatol. 1977;113:47–52. and HLA-A that modulate the risk of generalized
8. Lotti T, Hanna D, Buggiani G, Urple M. The color of vitiligo via antigen presentation. J Invest Dermatol.
the skin: Psycho-anthropologic implications. JCosmet 2012;132(6):1730–1733.
Dermatol. 2005;4(3):219–220. 25. Zhang XJ, Chen JJ, Liu JB. The genetic concept of
9. Ahmed I, Ahmed S, Nasreen S. Frequency and pattern vitiligo. J Dermatol Sci. 2005;39(3):137–146.
of psychiatric disorders in patients with vitiligo. 26. Lotti T, D’Erme AM. Vitiligo as a systemic disease.
J Ayub Med Coll Abbottabad. 2007;19(3):19–21. Clin Dermatol. 2014;32(3):430–434.
 References 33

27. Nejad SB, Qadim HH, Nazeman L et al. Frequency of 36. Akay BN, Bozkir M, Anadolu Y et al. Epidemiology
autoimmune diseases in those suffering from vitiligo of vitiligo, associated autoimmune diseases and
in comparison with normal population. Pak J Biol Sci. audiological abnormalities: Ankara study of 80
2013;16(12):570–574. patients in Turkey. J Eur Acad Dermatol Venereol.
28. Gill L, Zarbo A, Isedeh P et al. Comorbid autoimmune 2010;24(10):1144–1150.
diseases in patients with vitiligo: A cross-sectional 37. Anbar T, Hay RA, Abdel-Rahman AT et al. Clinical
study. J Am Acad Dermatol. 2016;74(2):295–302. study of nail changes in vitiligo. J Cosmet Dermatol.
29. Chen YT, Chen YJ, Hwang CY et al. Comorbidity 2013;12:67–72.
profiles in association with vitiligo: A nationwide 38. Ezzedine K, Lim HW, Suzuki T et al. Revised
population-based study in Taiwan. J Eur Acad classification/nomenclature of vitiligo and related
Dermatol Venereol. 2015;29(7):1362–1369. issues: The Vitiligo Global Issues Consensus
30. Pietrzak A, Bartosińska J, Hercogová J et al. Metabolic Conference. Pigment Cell Melanoma Res.
syndrome in vitiligo. Dermatol Ther. 2012;(25 Suppl 2012;25(3):E1–13.
1):S41–S43. 39. Ezzedine K, Gauthier Y, Léauté-Labrèze C et al.
31. Spritz RA. The genetics of generalized vitiligo: Segmental vitiligo associated with generalized
Autoimmune pathways and an inverse relationship vitiligo (mixed vitiligo): A retrospective case
with malignant melanoma. Genome Med. 2010;2:78. series of 19 patients. J Am Acad Dermatol.
32. Silverberg JI, Reja M, Silverberg NB. Regional 2011;65:965–971.
variation of and association of US birthplace with 40. Kovacevic M, Stanimirovic A, Vucic M et al.
vitiligo extent. JAMA Dermatol. 2014;150(12):​ Mixed vitiligo of Blaschko lines: A newly
1298–305. discovered presentation of vitiligo responsive to
33. Lee DY, Kim CR, Lee JH. Trichrome vitiligo in combination treatment. Dermatol Ther. 2016;29(4):​
segmental type. Photodermatol Photoimmunol 240–243.
Photomed. 2011;27(2):111–112. 41. Hann SK, Lee HJ. Segmental vitiligo: Clinical
34. Chandrashekar L. Dermatoscopy of blue vitiligo. Clin findings in 208 patients. J Am Acad Dermatol.
Exp Dermatol. 2009;34(5):e125–e126. 1996;35:671–674.
35. Huggins RH, Janusz CA, Schwartz RA. Vitiligo: A sign 42. Hercogová J, Schwartz RA, Lotti TM. Classification
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2006;72:68–71. 2012;25(Suppl 1):S10–S16.
Pathophysiology of vitiligo
ALEXANDRA MINIATI
5
CONTENTS
Genetic predisposition 35 Neuroendocrine phenomena 36
Oxidative stress 35 Conclusion 37
Autoimmunity 36 References 37

Vitiligo is an acquired chronic cutaneous disorder of OXIDATIVE STRESS

depigmentation, characterized by the absence of functional Oxidative stress has been historically suggested as the
melanocytes,1 with an estimated prevalence of 0.5%–2% initial event in vitiligo pathogenesis, causing lethal
of the general population.2 Clinically, it consists of well- effects on melanocytes through the production of free
demarcated, white macules and papules of varying size radicals.9 This hypothesis was based on the fact that some
and distribution. Despite the ease of clinical diagnosis, intermediates generated during melanin synthesis, such as
the exact pathophysiological mechanisms that lead to dopaquinones and indoles, are toxic to melanocytes.9 In
hypopigmentation are still unresolved. Several theories addition, an imbalance in enzymatic and nonenzymatic
are involved in melanocyte disappearance, namely antioxidant systems may also contribute in oxidative
genetic predisposition, environmental triggers, metabolic stress theory.9 Low levels of catalase have been implicated
abnormalities, and impaired inflammatory and immune in oxidative stress in segmental vitiligo, whereas the
responses leading to apoptosis.3 generation of oxidative stress in nonsegmental vitiligo
may be attributed to low levels of glutathione peroxidase
GENETIC PREDISPOSITION and reduced glutathione.9 In response to prolonged
The genetic etiology of vitiligo appears to be hydrogen peroxide (H 2O2) exposure, the function of
multifactorial, following a non-Mendelian pattern. HLA several proteins is affected, including stress proteins such
class I molecules present peptide antigens on the surface as heat shock protein 70 (Hsp70), which normally prevent
of almost all cells, whereas HLA class II molecules present degradation of cellular proteins.10 Once released into the
antigens on the surface of antigen-presenting cells, such extracellular environment, these stress proteins are very
as dendritic cells, mononuclear phagocytes, and B cells. immunogenic, serving as autoantigens. The intracellular
Autoimmune vitiligo is strongly associated with the MHC production of H2O2 in the epidermis is associated with
class II region and is associated with the production of the defective recycling of the tetrahydropterins 6BH4
cytokines that contribute to immune responses targeting and 7BH4. In particular, 6BH4 serves as the cofactor for
different pathogens.4 A total of 23 new risk susceptibility both phenylalanine hydroxylase (PAH) and tyrosine
loci have recently been identified using genome-wide hydroxylase (TH). Once formed, it is recycled by the
association studies of autoimmune vitiligo, encoding enzyme 4α-hydroxy-6BH4-dehydratase (DH). DH activity
for immunomodulatory proteins that participate in is decreased in melanocytes of vitiligo patients, leading to
melanocyte apoptosis. 5 the defective recycling of 6BH4, which in turn promotes
An interesting genetic fact was the identification of the formation of 7BH4.9 The latter can then inhibit PAH,
a polymorphism for the thymic stromal lymphopoietin causing the formation of free radicals. Increased 6BH4
(TSLP) gene −847C > T, which was found to increase levels can also inhibit tyrosinase, leading to defective
susceptibility to generalized vitiligo by decreasing melanin production.9
TSLP mRNA expression levels. 6 Moreover, a recent Under the condition of altered redox status in vitiligo
comprehensive association analysis of candidate genes epidermis, keratinocytes undergo vacuolar degeneration,
for generalized vitiligo showed strong evidence of secondary to apoptosis, resulting in their inability to
primary genetic association with vitiligo for TSLP, 7 produce an adequate amount of melanocyte growth factors,
suggesting the important role of this gene in disease such as stem cell factor (SCF), leading to melanocyte
pathogenesis. TSLP is a cytokine structurally and apoptosis.11 SCF, released by keratinocytes, is essential for
functionally similar to interleukin 7 (IL-7) and has been the survival of melanocytes, and binds to the c-kit receptor
implicated in conditions like asthma, allergic rhinitis, on melanocytes. Mutant alleles at the SCF/c-kit locus
and atopic dermatitis, based on its ability to maintain can lead to dysregulation of the expression of tyrosinase
immune homeostasis. 8 mRNA.12 Oxidative stress can trigger the loss of dendrites

35
36 Pathophysiology of vitiligo

of melanocytes, thus affecting melanosome transfer to methodology in patients with particularly nonsegmental
surrounding keratinocytes.9 Oxidative stress can also vitiligo and include antigens to γ-enolase, α-enolase, heat
induce apoptosis in melanocytes9 by releasing caspase- shock protein 90, osteopontin, ubiquitin-conjugating
activating cytochrome c from mitochondria, a mechanism enzyme, translation initiation factor 2, and GTP protein
that involves the imbalance between Bax (pro-apoptotic Rab38.20 Tyrosine hydroxylase is another recently identified
protein) and Bcl-2 (anti-apoptotic protein) levels.9 B-cell–dependent autoantigen involved in both segmental
and nonsegmental vitiligo,21 autoantibody levels of which
AUTOIMMUNITY were more frequent in patients with active disease.21
Most recent evidence suggests that autoimmune-based TNF is released in response to skin trauma,16 and it has
melanocyte damage is the main etiologic pathway in been shown to induce IL-8 (CXCL8) mRNA expression
vitiligo pathogenesis. 3 Both cell-mediated and humoral in a melanoma cell line; 22 it can also upregulate IL-8
immunity participate in melanocyte destruction. receptor expression in normal melanocytes.23 IL-8 is a
Histopathological evidence of the perilesional skin of chemokine important in inflammatory skin diseases and is
vitiligo have suggested the involvement of T lymphocytes, produced by monocytes, mast cells, fibroblasts, endothelial
mainly CD4+ and CD8+ T cells, in the disease process.13 cells, dendritic cells, and keratinocytes.24 IL-8 is also
Interferon-gamma (IFN-γ) produced by Th-1 cells chemotactic to neutrophils, T lymphocytes, basophils, and
increases angiogenesis through the expression of VEGF by keratinocytes.24 IL-8 relative gene expression was shown
both Th-1 cells and keratinocytes.14 VEGF, in turn, further to be significantly higher (p = 0.01) in lesional vitiligo skin
induces angiogenesis and vascular permeability, along than in control skin,25 and human melanocytes stimulated
with polarization of TH-1 cells, and increases the secretion by TNF and IL-1 showed increased release of IL-8. 25
of IFN-γ.14 High levels of cytotoxic CD8+ T lymphocytes It was recently also reported that chemically induced
against tyrosinase antigens have been detected in HLA- vitiligo led to increased production of IL-6 and IL-8. 26
positive vitiligo patients.15 The release of inflammatory These findings, along with the fact that IL-8 is a known
cytokines, especially interleukin-1 (IL-1), interleukin-6 chemokine to induce oxidative stress, leading indirectly to
(IL-6), tumor necrosis factor (TNF), and IFN-γ after skin both keratinocyte and melanocyte apoptosis in vitiligo, 2
trauma (known as the Koebner phenomenon) might be could suggest a possible pathophysiologic role of IL-8 in
an essential trigger that recruits T cells in the skin and the disease process.
exposes them to new antigen-expressing melanocytes.16
Autoreactive T cells kill melanocytes in experiments NEUROENDOCRINE PHENOMENA
in which T cells isolated from perilesional vitiligo skin Neuroimmune interactions are very important in
are co-incubated with autologous uninvolved skin.17 mediating the effects of stress in the skin27 and can also
Labeled T cells isolated from vitiligo lesions infiltrated affect the vitiligo development process. 28 For instance,
the normal skin, migrated to the epidermal-dermal corticotropin-releasing hormone (CRH) increases skin
junction, and were found in close association with dying inflammation,29 and in the skin upregulates the synthesis
melanocytes.17 Depletion of CD8+ T cells prevented and secretion of pro-opiomelanocortin (POMC) and its
melanocyte destruction, whereas enrichment for these peptides, with POMC being an important regulator of
cells enhanced it,17 supporting the key role of CD8+ T cells melanogenesis.28,30 Melanocortin-1, a product of POMC
in vitiligo. Recent evidence has also shown that IFN-γ- maturation, has a number of variants, including those of
derived chemokine CXCL10 is essential for driving vitiligo its receptor on melanocytes.31 mRNA expression of POMC
pathogenesis through the recruitment of autoreactive and its receptors, melanocortin receptor-1 (MC1R) and -4
CD8+ T cells to the epidermis, and autoreactive T cells (MC4R), is significantly decreased in lesional vitiligo skin
depend upon the chemokine receptor of CXCL10, CXCR3, and instead increased in nonlesional vitiligo skin compared
to transfer to the skin to kill melanocytes.18 IFN-γ signals to healthy controls.32 Polymorphisms in the melanocortin
through the IFN-γ receptor, which in turn recruits Janus system are associated with vitiligo. 33 Nevertheless, no
kinases (JAKs) to transduce the signal intracellularly. autoantibodies were identified in the blood of vitiligo
JAKs phosphorylate STAT1, a transcription factor that patients that could have interfered with the action of
then translocates to the nucleus to induce transcription α-melanocyte-stimulating hormone (α-MSH) on MC1R.34
of IFN-γ-inducible genes, including CXCL10.18 Blocking Neurochemical mediators that are secreted by
CXCL10 in diseased mice can prevent vitiligo and restore cutaneous axon terminals, such as norepinephrine (NE)
pigmentation.18 and acetylcholine (Ach), are toxic to melanocytes.9 NE has
Antibodies binding to melanocyte antigens induce direct melanocytotoxic effects by interfering with cellular
melanocyte necrosis in vitro through antibody-dependent sulfhydryl groups, impairing mitochondrial calcium
cellular cytotoxicity (ADCC) and complement activation.19 uptake, and inhibiting melanogenesis. Elevated levels
Such antibodies mainly belong to the IgG and IgA classes,19 of NE-degrading enzyme monoamine oxidase (MAO)
and the serum levels of these autoantibodies seem to in both melanocytes and keratinocytes in vitiligo skin
correlate with the extent of vitiligo.19 Recently, several result in the accumulation of toxic levels of free radicals,
B-cell autoantigens have been identified using phage display promoting melanocyte destruction.9
 References 37

CONCLUSION 12. McGill GG, Horstmann M, Widlund HR et al. Bcl-2

Literature review shows that the pathogenesis of vitiligo regulation by the melanocyte master regulator
typically involves more than one of the above-mentioned MITF modulates lineage survival and melanoma cell
mechanisms, with immunological parameters, mainly viability. Cell. 2002;109:707–718.
cytotoxic T lymphocytes, cytokines, and regulatory 13. Wańkowicz-Kalińska A, van de Wijngaard RM,
T cells, influencing the outcome of different treatments Tigges BJ et al. Immunopolarization of CD4+
for vitiligo. However, further scientific studies and and CD8+ T cells to type-1-like is associated with
efforts are needed, especially through clinical studies, to melanocyte loss in human vitiligo. Lab Invest.
elucidate the complex mechanisms underlying vitiligo, 2003;83(5):683–695.
leading to better therapeutic choices for the affected 14. Aroni K, Voudouris S, Ioannidis E et al. Increased
individuals. angiogenesis and mast cells in the center compared to
the periphery of vitiligo lesions. Arch Dermatol Res.
2010;302:601–607.
REFERENCES 15. Mandelcorn-Monson RL, Shear NH, Yay E et al.
1. Tobin DJ, Swanson NN, Pittelkow MR et al. Cytotoxic T lymphocyte reactivity to gp100, MelanA/
Melanocytes are not absent in lesional skin of MART1 and tyrosinase in HLA-A2-positive vitiligo
long duration vitiligo. J Pathol. 2000;191(4):407–416. patients. J Invest Dermatol. 2003;121:550–556.
2. Schallreuter KU, Bahadoran P, Picardo M et al. Vitiligo 16. Van Geel N, Speeckaert R, Taieb A et al. on behalf
pathogenesis: Autoimmune disease, genetic defect, of the other VETF members. Koebner’s phenomenon
excessive reactive oxygen species, calcium imbalance, in vitiligo: European position paper. Pigment Cell
or what else? Exp Dermatol. 2008;17(2):139–140. Melanoma Res. 2011;24(3):564–573.
3. Boniface K, Seneschal J, Picardo M et al. Vitiligo: 17. Van den Boorn JG, Konijnenberg D, Dellemijn TA
Focus on clinical aspects, immunopathogenesis and et al. Autoimmune destruction of skin melanocytes
therapy. Clin Rev Allergy Immunol. 2018;54(1):52–67. by perilesional T cells from vitiligo patients. J Invest
4. Cavalli G, Hayashi M, Jin Y et al. MHC class II super- Dermatol. 2009;129(9):2220–2232.
enhancer increases surface expression of HLA-DR 18. Rashighi M, Agarwal P, Richmond JM et al. CXCL10
and HLA-DQ and affects cytokine production is critical for the progression and maintenance of
in autoimmune vitiligo. Proc Natl Acad Sci USA. depigmentation in a mouse model of vitiligo. Sci
2016;113(5):1363–1368. Transl Med. 2014;6(223):223ra23.
5. Jin Y, Andersen G, Yorgov D et al. Genome- 19. Sandoval-Cruz M, Garcia-Carrasco M, Sánchez-
wide association studies of autoimmune vitiligo Porras R et al. Immunopathogenesis of vitiligo.
identify 23 new risk loci and highlight key Autoimmune Rev. 2011;10(21):762–765.
pathways and regulatory variants. Nat Genet. 20. Waterman EA, Gawkrodger DJ, Watson PF et al.
2016;48(11):1418–1424. Autoantigens in vitiligo identified by the serological
6. Cheong KA, Chae SC, Kim YS et al. Association selection of a phage-displayed melanocyte cDNA
of thymic stromal lymphopoietin gene −847C > T expression library. J Invest Dermatol. 2010;130(1):​
polymorphism in generalized vitiligo. Exp Dermatol. 230–240.
2009;18(12):1073–1075. 21. Kemp EH, Emhemad S, Akhtar S et al. Autoantibodies
7. Birlea SA, Jin Y, Bennett DC et al. Comprehensive against tyrosinase hydroxylase in patients with non-
association analysis of candidate genes for generalized segmental (generalized) vitiligo. Exp Dermatol.
vitiligo supports XBP1, FOXP3 and TSLP. J Invest 2011;20(1):35–40.
Dermatol. 2011;131:371–381. 22. Mohler T, Scheibenbogen C, Hafele J et al. Regulation
8. Ziegler SF, Artis D. Sensing the outside world: of interleukin-8 mRNA expression and protein
TSLP regulates barrier immunity. Nat Immunol. secretion in a melanoma cell line by tumour necrosis
2010;11(4):289–293. factor-alpha and interferon-gamma. Melanoma Res.
9. Guerra L, Dellambra E, Brescia S et al. Vitiligo: 1996;6:307–311.
Pathogenetic hypotheses and targets of current 23. Norgauer J, Dichmann S, Peters F et al. Tumor necrosis
therapies. Curr Drug Metab. 2010;11(5):451–467. factor alpha induces upregulation of CXC-chemokine
10. Salem MM, Shalbaf M, Gibbons NC et al. Enhanced receptor type II expression and magnifies the
DNA binding capacity on up-regulated epidermal proliferative activity of CXC-chemokines in human
wild-type p53 in vitiligo by H2O2-mediated oxidation: melanocytes. Eur J Dermatol. 2003;13:124–129.
A possible repair mechanism for DNA damage. 24. Luger TA, Schwarz T. Evidence of an epidermal
FASEB. 2009;23(11):3790–3807. cytokine network. J Invest Dermatol. 1990;95:100–14S.
11. Moretti S, Fabbri P, Baroni G et al. Keratinocyte 25. Miniati A, Weng Z, Zhang B et al. Stimulated human
dysfunction in vitiligo epidermis: Cytokine melanocytes express and release interleukin-8, which is
microenvironment and correlation to keratinocyte inhibited by luteolin: Relevance to early vitiligo. Clin
apoptosis. Histol Histopathol. 2009;24(7):849–857. and Experimental Dermatol. 2014;39:54–57.
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26. Toosi S, Orlow SJ, Manga P. Vitiligo-inducing phenols 31. Dessinioti C, Antoniou C, Katsambas A et al.
activate the unfolded protein response in melanocytes Melanocortin 1 receptor variants: Functional role
resulting in upregulation of IL-6 and IL-8. J Invest and pigmentary associations. Photochem Photobiol.
Dermatol. 2012;132:2601–2609. 2011;87(5):978–987.
27. Arck PC, Slominski AT, Theoharides TC et al. 32. Kingo K, Aunin E, Karelson M et al. Gene expression
Neuroimmunology of stress: Skin takes center stage. analysis of melanocortin system in vitiligo. J Dermatol
J Invest Dermatol. 2006;126(8):1697–1704. Sci. 2007;48(2):113–122.
28. Slominski AT, Wortsman J. Neuroendocrinology of 33. Traks T, Keermann M, Karelson M et al.
the skin. Endocr Rev. 2000;21:457–487. Polymorphism in melanocortin system and MYG1
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Segmental vitiligo
CHRISTINA BERGQVIST and KHALED EZZEDINE
6
CONTENTS
Introduction 39 Mixed vitiligo 41
Pathogenesis 39 Classification of segmental vitiligo on the face 41
Epidemiology 39 Treatment overview 41
Clinical features 40 References 42
Differential diagnosis 41

INTRODUCTION However, given that allergic and autoimmune disorders

Vitiligo is an acquired, chronic depigmenting disorder of are common in the general population, whether these
the skin characterized by progressive loss of melanocytes. associations are true or simply coincidental is controversial.
Segmental vitiligo (SV) is a distinct entity with distinctive Further and stronger epidemiological studies are needed to
clinical features. Indeed, the classification of segmental help elucidate this association.
vitiligo as a separate entity from vitiligo was first suggested Furthermore, halo nevus has been shown to be associated
by Koga in 19771 according to results of a sweat gland with SV nearly as frequently as with nonsegmental vitiligo
secretion stimulation test and the distribution of the lesions (8.6% in nonsegmental vitiligo vs. 6.4% in SV),8 and a family
(unilateral or bilateral). He referred to vitiligo distributed history of vitiligo has been found in approximately 12% of
in a dermatomal fashion as Type B to differentiate it from SV cases.7–9 More recent clinical reports of nonsegmental
the nondermatomal distribution of vitiligo referred to and mixed vitiligo have questioned the notion that these
as type A. In 2011, an international consensus classified forms of vitiligo are different and support the hypothesis
segmental vitiligo separately from all other forms of vitiligo, that SV and nonsegmental vitiligo are parts of the same
and the term “vitiligo” was defined to designate all forms disease spectrum and that SV could have a polygenetic
of nonsegmental vitiligo (including acrofacial, mucosal, background as well.10–15
generalized, universal, mixed, and rare variants).2 “Mixed Early studies on SV have provided evidence that
vitiligo” (MV), in which segmental and nonsegmental physiologic abnormalities associated with sympathetic
vitiligo coexist in one patient, is classified as a subgroup nerve dysfunction play a role in the pathogenesis of SV.
of nonsegmental vitiligo. Distinguishing SV from other Wu et al. have demonstrated an increased cutaneous
types of vitiligo was one of the most important decisions blood flow in segmental vitiligo lesions compared to the
of the consensus, primarily because of its prognostic contralateral normal skin and a significantly increased a-
implications. and b-adrenoceptor response in those lesions.16 However,
Taieb et al. suggested that these sympathetic abnormalities
PATHOGENESIS found in SV may simply be a confounding factor associated
The pathophysiology of the segmental distribution remains with the absence of melanocytes, since these latter have
highly controversial. 3,4 To date, there is no consensus the capacity to release several neuromediators in the skin.
concerning the mechanism underlying lesion distribution Moreover, they suggested the somatic mosaicism hypothesis
in SV. The basis for Koga’s notion of differentiating SV from of SV, and that SV and nonsegmental vitiligo are found
nonsegmental vitiligo was originally established on an along a continuum with shared predisposing genetic factors
etiologic basis.1,5 Indeed, in 1977, Koga proposed that the that would affect first the skin pigmentary system and
pathogenesis of the two types differ: whereas he considered secondarily activate skin immune/inflammatory responses,
the nonsegmental type an immunologic disorder associated leading to a more severe expression of the disease.4
with autoimmune disease, he suggested the segmental type Moreover, evidence of inflammation has been reported
was the result of a dysfunction of the sympathetic nerves in early cases of SV, further pointing toward the fact that
in the affected area.1 In both types, however, acquired both nonsegmental vitiligo and SV may have a related
melanocyte loss is the common denominator. According inflammatory or immune-related etiology.3
to El Mofty, unlike in generalized vitiligo, the association
with autoimmune diseases seems to be less significant in EPIDEMIOLOGY
SV.6 On the other hand, several reports have debated this Although the worldwide prevalence of vitiligo is 0.5%–
concept. In the report of Hann and Lee, 6.7% of patients 1%,2 the incidence of SV is not well established. Segmental
with SV had an associated allergic or autoimmune disease.7 vitiligo accounts for 5%–16% of overall vitiligo cases.7,17

39
40 Segmental vitiligo

In a study on an Egyptian population, El-Mofty et al. Monosegmental vitiligo is the most common form
reported that only 5% (41 out of 821) of patients had of SV;7,20 however, other distribution patterns are
segmental vitiligo.6 Koga and Tango reported that 27.9% possible whereby the depigmented patch overlaps several
of their patients (134 out of 481) had SV (referred to as ipsi or contralateral dermatomes or occurs on large
type B). 5 Several studies reported that the prevalence areas delineated by Blaschko lines. The onset may be
of SV in Korean vitiligo patients ranged from 5.5% to simultaneous or not. An evident segmental distribution
29.6%.7 On the contrary, a study done on a large number of the lesions with midline demarcation, along with the
of Chinese vitiligo patients showed lower prevalence of the characteristic features of segmental vitiligo (protracted
segmental form (2.5% of the total prevalence) and higher course, leukotrichia), help in distinguishing this diagnosis
prevalence of focal vitiligo (36%) than reported in other from nonsegmental vitiligo in bilateral cases. In Hann’s
studies.18 This variability in epidemiological data could be report, 5 out of the 240 patients with SV had two different
accounted for by differences in disease classification due depigmented segments. The clinical course of bilateral SV
to the lack of consensus in previous years, inconsistent seems similar to that of unilateral SV.
reporting by patients, and varied populations. The head is involved in more than 50% of cases.7,8
Segmental vitiligo tends to occur at a younger age than The most commonly involved dermatome is that of the
nonsegmental vitiligo,19 before the age of 30 years in 87% trigeminal nerve.7,9,21 The next common locations in
of cases and before the age of 10 years in 41.3%.7 In Hann decreasing order of frequency are: the trunk, the limbs,
and Lee’s report, the mean age of onset was 15.6 years.7 The the extremities, and the neck.6–9
earliest reported onset was immediately after birth, whereas Early SV starts as an oval-shaped white macule or patch
the latest was 54 years. Most cases were less than 3 years in that is difficult to differentiate from focal vitiligo. Focal
duration at referral, ranging from 2 months to 15 years.7 vitiligo refers to a small, isolated, depigmented lesion
without an obvious distribution pattern. It can be a part
CLINICAL FEATURES of segmental or nonsegmental vitiligo; however, if after
Segmental vitiligo refers to depigmented macules distributed 1–2 years it still has not evolved into nonsegmental or
in a segmental distribution, and typically it is associated segmental vitiligo, it is regarded as unclassifiable vitiligo.2
with leukotrichia and a rapid onset (Figure 6.1). The In SV, the depigmentation spreads within the segment
characteristic lesion is clinically similar to the macule seen over a period of 6–24 months. After initial rapid spreading
in nonsegmental vitiligo: a totally amelanotic, nonscaly, in the affected dermatome, the SV patch most often
chalky-white macule with distinct margins. However, a less remains stable.7 Rarely, however, it can progress again after
uniform depigmentation pattern has also been reported in SV being quiescent for several years, and if does so, it usually
compared to nonsegmental vitiligo. In fair-skinned patients, spreads over the same dermatome. Disease recurrence can
the lesions are not easily distinguishable under normal light, occur after years of stability.22 However, in very rare cases,
but can be discernible with Wood’s light examination. lesions may become generalized and become part of mixed
The depigmented patches are usually confined to a single vitiligo.11,22
dermatome, with partial or complete involvement. Indeed,
monosegmental vitiligo is defined as one or more white Distinguishing features from nonsegmental vitiligo
depigmented macules distributed on one side of the body, It is important to distinguish SV from other types of
usually respecting the midline with early leukotrichia, vitiligo, principally because of its prognostic implications.
with a rapid onset over a few weeks or months and a rapid In addition to its limited, segmental distribution, SV
stabilization with an overall protracted course. They may has other distinguishing characteristics as compared to
sometimes cross the midline. nonsegmental vitiligo.

• Nonsegmental vitiligo can occur at any age, whereas SV

typically has an earlier age of onset than nonsegmental
vitiligo.7,9,21
• Segmental vitiligo typically has a rapidly progressive
(over a period of 6–24 months) but limited course.
Nonsegmental vitiligo typically evolves over time, in
both distribution and extension patterns.
• SV has early involvement of melanocytes of hair follicles,
with up to 50% of SV patients presenting poliosis in
affected areas. In nonsegmental vitiligo, body hair
remains pigmented, although hair depigmentation can
occur in later stages with disease progression.
• Melanocyte autologous grafting typically yields a
good long-term response in SV patients, with stable
Figure 6.1 Large segmental vitiligo of the left hip and repigmentation, whereas nonsegmental vitiligo usually
abdomen in a 5-year-old boy. relapses within autologous grafting sites.
 Treatment overview 41

DIFFERENTIAL DIAGNOSIS • Type 1b is the mirror image of 1a. The lesion originates
The most common differential diagnosis is nevus from the left side of the face and spreads down the right
depigmentosus, also known as achromic nevus since it side of the face, crossing the midline.
presents as a congenital hypomelanoses of segmental • Type 2 represents the lesion that originates from the area
distribution. Indeed, it is usually congenital or seen within between the nose and lip, then arches to the preauricular
the first year of life and grows proportionally to the child’s area.
growth. The achromic nevus usually includes a normal • Type 3 represents the lesion that originates from the
number of melanocytes compared with perilesional skin; lower lip and spreads down to the chin and neck.
however, it is the production of melanin pigment that is • Type 4 represents the lesion that originates from the
reduced. In difficult cases, a biopsy is needed to differentiate right side of the forehead and spreads down to the
nevus depigmentosus from SV. eyeball, nose, and cheek areas without crossing the
midline.
MIXED VITILIGO
• Type 5 represents the lesion that is confined to the left
cheek area.
Mixed vitiligo refers to the concomitant occurrence of
SV and nonsegmental vitiligo. In general, SV typically In their study, type 1 was the most common and type 5
precedes nonsegmental vitiligo. the least common.
Mixed vitiligo was first reported in a child treated with Gauthier and Taïeb proposed a simplified classification
UVB, which left a recalcitrant segmental lesion suggestive of SV of the face based on studies comparing sites involved
of preexisting SV.23 The term “mixed vitiligo” as referring by herpes zoster and SV:26
to the concomitant occurrence of SV and nonsegmental
vitiligo was first coined by Mulekar et al. in 2006.13
• Type I: V1 ophthalmic branch (partial or total
involvement)
Ezzedine et al. subsequently proposed definition criteria
• Type II: V2 maxillar branch (partial or total involvement)
in a case series.11 These include:
• Type III: V3 mandibular branch (partial or total
• Absence of depigmented areas in a segmental distribution involvement)
at birth and in the first year of life, and an examination • Type IV: Mixed distribution patterns on several
by Wood’s lamp that excludes nevus depigmentosus. dermatomes
• SV followed by nonsegmental vitiligo with a delay of at
least 6 months. IVa = V1 + V2
• SV affecting at least 20% of the theoretical distribution of
a dermatomal segment or presenting a definite Blaschko
IVb = V2 + V3
linear distribution.
• Response to narrowband UVB treatment in between
IVc = V1 + V2 + V3
SV (poor response) and nonsegmental vitiligo (good
response).
• Type V: Cervicofacial distribution
Leukotrichia and halo nevi at onset may be risk factors
In the majority of cases (64%), SV did not exactly follow
for developing MV in patients with SV.10
some dermatomes and instead overlapped one, two, or
The co-occurrence of SV and nonsegmental vitiligo
three dermatomes. On the other hand, SV was distributed
in the same patient has been viewed as a superimposed
exactly to a trigeminal dermatome: ophthalmic (V1),
segmental manifestation of a generalized polygenic
maxillary (V2), and mandibular (V3) in 26% of cases.
disorder, in which segmental involvement precedes disease
generalization and is more resistant to therapy.24,25
TREATMENT OVERVIEW
CLASSIFICATION OF SEGMENTAL VITILIGO Reliable data regarding the treatment of SV are limited
ON THE FACE given the fact that most studies did not differentiate
between the types of vitiligo.
The progression of SV is usually limited to months or a
SV was long considered to be resistant to treatment.
few years. Since SV occurs most frequently on the face,
However, recent studies have been reporting promising
understanding the precise spreading pattern is of interest
results, especially when introduced at an early stage.
for both patients and physicians, as it helps in predicting
Within the first 6 months, patients should be offered a
the prognosis.
treatment with potent topical corticosteroids or topical
Hann et al. classified patterns of SV distribution on the
immune modulators combined with light therapy, such as
face:21
narrowband UVB light or targeted excimer lamp or laser.
• Type 1a represents the lesion that originates from the Oral steroid mini-pulse therapy is also another option if the
right side of the forehead, crosses the midline of the face, lesion is still in the active phase. In a recent retrospective
and spreads down to the eyeball, nose, and cheek of the study of 159 cases, the authors found that combination
left side of the face. therapy with 308-nm excimer laser, topical tacrolimus,
42 Segmental vitiligo

and short-term systemic corticosteroids were associated 12. van Geel N, De Lille S, Vandenhaute S et al. Different
with good response in segmental vitiligo. In this study, phenotypes of segmental vitiligo based on a clinical
prolonged disease duration, poliosis, and plurisegmental observational study. J Eur Acad Dermatol Venereol.
subtype were shown to be independent prognostic factors 2011;25:673–678.
of poor response in patients with SV.27 13. Mulekar SV, Al Issa A, Asaad M et al. Mixed vitiligo.
On the other hand, if these medical therapies fail, or if J Cutan Med Surg. 2006;10:104–107.
the disease is at a later stage, surgery can be considered. 14. Schallreuter KU, Kruger C, Rokos H et al. Basic
Overall, stable SV is a good indication for epidermal research confirms coexistence of acquired
grafting, especially given that the presence of leukotrichia Blaschkolinear vitiligo and acrofacial vitiligo. Arch
in SV makes it more resistant to standard medical therapies. Dermatol Res. 2007;299:225–230.
The surgical techniques that are recommended by the 15. Schallreuter KU, Kruger C, Wurfel BA et al. From
European guidelines comprise tissue grafts (full-thickness basic research to the bedside: Efficacy of topical
punch, split-thickness, and suction-blister grafts) and treatment with pseudocatalase PC-KUS in 71 children
cellular grafts (cultured melanocytes and noncultured with vitiligo. Int J Dermatol. 2008;47:743–753.
epidermal cellular grafts). The three tissue grafting methods 16. Wu CS, Yu HS, Chang HR et al. Cutaneous
seem to have similar success rates of repigmentation.28 blood flow and adrenoceptor response increase
in segmental-type vitiligo lesions. J Dermatol Sci.
REFERENCES 2000;23:53–62.
1. Koga M. Vitiligo: A new classification and therapy. Br 17. Silverberg NB. Update on childhood vitiligo. Curr
J Dermatol. 1977;97:255–261. Opin Pediatr. 2010;22:445–452.
2. Ezzedine K, Lim HW, Suzuki T et al. Revised 18. Wang X, Du J, Wang T et al. Prevalence and clinical
classification/nomenclature of vitiligo and related profile of vitiligo in China: A community-based study
issues: The Vitiligo Global Issues Consensus in six cities. Acta Derm Venereol. 2013;93:62–65.
Conference. Pigment Cell Melanoma Res. 2012;​ 19. Nicolaidou E, Antoniou C, Miniati A et al. Childhood-
25:E1–E13. and later-onset vitiligo have diverse epidemiologic
3. van Geel NA, Mollet IG, De Schepper S et al. First and clinical characteristics. J Am Acad Dermatol.
histopathological and immunophenotypic analysis 2012;66:954–958.
of early dynamic events in a patient with segmental 20. Lerner AB. Vitiligo. J Invest Dermatol.
vitiligo associated with halo nevi. Pigment Cell 1959;32:285–310.
Melanoma Res. 2010;23:375–384. 21. Hann SK, Chang JH, Lee HS et al. The classification
4. Taieb A, Morice-Picard F, Jouary T et al. Segmental of segmental vitiligo on the face. Yonsei Med J.
vitiligo as the possible expression of cutaneous 2000;41:209–212.
somatic mosaicism: Implications for common non- 22. Park JH, Jung MY, Lee JH et al. Clinical course of
segmental vitiligo. Pigment Cell Melanoma Res. segmental vitiligo: A retrospective study of eighty-
2008;21:646–652. seven patients. Ann Dermatol. 2014;26:61–65.
5. Koga M, Tango T. Clinical features and course 23. Gauthier Y, Cario Andre M, Taieb A. A critical
of type A and type B vitiligo. Br J Dermatol. 1988;​ appraisal of vitiligo etiologic theories. Is melanocyte
118:223–228. loss a melanocytorrhagy? Pigment Cell Res.
6. el-Mofty AM, el-Mofty M. Vitiligo. A symptom 2003;16:322–332.
complex. Int J Dermatol. 1980;19:237–244. 24. Happle R. [Segmental type 2 manifestation of
7. Hann SK, Lee HJ. Segmental vitiligo: Clinical autosome dominant skin diseases. Development
findings in 208 patients. J Am Acad Dermatol. of a new formal genetic concept]. Hautarzt.
1996;35:671–674. 2001;52:283–287.
8. Barona MI, Arrunategui A, Falabella R et al. An 25. Happle R. Superimposed segmental manifestation
epidemiologic case-control study in a population of polygenic skin disorders. J Am Acad Dermatol.
with vitiligo. J Am Acad Dermatol. 1995;33:621–625. 2007;57:690–699.
9. Hann SK, Park YK, Chun WH. Clinical features of 26. Gauthier Y, Taïb A. Proposal for a new classification of
vitiligo. Clin Dermatol. 1997;15:891–897. segmental vitiligo of the face. Pigment Cell Melanoma
10. Ezzedine K, Diallo A, Leaute-Labreze C et al. Halo Res. 2006;19:515.
naevi and leukotrichia are strong predictors of the 27. Bae JM, Yoo HJ, Kim H, Lee JH, Kim GM. Combination
passage to mixed vitiligo in a subgroup of segmental therapy with 308-nm excimer laser, topical
vitiligo. Br J Dermatol. 2012; 166:539–544. tacrolimus, and short-term systemic corticosteroids
11. Ezzedine K, Gauthier Y, Leaute-Labreze C et al. for segmental vitiligo: A retrospective study of 159
Segmental vitiligo associated with generalized patients. J Am Acad Dermatol. 2015;73:76–82.
vitiligo (mixed vitiligo): A retrospective case series 28. Ezzedine K, Eleftheriadou V, Whitton M et al.
of 19 patients. J Am Acad Dermatol. 2011;65:965–971. Vitiligo. Lancet. 2015;386:74–84.
Childhood versus post-childhood vitiligo
ELECTRA NICOLAIDOU and STYLIANI MASTRAFTSI
7
CONTENTS
Introduction 43 The psychological burden of vitiligo 45
Epidemiology 43 Differential diagnosis 45
Clinical presentation 43 Treatment 45
Comorbidities 44 References 47
Halo nevi 44

INTRODUCTION PCV is also unclear. Most studies reported no difference

Vitiligo is a chronic, difficult-to-manage, acquired disease in the male:female ratio between CV and PCV,4,5,8 but a
characterized by the appearance of milk-white macules female preponderance in CV compared to PCV has also
and patches of different shapes and sizes. It is a common been reported.6
disease, with a worldwide prevalence in the general
population that ranges from 0.06% to 2.28%.1 CLINICAL PRESENTATION
Many different pathogenetic mechanisms have been The typical clinical lesion of vitiligo, which consists of well-
proposed for vitiligo,2 and the disease is characterized by demarcated milk-white macules and patches, is the same in
various clinical types,3 so it has been proposed that vitiligo both CV and PCV. The frequently affected sites (face, dorsal
may represent a heterogeneous group of disorders that surface of the hands and feet, fingers, elbows, knees, shins,
present with the same phenotype. axillae, and anogenital region) are also the same.17 Koebner
Vitiligo may appear from shortly after birth to late phenomenon, characterized by the development of vitiligo
adulthood. Childhood vitiligo (CV) is defined as disease lesions at sites of trauma, is also a feature of CV and has been
onset before the age of 12 years. Studies from Greece,4 observed in 11%11–24%6 of children with vitiligo in India.
France,5 and India6 report disease onset in childhood in The sites of initial disease presentation seem to differ
32%–40% of patients. between CV and PCV. CV frequently appears initially on
Several differences have been described in epidemiology the head and neck area, especially on the eyelids.4 Studies
and clinical presentation between CV and post-childhood from Greece,4 Korea,8 and India6,11 showed that, in 31%–
vitiligo (PCV).4–8 In this chapter, we will present recent data 59% of patients, the disease begins in the head and neck
regarding CV with an emphasis on the differences between area. CV only rarely begins in the upper limbs.4,6,8,11 The
CV and PCV. Treatment options for CV will also be discussed. sites of initial disease presentation have been compared
between CV and PCV in two studies 4,6 and have been
EPIDEMIOLOGY found to be significantly different, with far more patients
The prevalence of vitiligo in children and adolescents with PCV developing lesions initially in the upper limbs,
worldwide ranges from 0% to 2.16%.1 A large study from especially the hands and fingers.4
Denmark 9 showed a prevalence of 0.09% in children up Leukotrichia may be associated with CV due to the
to 9 years of age and of 0.15% in children and adolescents involvement of the melanocytic reservoir that exists in the
from 10 to 20 years of age. A Chinese study10 reported a hair follicles. Leukotrichia may be present both in vitiliginous
prevalence of 0.1% in children 0 to 9 years of age, similar areas and in areas with clinically normal-appearing skin.18
to the Danish study, but a higher prevalence of 0.36% in Even though vitiligo is usually asymptomatic, symptoms
children and adolescents from 10 to 19 years of age. such as pruritus and burning sensation of the skin have
Typically, vitiligo appears after the age of 4.4,6,11–13 Two been demonstrated in 30% of children and adolescents
studies from India6,11 and one from China12 reported onset with the disease.19
of vitiligo before the age of 4 in only 17% of affected children. According to the more recent classification system for
There seems to be no agreement among studies for vitiligo, the disease is divided into two major clinical
the sex preference of CV. Studies from Greece,4 France,5 forms, vitiligo/nonsegmental vitiligo (NSV) and segmental
India, 6,11 Brazil,13 and the United States14 described a vitiligo (SV).3
female predominance of 57%–66%. In contrast, studies In NSV, the depigmented lesions vary greatly in size and
from Korea, 8 China,12 the United States,15 and Jordan16 usually involve both sides of the body, with a symmetrical
reported equal numbers of boys and girls with the disease. distribution (Figures 7.1 and 7.2). NSV is much more
Whether the male:female ratio is different between CV and common than SV in both CV and PCV. In CV, 67%–95%

43
44 Childhood versus post-childhood vitiligo

Figure 7.3 Segmental CV.

Figure 7.1 Nonsegmental CV. 5%–33% of all forms of CV4,6,8,11,12 and is more common in
CV compared to PCV.4,6,8

(a) COMORBIDITIES
NSV may be associated with several other autoimmune
disorders, including autoimmune thyroid disease,
rheumatoid arthritis, pernicious anemia, alopecia areata,
psoriasis, adult-onset type 1 diabetes, and Addison
disease.17,20 Thyroid disorders are the most common
comorbidity.21 Thyroid dysfunction has been observed in
several studies that included patients with CV. 22–25 Vitiligo
usually precedes the development of thyroid dysfunction,
and thyroid dysfunction can be subclinical. 23
Comorbidities seem to differ between CV and PCV.
In a cross-sectional study that included 233 patients, a
significantly higher prevalence of thyroid disease was
observed in patients with PCV compared to patients with
CV.4 Furthermore, in a prospective observational study
that included 679 patients, thyroid disease or the presence
(b)
of thyroid antibodies was independently associated with
PCV compared to CV.5 In contrast to thyroid disease,
allergic diseases4 and atopic dermatitis5 have been reported
more frequently in CV compared to PCV.

HALO NEVI
A halo nevus (Figure 7.4), also termed Sutton’s nevus, is a
melanocytic nevus that is surrounded by a depigmented

Figure 7.2 Nonsegmental CV: symmetrical lesions on

the neck.

of patients present with NSV.4,6,8,11,12 Segmental vitiligo

is confined to a unilateral segment (Figure 7.3), and it
is characterized by an early age of onset. SV typically
progresses within the involved segment over a period of
6–24 months and then usually stabilizes. SV accounts for Figure 7.4 Halo nevus in CV.
 Treatment 45

rim. The presence of halo nevi in children with vitiligo varies burning of vitiliginous skin as well as tanning of
greatly among different countries and races: 2.5% in a study perilesional skin, which will increase the contrast with
from Korea,8 7.2% in a Chinese study,12 18.4% in a study from lesions. Cosmetic camouflage may be used to conceal
France,26 and 26% in a study from the United States.27 An visible affected areas. In case of recognized psychosocial
Italian study that included 27 children with halo nevi and impairment, psychological therapeutic interventions are
vitiligo reported that in 11 children (40.7%), the appearance recommended.
of halo nevi and vitiligo was almost simultaneous; in 9 Annual thyroid screening is suggested for children with
children (33.3%), halo nevi preceded vitiligo; while in 7 vitiligo, especially for those with nonsegmental disease.
children (25.9%), halo nevi followed the onset of vitiligo.28 Topical treatment and phototherapy are the main
Halo nevi are more commonly found in patients with treatment modalities for children with vitiligo.
disease onset in childhood or adolescence. A positive
association between age at vitiligo onset younger than 18 Topical treatment: Corticosteroids and calcineurin
years and the appearance of halo nevi in vitiligo patients has inhibitors
been reported.29 In another study, the presence of halo nevi Topical corticosteroids (TCSs) and topical calcineurin
were independently associated with CV compared to PCV.5 inhibitors (TCIs) are the most commonly used topical
The significance of the presence of halo nevi in children agents for the treatment of vitiligo in children. Sun-
has not been fully studied. In a study that followed 54 exposed areas (face and neck), patients with dark skin, and
children with halo nevi for more than 5 years, 2 children, recent lesions respond better to topical treatments, while
both with multiple halo nevi, developed vitiligo.28 The same acral lesions respond poorly.36
study concluded that in children with multiple halo nevi, Topical corticosteroids have been found to offer benefits
the risk of vitiligo and other autoimmune diseases seemed in both facial and nonfacial childhood vitiligo. Their
to be higher compared to children with a single halo nevus. effectiveness may be attributed to their anti-inflammatory
and immunosuppressive effects. A retrospective study that
THE PSYCHOLOGICAL BURDEN OF VITILIGO included 101 children with vitiligo treated with moderate-
Vitiligo may have significant psychological and emotional to high-potency TCS reported repigmentation of lesions in
impact on both children and their parents, and it has 64% of children.37 However, the long-term use of TCS is
been associated with impairment of quality of life, social a concern due to local and systemic side effects. Ongoing
stigmatization, emotional distress, anxiety, depression, usage of corticosteroids topically can result in skin atrophy,
embarrassment, low self-esteem, deterioration of self- telangiectasias, hypertrichosis, acneiform eruptions,
confidence, and social isolation.30–34 Teenagers seem to be striae, glaucoma, systemic absorption, suppression of
affected to a greater extent compared to younger children.19 hypothalamic-pituitary-adrenal axis, Cushing syndrome,
and growth retardation in children. Risk factors for systemic
DIFFERENTIAL DIAGNOSIS adverse effects are thought to include young age, extent of
The differential diagnosis of nonsegmental CV includes skin surface treated, frequency and length of treatment,
a wide range of congenital and acquired disorders. For potency of drug, and use of occlusion. In the previously
lesions appearing before the age of 2 years, congenital mentioned retrospective study, children with vitiligo
hypomelanoses35 must be ruled out, including piebaldism, treated with TCS on the face and neck were 8.36 times more
tuberous sclerosis, albinism, and Waardenburg syn­ likely to have systemic absorption and abnormal cortisol
drome. For acquired lesions appearing at a later age, levels compared with children treated on other body areas.37
several acquired hypomelanoses must be excluded. Topical calcineurin inhibitors, tacrolimus and pimecro­
These include pityriasis versicolor, progressive macular limus, have showed good therapeutic efficacy in the
hypomelanosis, atopic dermatitis, pityriasis alba, lichen management of CV without the side effects related to TCS
sclerosus et atrophicus, morphea, and hypopigmented use. However, up to now, their prescription for vitiligo is off
mycosis fungoides. label in most countries, as tacrolimus has been approved
The differential diagnosis of childhood SV mainly as a topical agent for moderate to severe atopic dermatitis
includes the nevus depigmentosus/hypochromic nevus and pimecrolimus for mild to moderate atopic dermatitis.
and the nevus anemicus. Nevus depigmentosus is usually Tacrolimus and pimecrolimus inhibit the activation and
a congenital lesion that is stable in shape, which grows proliferation of T cells and subsequently the production
in proportion to the child’s growth. Nevus anemicus is of cytokines, including TNF-α and IFN-γ, which have
a congenital solitary, hypopigmented lesion, which is been found to be elevated in patients with vitiligo. These
caused by a localized hypersensitivity to catecholamines agents are not atrophogenic and can therefore be applied
with resultant vasoconstriction. The lesional skin in long-term on sensitive sites such as the face, intertriginous
nevus anemicus is characterized by a normal number of regions, and genitalia. In a prospective, randomized,
melanocytes and normal amount of melanin. double-blind, placebo-controlled study38 that compared
the efficacy of topical clobetasol propionate 0.05% and
TREATMENT tacrolimus ointment 0.1% in 100 children with facial and
Adequate sun protection should be recommended for nonfacial vitiligo, clobetasol propionate and tacrolimus
children with vitiligo for the prevention of potential were found to be equally effective in both facial and
46 Childhood versus post-childhood vitiligo

nonfacial lesions, with facial lesions responding faster with TCI gives rise to concerns about the possible increased
than nonfacial ones. risk of skin carcinogenesis.
Topical pimecrolimus has been also used with good In conclusion, NB-UVB has been reported to be an
results in vitiligo lesions, especially facial ones. In an effective, safe, and well-tolerated treatment modality for
open, comparative study that compared the efficacy childhood vitiligo, with no systemic effects. Acute adverse
of topical mometasone cream versus pimecrolimus effects are mild and transient and include erythema,
cream in 40 children with localized vitiligo, the mean pruritus, and xerosis. However, long-term NB-UVB
repigmentation rate, after 3 months of treatment, was 65% therapy carries the risk for photocarcinogenesis and
in the mometasone group and 42% in the pimecrolimus photoaging.51 Therefore, NB-UVB phototherapy should
group, but the difference was not statistically significant.39 be used cautiously for periods longer than 12 months
Pimecrolimus was effective only on facial lesions. in children. In case of nonresponse after 6 months,
Side effects of TCI are not common and include transient discontinuation of treatment should be considered.
pruritus, burning sensation, and erythema. Both agents
should be used in children older than 2 years of age. They 308-nm excimer laser
also bear a black-box warning regarding a theoretical risk The 308-nm excimer laser has also been used as a targeted
of malignancy. phototherapy modality for CV. The main advantage of the
excimer laser is the selective, targeted treatment of lesional
Phototherapy skin only. Thus, the risk of adverse effects associated with
Psoralens plus ultraviolet A (PUVA) phototherapy is generalized phototherapy is reduced.42 Furthermore, the
contraindicated in children, but narrowband (311 nm) excimer laser can reach lesions located on body areas
ultraviolet B (NB-UVB) phototherapy has been exten­ hardly accessible by NB-UVB phototherapy, such as skin
sively used in CV, resulting in stabilization and folds. However, the excimer laser may fail to stabilize
repigmentation of lesions in widespread and progressive vitiligo, since unlesional skin remains untreated.
disease.40 Repigmentation may be initiated by activation, The 308-nm excimer laser is indicated for macules and
proliferation, and migration of melanocytes upward along small patches of vitiligo. In a retrospective study that
the surface of the outer root sheath to the nearby epidermis, included children with vitiligo, 50% of 40 vitiligo patches
where they form perifollicular pigmentation islands.41 treated twice weekly with the 308-nm excimer laser
Response to treatment varies among studies.42 Njoo et al., obtained an acceptable degree (>50%) of repigmentation,
in an open, uncontrolled trial,43 evaluated the efficacy and with lesions located on the face, neck, and trunk responding
safety of NB-UVB in 51 children with generalized vitiligo better to treatment. 52 Another retrospective study of
(half with skin phototypes II to III and half with skin Asian children with vitiligo demonstrated good response
phototypes IV to V) treated with twice-weekly NB-UVB in 53% of children treated with the 308-nm excimer
therapy for a maximum period of 1 year. Treatment laser.53 A synergistic effect between the excimer laser and
resulted in >75% repigmentation in 53% of children and in pimecrolimus has also been described. In a randomized,
stabilization of the disease in 80%, with limited and transient single-blinded Chinese study,54 71% of childhood vitiligo
adverse events. The best repigmentation rate was achieved in lesions treated with excimer laser twice weekly combined
lesions located on the face (72% of the lesions) and neck (74% with 1% topical pimecrolimus twice daily achieved >50%
of the lesions). In a recent retrospective study that included repigmentation, compared with 50% of lesions treated
71 Asian children with vitiligo, with skin phototypes of IV with excimer laser alone twice weekly. The excimer laser
to VI, at least 50% repigmentation rate was achieved in 74% showed excellent therapeutic results on the face and trunk,
of children treated with NB-UVB phototherapy. Children while the combined therapy was superior to single laser
with generalized vitiligo responded better (good response in treatment only for facial lesions.
62%) than those with segmental vitiligo (good response in Adverse effects of the excimer laser include mild to
44%).44 Generally, lesions on the face and neck43,45 and dark severe erythema, while pruritus and blistering might
skin phototypes (IV to V) responded better to treatment in also be observed.52–54 In case of nonresponse after 20–30
both adults and children.42–47 sessions (3–5 months of a twice-weekly treatment schedule),
NB-UVB has also been used in combination with topical different therapeutic options should be considered.
treatment. NB-UVB and TCI seem to act synergistically in
both adults48,49 and children.50 One open-label, prospective Surgical treatment
study that evaluated the combined therapy of NB-UVB Several surgical techniques that include tissue and cellular
with topical tacrolimus 0.03% ointment in children with grafts have been developed for the treatment of recalcitrant
vitiligo 4–14 years of age reported >50% repigmentation vitiligo lesions in patients with stable disease (no new or
in 60% of vitiligo patches treated with combination expanding lesions for at least 1 year) and a negative history
therapy and only in 20% of lesions treated with NB-UVB of Koebner phenomenon.
monotherapy. All patches on the face and trunk showed Skin grafting is not an ordinary treatment modality for
good to excellent response, compared to 33.3% of patches childhood vitiligo. However, several techniques, including
on the extremities.50 Despite the satisfactory results that suction blister epidermal grafting,55 noncultured cellular
have been reported, the combination therapy of NB-UVB grafting,56,57 and cultured melanocyte transplantation,58,59
 References 47

have been used in children with good results. Mottled 16. A-Refu K. Vitiligo in children: A clinical-epidemiologic
repigmentation and irregular texture of repigmented skin study in Jordan. Pediatr Dermatol. 2012;29:​114–115.
can occur. Side effects include pain, infection, and scarring. 17. Alikhan A, Felsten LM, Daly M et al. Vitiligo:
A comprehensive overview Part I. Introduction,
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2. Malhotra N, Dytoc M. The pathogenesis of vitiligo. vitiligo: A report of 8 cases. J Am Acad Dermatol.
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Pigment Cell Melanoma Res. 2012;25:E1–13. 20. Silverberg NB. Pediatric vitiligo. Pediatr Clin North
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32. Catucci Boza J, Giongo N, Machado P et al. Quality of and long-term follow-up in vitiligo patients treated
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cross-sectional study based on dermatology-specific Dermatol. 2007;56:274–278.
and disease-specific quality of life instruments. 47. Kanwar AJ, Dogra S. Narrow-band UVB for the
Dermatology. 2016;232(5):619–625. treatment of generalized vitiligo in children. Clin Exp
33. Amer AA, Mchepange UO, Gao XH et al. Hidden Dermatol. 2005;30(4):332–336.
victims of childhood vitiligo: Impact on parents’ 48. Esfandiarpour I, Ekhlasi A, Farajzadeh S et al. The
mental health and quality of life. Acta Derm Venereol. efficacy of pimecrolimus 1% cream plus narrow-band
2015;95(3):322–325. ultraviolet B in the treatment of vitiligo: A double-
34. Manzoni AP, Weber MB, Nagatomi AR et al. blind, placebo-controlled clinical trial. J Dermatolog
Assessing depression and anxiety in the caregivers Treat. 2009;20(1):14–18.
of pediatric patients with chronic skin disorders. An 49. Majid I. Does topical tacrolimus ointment enhance
Bras Dermatol. 2013;88(6):894–899. the efficacy of narrowband ultraviolet B therapy in
35. van Geel N, Speeckaert M, Chevolet I et al. vitiligo? A left-right comparison study. Photodermatol
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management of vitiligo: The European Dermatology ultraviolet B phototherapy. Pediatr Dermatol.
Forum consensus. Br J Dermatol. 2013;168(1):5–19. 2016;33(6):646–651.
37. Kwinter J, Pelletier J, Khambalia A et al. High-potency 51. Ezzedine K, Silverberg N. A practical approach to
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38. Ho N, Pope E, Weinstein M et al. A double-blind, 52. Cho S, Zheng Z, Park YK et al. The 308-nm excimer
randomized, placebo-controlled trial of topical laser: A promising device for the treatment of
tacrolimus 0.1% vs. clobetasol propionate 0.05% in childhood vitiligo. Photodermatol Photoimmunol
childhood vitiligo. Br J Dermatol. 2011;165(3):626–632. Photomed. 2011;27(1):24–29.
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2010;21(3):133–139. 54. Hui-Lan Y, Xiao-Yan H, Jian-Yong F et al.
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41. Wu CS, Yu CL, Wu CS, Lan CCE, Yu HS. Narrow- 55. Hu JJ, Xu AE, Wu XG et al. Small-sized lesions
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Am Acad Dermatol. 2009;60(3):470–477. 57. Mulekar SV, Al Eisa A, Delvi MB et al. Childhood
43. Njoo MD, Bos JD, Westerhof W. Treatment of vitiligo: A long-term study of localized vitiligo treated
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2000;42:245–253. 58. Hong WS, Hu DN, Qian GP et al. Treatment of vitiligo
44. Koh MJ, Mok ZR, Chong WS. Phototherapy for in children and adolescents by autologous cultured
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Dermatol. 2015;32(2):192–197. of efficacy to results in adults. J Eur Acad Dermatol
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C, Katsambas AD. Efficacy, predictors of response
Pharmacological therapy of vitiligo
IVANA BINIĆ and ANDRIJA STANIMIROVIĆ
8
CONTENTS
Topical therapy of vitiligo 49 Systemic therapy of vitiligo 60
Miscellaneous topical agents 52 References 64

TOPICAL THERAPY OF VITILIGO inhibitors (TCIs) may be advisable. Also, the potential for
Topical corticosteroids systemic absorption should be kept in mind and regularly
monitored, particularly in patients with head and/or neck
Topical corticosteroids (TCSs) have been applied in
locations of the disease.7
vitiligo since the1950s for their anti-inflammatory and
immunomodulating effects, and they still remain the
Calcineurin inhibitors
first-line treatment option. Implication of both cellular
and humoral immune responses in the pathogenesis of Topical tacrolimus and pimecrolimus belong to the drug
vitiligo provides a rationale for the use of corticosteroids.1 group of calcineurin inhibitors, which affects T-cell activity,
Corticosteroids might decrease disease progression, but it inhibits their activation and maturation, and decreases
should be clearly explained to the patient that the primary the production of proinflammatory cytokines. In vitro
aim of TCS is to achieve disease stability. Advantages are a experiments showed their ability to enhance melanocyte
relative low cost, ease of application, and ability for home migration and induce skin pigmentation.18
usage. Most repigmentation can be observed in the face The use of tacrolimus for vitiligo was reported for the
and neck, while the trunk, extremities, and especially the first time in 2002, particularly for skin areas where the use
hands/feet usually display only limited repigmentation.2 of potent TCS is contraindicated.19 Further studies (Table
Recent lesions have a higher tendency for repigmentation.3 8.2) have shown efficacy and good tolerability of tacrolimus
The efficacy rate between potent and ultrapotent for children with vitiligo in Asia,20 and very good response
corticosteroids seems to be similar. Topical steroids should of segmental vitiligo of head and trunk lesions.21 However,
be used only for a limited time and only in localized vitiligo another study showed that treatment of lesions on the
(less than 10% total body surface).4 body (not the face) with pimecrolimus cream 1% was not
Since the 1970s, many studies have been conducted effective in a group of adult patients.22 So, as monotherapy,
to test the efficacy of topical corticosteroids alone or in TCIs are used mainly for lesions on the head and neck both
combination with phototherapy. Furthermore, many in adults and children (Figure 8.2).
comparative studies with other topical preparations have In studies comparing tacrolimus and pimecrolimus,
also been performed. Most of these studies demonstrate some authors have found equal efficacy, 23 but others
good efficacy of topical corticosteroids, with varying have found slightly higher response rates in patients
percentages of repigmentation (Table 8.1). A recent meta- treated with tacrolimus (61%) than in those treated
analysis has confirmed their effectiveness for localized with pimecrolimus (54.6%). 24 Twice-daily application
vitiligo.5 Steroid-induced repigmentation occurs within of tacrolimus has been shown to be more effective
1–4 months of treatment both in a perifollicular pattern compared with once-daily application, 25 and occlusive
and from the lesion margins (Figure 8.1). treatment enhanced the efficacy of tacrolimus ointment
In children and adults, once-daily application of potent 0.1% beyond the face and neck in a study that included
TCS can be advised for patients with limited involvement 20 adult patients with vitiligo. 26 Ultraviolet radiation
for a period no longer than 3 months, according to a exposure during treatment with TCI may be favorable, 27
continuous treatment scheme or, better, a discontinuous but long-term safety studies are not available. The most
scheme (15 days per month for 6 months with a strict frequent side effect of topical calcineurin inhibitors is a
assessment of response based on photographs).6 Currently, burning sensation at the beginning of therapy, lasting
there are still no studies on optimal duration of TCS for 10–14 days. 28 Data on the duration of therapy, as well
therapy. Side effects include skin atrophy, telangiectasia, as on the possibilities of intermittent therapy, are not yet
and striae, which are rare if a discontinuous treatment available.6
scheme is used (e.g., 15 days of application per month). TCI can be a safer alternative to topical corticosteroids,
In the case of the occurrence of acneiform eruptions because of fewer side effects, but there is a need for longer
(especially on the face), a switch to topical calcineurin follow-up studies.

49
 50

Table 8.1 Topical corticosteroids alone or in combination in vitiligo treatment

Number of Treatment
Author/year Type of study Drug patients duration Results Side effects Observation
Pharmacological therapy of vitiligo

Kandil, 1974 (8) Randomized 0.1% betamethasone 19 4 months More lesions showed Hypertrichosis (2 patients)
controlled trial valerate in 50% isopropyl complete repigmentation Localised acneiform eruption
alcohol versus alcohol base with active product (3 patients)
Clayton, Randomized 0.05% clobetasol propionate 23 4 months Active product was All patients had skin atrophy
1977 (9) double-blind in a cream base versus significantly better, 50%
controlled trial cream base alone of patients had partial
repigmentation
Khalid et al., Randomized parallel PUVAsol versus clobetasol 50 (children) 6 months Clobetasol showed Mild atrophy (4 patients),
1995 (10) group study propionate (0.05%) bd favorable response telangiectasia, acneiform
eruption (2 patients)
Lepe et al., Randomized 0.1% tacrolimus versus 20 (children) 2 months The mean percentage of Mild atrophy (3 patients),
2003 (11) double-blind 0.05% clobetasol repigmentation for CP telangiectasia (2 patients)
trial propionate (CP) was 49.3%, and 41.3% for with CP
tacrolimus
Kumaran et al., Randomized trial Betamethasone 3 months Combined therapy showed Atrophy and lesional Combined therapy
2006 (12) dipropionate (0.05%) versus faster and more stable burning sensation were showed faster and
calcipotriol 49 (0.005%) bd repigmentation more common in BD group stable
versus betamethasone repigmentation
dipropionate (0.05%) in the with lesser
morning and calcipotriol side effects
(0.005%) in the evening
Sanclemente Randomized, 0.05% betamethasone 25 10 months Percentage of skin Mild, not a reason for Used digital
et al., 2008 matched-paired, versus topical catalase/ repigmentation discontinuation of therapy morphometry
(13) double-blind trial dismutase superoxide 18.5 ±93.14% with
betamethasone and to
12.4 ± 59% with C/DSO,
no statistical difference
(Continued)
Table 8.1 (Continued) Topical corticosteroids alone or in combination in vitiligo treatment

Number of Treatment
Author/year Type of study Drug patients duration Results Side effects Observation
Köse et al., Randomized parallel 0.1% mometasone (M-Furo) 50 (children) 3 months The mean repigmentation Some expected side effects
2010 (14) group study od versus 1% pimecrolimus rate was 65% in the were assessed such as
(Elidel) bd mometasone group and atrophy, telangiectasia and
42% in the pimecrolimus erythema in the
group mometasone group and
burning sensation and
pruritus in the
pimecrolimus group
Yaghoobi et al., Randomized parallel 0.05% CP in isopropyl alcohol 35 4 months The mean of responses in
2011 (15) group study for body and 0.1% the corticosteroid group
triamcinolone acetonide for and the zinc sulfate-
the face and flexures, used corticosteroid combination
twice daily for both groups group were 21.43% and
Oral zinc was added in the 24.7%, respectively, without
combination group statistical difference
Kathuria et al., Randomized parallel 0.1% tacrolimus bd versus 60 6 months Median repigmentation with Side effects were minimal
2012 (16) group study 0.05% fluticasone tacrolimus was 15%, and did not warrant
propionate od median repigmentation withdrawal from the study
with fluticasone propionate
was 5%
Iraji et al., Randomized, Betamethasone valerate 0.1% 88 12 weeks 26.3% had more than 50%
2017 (17) controlled study cream bd versus repigmentation in the
betamethasone valerate betamethasone valerate
0.1% cream bd and oral group and 37% in the
simvastatin 80 mg combination group, no
statistical difference
Topical therapy of vitiligo
51
52 Pharmacological therapy of vitiligo

Figure 8.1 Vitiligo lesions on elbows before and after 8 weeks twice-daily topical treatment with 0.05% clobetasole propionate
ointment.

Vitamin D analogues therapy has shown improvement in a few studies;40–42 on

Vitamin D3, or 1,25(OH)2D3, is a hormone responsible the contrary, other investigators43,44 could not find any
for regulating calcium homeostasis. It has already been such benefit when compared with phototherapy alone. The
proven that keratinocytes and melanocytes of vitiligo adverse effects due to calcipotriol are transient in the form
skin lesions show defective calcium uptake, which of mild burning and irritation of the skin, and most of the
could inhibit melanogenesis through downregulation investigators did not document them.
of tyrosinase activity. Two low calcemic synthetic
MISCELLANEOUS TOPICAL AGENTS
analogs, with accentuated antiproliferative and cell-
differentiating properties, calcipotriol and tacalcitol, Pseudocatalase
have proven their efficacy in psoriasis, with the onset of The use of creams/ointments containing pseudocatalase
perilesional hyperpigmentation during therapy. This may help in vitiligo repigmentation and in stabilizing
feature has encouraged researchers to try to evaluate the lesions (Table 8.4). Treatment is based on the
their efficacy in vitiligo, 32 used as monotherapy or in evidence that the vitiligo epidermis shows oxidative
association with ultraviolet light or corticosteroids (Table stress, which is believed to have a important role in
8.3). The exact mechanism of action is still unclear, but melanocyte degeneration. Pseudocatalase treatment
it is possible that they stimulate 1,25-dihydroxyvitamin aims to substitute low levels of catalase known to exist
D3 receptors, expressed on human melanocytes33 and in vitiliginous skin and consequently aims to degrade
possibly adjusting calcium levels. The first results were excessive hydrogen peroxide.45 Second, it aims to correct
encouraging,34 with marked repigmentation in 55.6% of abnormalities in calcium homeostasis also known to exist
children treated; in this study, calcipotriol was used as in vitiligo. NB-UVB phototherapy is used to activate the
once-daily application on all lesions for varying periods. pseudocatalase.
Later studies used mostly combination therapy. Kumaran In the first study of pseudocatalase, 33 patients46 were
et al.12 studied calcipotriol and betamethasone alone treated with pseudocatalase and calcium cream to the total
or in combination; repigmentation with the combined body surface twice-daily, followed by suberythemogenic
treatment was faster, stable, and with fewer side effects doses of UVB over 15 months. Results were encouraging;
compared to either of the treatments used as monotherapy. the first repigmentation was noted after 2–4 months
Similar results were documented by Travis et al.,35 where and the best results were observed on the face and dorsa
83% of patients responded to combination therapy with on the hands in 90% of cases. Also, disease activity was
an average of 95% repigmentation by body surface area stopped in all cases. In an uncontrolled retrospective
and the best results achieved on eyelids and facial skin study of pseudocatalase cream plus NB-UVB in 71
lesions. Some researchers have reported better results with children with generalized or segmental vitiligo, complete
calcipotriol ointment compared to cream.36 The use of cessation of vitiligo progression was seen in 70 patients:
topical vitamin D analogues and sun exposure has been more than 75% repigmentation was found in 66, with an
evaluated in several studies, but without good results,37–39 observation that the response on the hands and feet was
so this combination is not recommended, due to its lack disappointing.47 Later, several studies were conducted to
of significant efficacy and the possible carcinogenic risk confirm the usefulness of pseudocatalase as monotherapy
associated with unregulated ultraviolet (UV) exposure.38 or in combination with NB-UVB but failed to show any
The combination of calcipotriol and psoralen-ultraviolet A benefit.48–50 One study compared topical catalase/dismutase
(PUVA) or narrowband ultraviolet B (NB-UVB) in vitiligo superoxide (C/DSO) with topical corticosteroids and found
Table 8.2 Topical calcineurin inhibitors in vitiligo treatment
Number
of Treatment
Author/year Type of study Drug/aim of study patients duration Results Side effects Observations
Silverberg Randomized Assess the efficacy of 57 children ≥3 months Partial response on head and neck Two patients initially Topical tacrolimus
et al., 2004 double-blind trial topical tacrolimus (89%) and trunk and extremities experienced burning ointment is effective
(21) ointment in treatment of (63%); segmental facial vitiligo on application alternative therapy for
pediatric vitiligo had the best response rate childhood vitiligo,
particularly involving
head and neck
Kanwar et al., Prospective pilot Topical 0.03% tacrolimus 25 children 8 weeks 19 (86.4%) children showed some Side effects minimal,
2004 (20) study ointment twice daily repigmentation at the end; such as pruritus and
another 3 had no response. Of burning in three
19 children, repigmentation was patients
marked to complete in 11
(57.9%), moderate in 5 (26.3%),
and mild in 3 (15.7%)
Dawid et al., Double-blind, Pimecrolimus 1% cream vs 20 6 months Treatment with pimecrolimus In this group of adult
2006 (22) placebo controlled vehicle cream, left–right cream 1% or vehicle resulted in patients with symmetrical
study comparison no significant change in mean vitiligo, treatment of body
target lesion size. Modest lesions (except face) with
repigmentation (1–25%). No pimecrolimus cream 1%
side effects were noted with could not be shown to be
pimecrolimus at month 2 in 12 effective
of 17 patients
Radakovic Controlled, Assess the response of 15 patients 6 months Twice-daily treatment induced Tacrolimus ointment
et al., 2009 prospective, vitiligo to once- or with 40 excellent (>75%) repigmentation appears to be an effective
(25) randomized, twice-daily treatment target in two lesions, moderate treatment option for facial
observer-blinded with 0.1% tacrolimus lesions (>25–50%) and poor (1–25%) vitiligo
trial repigmentation in four lesions
each, and no response in five
lesions. Once-daily treatment
resulted in moderate
repigmentation in two lesions
and poor repigmentation in five
lesions, whereas no effect was
observed in the remaining eight
lesions. Facial lesions showed the
best response
Miscellaneous topical agents 53

(Continued)
 54

Table 8.2 (Continued) Topical calcineurin inhibitors in vitiligo treatment

Number
Pharmacological therapy of vitiligo

of Treatment
Author/year Type of study Drug/aim of study patients duration Results Side effects Observations
Xu et al., 2009 Prospective pilot Forty target lesions were 30 4 months 25 (83.3%) patients showed some Four patients initially Different sites of lesions
(29) study selected to apply 0.1% repigmentation at the end of 4 experienced burning
tacrolimus ointment twice months. The mean percentage of on application
a day repigmentation on the head and
neck was greater than that on the
trunk and extremities
Lo et al., 2010 Multicenter, To determine the efficacy 61 12 weeks At the end of treatment, all 15 adverse events
(30) open-label, and safety of topical patients showed repigmentation related to the ointment
non-comparative tacrolimus as and 45.9% of patients showed were reported. All the
study monotherapy for the more than 25% repigmentation reported adverse
treatment of face/neck events were mild
vitiligo
Shim et al., Prospective pilot Therapeutic efficacy and 4 of 9 patients achieved mild to Not double-blinded,
2013 (31) study safety of 1% pimecrolimus moderate responses after 3 treatment, duration not
cream for segmental months of treatment and controlled, small number
childhood vitiligo continued with treatment; of of patients
these four patients, three
achieved excellent response and
one achieved moderate
response, with a mean treatment
duration of 7.3 months
 Miscellaneous topical agents 55

Figure 8.2 Vitiligo lesions on the face before and after 16 weeks twice-daily topical treatment with 0.1% tacrolimus ointment.

that objective vitiligo repigmentation with topical C/DSO vitiligo showed that bimatoprost alone or in combination
at month 10 was similar to topical 0.05% betamethasone.51 with mometasone was more effective than mometasone
A very recent comparative, prospective, randomized monotherapy.56
study that included 30 patients demonstrated that the
Miscellaneous and new topical therapies for vitiligo
combination of excimer light and a topical antioxidant
hydrogel was more effective compared to excimer light Melagenina is an alcohol extract of the human placenta,
alone, especially on UV-sensitive areas.52 which has been considered for the topical treatment of
vitiligo.57 The exact mechanism of action is still unknown,
Prostaglandins but it seems to stimulate melanogenesis.58 One pilot study
Prostaglandins (PGs) are biologically active derivatives evaluated the efficacy of topical melagenina, combined
of 20 carbon atom polyunsaturated essential fatty acids with 20 minutes of infrared exposure twice daily, for
released from cell membrane phospholipids. Primary repigmentation in children with scalp vitiligo. The study
PGs are PGE2 and PGF2. PGE2 is synthesized in skin and concluded that the combination could be an efficient and
affects keratinocytes, Langerhans cells, and melanocytes, safe treatment option for vitiligo, without side effects.59
causing proliferation of melanocytes and at the same time Recently, a new formulation has been created called
influencing the responsiveness of melanocytes to neuronal Melagenina Plus, which consists of a placental extract with
stimuli.53 calcium; one study has shown efficacy in repigmentation of
The first study that used PGs in the treatment of vitiligo vitiligo lesions.60
was reported in 2002 by Parsad et al.,53 with encouraging In recent years, several studies have assessed some
results in patients with limited vitiligo with a body surface new drugs for the treatment of vitiligo. A very recent
area involvement of less than 5% (Table 8.5). In this study, study showed that the use of a topical histamine for 5
a translucent gel containing 0.5 mg/3 g (166.6 mg/g) weeks significantly reduced the size of vitiligo lesions
PGE2 was used once daily on depigmented skin. Of the and increased the melanin index by over 130%.61 It is also
24 patients included, marked to complete repigmentation important that the improvement of the melanin index did
was seen in 15, 3 patients showed moderate improvement, not correlate with disease duration. Another pilot study
and 6 patients did not respond. In another study54 that evaluated the efficacy of topical mycophenolate mofetil
included 56 patients also with stable vitiligo and body in the treatment of vitiligo.62 The authors concluded that
surface area involvement less than 5%, repigmentation this drug can be effective in some cases of vitiligo, mostly
was seen in 40 of 56 patients (71%), with mean onset at on sun-exposed areas, but its use may not be warranted
2 months. Patients with disease duration of 6 months or in cases resistant to topical steroids. The latest attempt
less repigmented best, with face and scalp responding for management of the disease is the use of topical Janus
earliest (1–1.5 months). In 8 of these 40 patients, 6 of kinase (JAK) inhibitors. In the first study, the topical
whom had lesions on the face, complete repigmentation JAK inhibitor ruxolitinib was applied as a 1.5% cream
occurred. In a study by Anbar et al., 55 latanoprost was in nine patients. A 23% improvement was reported in
found to be better than placebo and comparable with overall Vitiligo Area Scoring Index scores in all enrolled
NB-UVB treatment. In the same study, the combination patients, with better results in facial vitiligo.63 Some other
of latanoprost with NB-UVB produced significantly studies underline the importance of the use of NB-UVB
better results compared to NB-UVB monotherapy (Figure in combination with topical JAK inhibitors in order to
8.3). Recently, a randomized, double-blind, controlled achieve better results.64,65 The above-mentioned studies
study that used another PGE, bimatoprost, for nonfacial are summarized in Table 8.6.
Table 8.3 Vitamin D3 analogues in vitiligo treatment
Number of Treatment
Author/year Type of study Drug/aim of study patients duration Results Side effects Observations
Parsad et al., Prospective pilot Topical calcipotriol– 21 children 6–12 wks (3-week 75%–100% repigmentation Three patients did not Most of them were
1999 (34) study ultraviolet light (sunlight) interval) in 55.6% patients tolerate the drug repigmented by 6–12
therapy. Calcipotriol 50% repigmentation in 22.2% and complained of weeks of therapy
50 lg/g + PUVA in the patients mild irritation
evening and exposure to 0%–25% repigmentation in
sunlight the next day for 22.2% patients
10–15 minutes
Yalçın et al., Prospective Patients received 60 21 20 weeks 15 of 21 patients (71.5%) had Mild to moderate
56 Pharmacological therapy of vitiligo

2001 (42) study sessions of PUVA 3 times some degree of pruritus, irritation,
a week and 0.005% pigmentation. Of these 15 and erythema on the
topical calcipotriol twice patients, 6 (29%) had regions in which
daily excellent or good response calcipotriol had been
applied were noted
in 5 patients (24%)
Gargoom et al., Randomized, Calcipotriol twice daily 14 children 4–6 months Of treated patients, 10 One patient (5.5%) Better results obtained
2004 (36) Interventional 50 lg/g cream or (77.8%) showed developed irritation with ointment than with
study ointment for 2 wks then improvement; of cream
monthly for 4–6 mos responders, 3 (21.4%)
showed complete
resolution, 4 (28.6%)
showed 50–80%
improvement, and 3 (21.4%)
showed 30%–50%
improvement
Travis et al., Prospective Topical corticosteroid was 12 patients, 3 months 83% responded to therapy, No adverse effects This combination can
2004 (35) study applied in the morning 10 children, with an average of 95% repigment vitiligo even
and topical calcipotriene 2 adults repigmentation by body in those patients with
in the evening surface area topical corticosteroid
failure
Sarma et al., Prospective, Topical calcipotriol and 8 children 6 months Mean repigmentation 41.5, Earliest onset of
2004 (39) randomized sunlight for 15–20 min range repigmentation pigmentation at the 4th
and once daily 21%–100% week
uncontrolled
(Continued)
Table 8.3 (Continued) Vitamin D3 analogues in vitiligo treatment
Number of Treatment
Author/year Type of study Drug/aim of study patients duration Results Side effects Observations
Kumaran et al., Randomized Group I patients were 45 3 months No patient achieved excellent Degree of repigmentation
2006 (12) open-label treated with (>75%) pigmentation; was greater in the
betamethasone Marked (50% to 75%) combination group, but
dipropionate (0.05%) repigmentation was without statistical
cream twice daily. Group observed in 2 (13.3%), 1 significance
II patients were treated (6.7%), and 4 (26.7%)
with calcipotriol patients in groups I, II, and
ointment (0.005%) twice III, respectively
daily, and group III with
betamethasone
dipropionate (0.05%) in
the morning and
calcipotriol (0.005%) in
the evening
Rodríguez- Rndomized 30 min sunlight/day for Tacalcitol 32 Poor response: Tacalcitol 53% No statistical difference
Martín et al., double blind 4 months+/−topical Control 32 Control 31% found between the
2009 (37) tacalcitol once daily >25% of lesional combination of tacalcitol
repigmentation and sunlight versus
Tacalcitol: none placebo and sunlight
Control: 16%
Leone et al., Randomize open NB_UVB twice a week 32 with paired 6 months Repigmentation score:
2006 (43) label +/−topical tacalcitol lesions Combination 2,4
ointment once daily NB-UVB: 1,2
Score 0: none, 1: <50%,
2: >50%
Baysal et al., Randomized PUVA twice a week +/− 18 with paired Repigmentation rate on No statistical significance
2003 (44) placebo- topical calcipotriol twice lesions trunk: was found between
controlled a day Combination 77% combination calcipotriol
PUVA monoth: 78% and PUVA versus PUVA
Acral region: alone
Combination 23%
PUVA: 23%
Extremities:
Combination 78%
PUVA: 77%
Miscellaneous topical agents 57
Table 8.4 Topical pseudocatalase in vitiligo treatment
Number of Treatment
Author/year Type of study Drug patients duration Results Side effects Observation
Schallreuter Retrospective study Pseudocatalase PC-KUS 71 children 12 months More than 75% No adverse
et al., 2008 (47) twice daily to the entire repigmentation was side effects
body surface, followed by achieved in 66 of 71
58 Pharmacological therapy of vitiligo

NB-UV-B irradiation patients on the face/neck,

48 of 61 on the trunk, and
40 of 55 on the
extremities
Yuksel et al., Randomized placebo NB UVB + topical 30 6 months >75% repigmentation None There was no statistically
2009 (48) controlled formulation including NB-UVB: 0% significant difference
Cucumis melo superoxide Combination: 2.8% according to healing
dismutase and catalase >50% repigmentation percentages between the
(Vitix®) versus NB UVB NB-UVB 9.5% two groups
alone Combination: 19%
Sanclemente Randomized, matched Topical 0.05% 25 (paired 10 months Catalase/dismutase Mild with
et al., 2008 (51) paired study betamethasone versus lesions) superoxide 12% corticosteroids
topical catalase/ Betamethasone 19%, no
dismutase superoxide statistical difference
twice a day
Bakis-Petsoglou Double-blind, placebo- Pseudocatalase cream/ 32 24 weeks Pseudocatalase cream No side effects
et al., 2009 (49) controlled, randomized placebo twice daily does not appear to add
NB UVB three times a week any incremental benefit
to NB-UVB alone
Naini et al., Pilot randomized, Pseudocatalase cream/ 23 6 months There were no significant
2012 (50) double-blind, placebo twice daily (46 changes in lesion area
placebo-ontrolled 30 min sun exposure daily symmetrical and no perifollicular
lesions) pigmentation in each
group
Table 8.5 Prostaglandins in vitiligo treatment
Number of Treatment
Author/year Type of study Drug patients duration Results Side effects Observation
Parsad et al., Nonrandomized, PGE2 24 6 months 15 patients had moderate to Not shown
2002 (53) uncontrolled Topicaly, 1 × day marked repigmentation
(50%–70%)
Kapoor et al., Nonrandomized, Translucent PGE2 (0.25 mg g−1) 56 6 months Repigmentation in 40 (71%) In 18%, mainly a transient
2009 (54) uncontrolled gel twice daily patients, with mean onset at burning sensation
2 months especially on the lips
Anbar et al., Randomized, Three groups of patients 22 3 months 1. Better than placebo No observed side effects Follow-up 6
2014 (55) controlled 1. Latanoprost (LP)/placebo 2. Equal with NB-UVB months after
2. LP/NB-UVB 3. Better in combination termination of
3. LP + NB-UVB/ NB-UVB therapy
Grimes, 2016 Randomized, double- Three groups of patients: 32 20 weeks Bimatoprost plus No side effects
(56) blind, controlled 1. Bimatoprost monotherapy mometasone group had the
study 2. Bimatoprost + mometasone maximum repigmentation
3. Mometasone + placebo
Miscellaneous topical agents 59
60 Pharmacological therapy of vitiligo

Figure 8.3 Vitiligo lesions on the dorsal side of the hands before and after 8 weeks topical treatment with 0.005% latanoprost
solution twice-daily, combined with UVB 311-nm phototherapy three times weekly.

SYSTEMIC THERAPY OF VITILIGO the disease in 100% of patients, and it also induced rapid
Systemic corticosteroids repigmentation. However, caution is warranted for long-
term side effects when combining UVB with systemic
Oral steroids are occasionally used in the treatment of fast-
immunosuppressants.70 In a retrospective study by
spreading adult vitiligo in an attempt to halt the spread
Kanwar et al., in 408 (91.8%) out of 444 patients, arrest of
of the disease (Table 8.7). Mostly, oral corticosteroids are
disease activity was achieved with low dose oral minipulse
administered as minipulse therapy. This mode of therapy
dexamethasone therapy, and the time needed for this varied
refers to intermittent use of moderate or large doses of
from 12 to 24 weeks.71 A randomized study comparing the
corticosteroids in order to enhance their therapeutic
effectiveness of dexamethasone oral minipulse therapy versus
efficacy—and at the same time reduce their side effects.
oral minocycline in patients with active vitiligo vulgaris
The first reported study was from India, with oral
showed that both drugs were effective in managing the arrest
minipulse (OMP) of moderate doses of betamethasone/
of disease activity.72 A very recent randomized controlled
dexamethasone 5 mg on two consecutive days a week until
trial aimed to evaluate the role of systemic steroid therapy
adequate response was achieved.66 Within 1–3 months, in
and phototherapy in stable vitiligo; patients were divided
89% of patients with progressive vitiligo, spreading of the
into three groups: combined oral minipulses of prednisolone
disease was stopped. The percentage of repigmentation
and NB-UVB, minipulses alone, and NB-UVB alone.73
varied a lot between patients, ranging from <10% to 90%.
The authors concluded that both combination therapy and
Another study used a daily dosing schedule of prednisolone
NB-UVB were superior to oral minipulses of steroids alone
for 4 months with an initial dose of 0.3 mg/kg body weight
and suggested that adding steroid pulses to phototherapy can
daily for the first 2 months, then halved in the third month,
maintain success for a longer period.
and again halved in the final, fourth month.67 The results
showed arrested progression of vitiligo and repigmentation Systemic immunosuppressive treatments
in 87.7% and 70.4% of patients, respectively. Statistical Systemic immunosuppressants are rarely used in vitiligo
significance was noted in patients under 15 years of age, therapy and there are some anecdotal reports on a
male patients, and patients with a disease duration of less small number of patients or case reports (Table 8.8).
than 2 years. Side effects were minimal and did not affect Cyclophosphamide74 and cyclosporine75 have been studied,
the treatment. In another study, dexamethasone minipulses but there is not enough evidence of their effectiveness. Also,
of 10 mg daily on two consecutive days per week up to 24 the potential side effects of these agents can be serious and
weeks were used. The authors concluded that this kind of do not justify their use in vitiligo.6 Methotrexate has also
treatment was effective in arresting progression of vitiligo, been used in a number of small studies with limited success.
but failed to induce satisfactory repigmentation.68 Side The doses used ranged from 7.5 to 25 mg per week and the
effects (weight gain, insomnia, agitation, acne, menstrual treatment was given for 3–16 months. It is important to
disturbances, and hypertrichosis) were observed in 69% of note that no side effects were reported and the drug was
patients. well tolerated.76–78 One study compared the efficacy of oral
More recent studies have explored the efficacy of systemic minipulses of dexamethasone (5 mg per week with 2.5 mg
steroids in combination with phototherapy, both the taken on two consecutive days) to that of methotrexate
combination of intravenous prednisolone and psoralen (10 mg per week); after 6 months of treatment, both group
ultraviolet A69 and oral methylprednisolone (MPD) mini­ of patients had similar reduction in vitiligo disease activity
pulse therapy combined with narrowband UVB.70 The latter score, and the investigators concluded that both drugs were
combination was effective in stopping the progression of equally effective in controlling the activity of the disease.79
Table 8.6 Miscellaneous and new topical therapies for vitiligo
Number of Treatment
Author/year Type of study Drug patients duration Results Side effects Observation
Xu et al., 2004 Nonrandomized, Melagenina + 20 minutes 22 (children) 2 × 3 months 18.2% full repigmenation, None
(59) uncontrolled Infrared exposure twice 8.2% no response
daily
Liu et al., 2017 Nonrandomized, Topical histamine/placebo 23 (children 5 weeks Melanin index increased by Mild erythema and
(61) uncontrolled and adults) over 130%, histamin pruritus occurred in
significantly reduced lesion 8 patients
size
Handjani et al., Nonrandomized Topical 15% 30 3 months 36.6% (n = 11) of the patients None
2017 (62) uncontrolled Mycophenolate mofetil showed 25% repigmentation
Rothstein et al., Open-label, proof-of- Topical ruxolitinib 1.5% 12 20 weeks 23% improvement in overall Minor, including
2017 (63) concept trial Vitiligo Area Scoring Index erythema,
scores were observed in all hyperpigmentation,
enrolled patients and transient acne
Systemic therapy of vitiligo 61
Table 8.7 Systemic corticosteroid therapy for vitiligo
Number of
Author/year Type of study Drug patients Treatment duration Results Side effects Observation
Paricha et al., Prospective, open 5 mg oral betamethasone/ 40 (children and As long as the Within 1–3 months, in 89% Weight gain, mild Extensive and/or
1993 (66) label trial dexamethasone /day adults) adequate response of patients with active headache, general rapidly
2d/week was achieved (>2 disease, the progression weekness, bad spreading
years) was stopped. Rate of taste in the mouth vitiligo
62 Pharmacological therapy of vitiligo

repigmentation varied
from <10% to 90%
Kim et al., 1999 Prospective, open Oral prednisolone 81 (children and 4 months Arrested progression of Minimal, did not
(67) label trial (0.3 mg/kg body weight) adults) vitiligo and affect the course of
daily (2 months), halved repigmentation were treatment
(3rd month) halved noted in 87.7% and 70.4%
(4th month) of patients, respectively
Radakovic-Fijan Prospective, open 10 mg oral 29 24 weeks Disease activity was 20 (69%) of patients:
et al., 2001 (68) label trial dexamethasone/day arrested in 88% of weight gain,
2d/week patients. No effect on insomnia, acne,
repigmentation agitation,
menstrual
disturbance, and
hypertrichosis
Kanwar et al., Retrospective 2.5 mg oral 444 Until the arrest of In 408 (91.8%) of patients, In 41(9.2%) of
2013 (71) dexamethasone/day disease activity arrest of disease activity patients: weight
2d/week (maximum 6 was achieved gain, bloated
months) appearance, gastric
upset, lethargy
acne, and joint
pains
El Mofty et al., Prospective, Group A: 30 mg 45 3 months Patients showing None Follow-up for
2016 (73) randomized, prednisolone daily, improvement 6 months
controlled 2d/week+ NB-UVB Group A: 100%
Group B: Prednisolone Group B: 33.33%
Group C: NB-UVB Group C: 100%
Table 8.8 Systemic immunosuppressive treatments for vitiligo
Number of Treatment
Author/year Type of study Drug patients duration Results Side effects Observation
Sandra et al., Case report Methotrexate 1 3 months Stopping the None
1998 (76) 7.5 mg/week appearance of new
lesions
Alghamdi et al., Pilot prospective Methotrexate 25 mg/week 6 6 months No change in vitiligo None
2013 (77) lesions
Garza-Mayers Case series Methotrexate 3 11–16 months Clinically significant None
et al., 2017 (78) 12.5–25 mg/week skin repigmentation
Singh et al., Prospective Group 1: 10 mg 52 24 weeks Similar reduction in 4% in I group (nausea)
2015 (79) randomized open methotrexate/week the vitiligo disease 5% in II group (weight
label Group 2: OMP activity score gain, acne)
dexamethasone
2.5 mg on 2 consecutive
days/week
Radmanesh Prospective Group 1: azathioprine 60 4 months The mean total None
et al., 2006 (80) randomized (0.6–0.75 mg/kg) + PUVA repigmentation rate
Group 2: PUVA was 58.4% for group 1
and 24.8% for group 2
Systemic therapy of vitiligo 63
64 Pharmacological therapy of vitiligo

Figure 8.4 Vitiligo lesions on the neck before and after 8 weeks of therapy with perorally Polypodium leucotomos 240 mg per day
combined with UVB 311-nm phototherapy twice weekly.

Azathioprine has also been used in combination with agent, significantly improved the repigmentation rates
oral PUVA, in a study that compared this combination in the head and neck area when used in association with
versus PUVA therapy alone.80 The conclusion was that NB-UVB (Figure 8.4).92
azathioprine may potentiate the repigmentary effects of
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41. Leone G, Pacifico A, Iacovelli P, Paro Vidolin A, 54. Kapoor R, Phiske MM, Jerajani HR. Evaluation of
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in vitiligo? J Eur Acad Dermatol Venereol. 59. Xu AE, Wei XD. Topical melagenine for repigmentation
2003;17:299–302. in twenty-two child patients with vitiligo on the scalp.
45. Schallreuter KU, Wood JM, Berger J. Low catalase Chin Med J (Engl). 2004;117:199–201.
levels in the epidermis of patients with vitiligo. J 60. Miyares CM, Hollands Barca I, Miyares Diaz E,
Invest Dermatol. 1991;97:1081–1085. Pernas González A. Effectiveness of human placental
46. Schallreuter KU, Wood JM, Lemke KR, Levenig extract with calcium (Melagenina Plus) for the
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with short-term UVB exposure: A case study on 33 61. Liu J, Xu Y, Lin TK, Lv C, Elias PM, Man MQ. Topical
patients. Dermatology. 1995;190:223–229. histamine stimulates repigmentation of nonsegmental
47. Schallreuter KU, Krüger C, Würfel BA, Panske A, vitiligo by a receptor-dependent mechanism. Skin
Wood JM. From basic research to the bedside: Efficacy Pharmacol Physiol. 2017;30:139–145.
of topical treatment with pseudocatalase PC-KUS in 71 62. Handjani F, Aghaei S, Moezzi I, Saki N. Topical
children with vitiligo. Int J Dermatol. 2008;47:743–753. mycophenolate mofetil in the treatment of vitiligo: A
48. Yuksel EP, Aydin F, Senturk N, Canturk T, Turanli AY. pilot study. Dermatol Pract Concept. 2017;7:31–33.
Comparison of the efficacy of narrow band ultraviolet 63. Rothstein B, Joshipura D, Saraiya A et al.
B and narrow band ultraviolet B plus topical catalase- Treatment of vitiligo with the topical Janus kinase
superoxide dismutase treatment in vitiligo patients. inhibitor ruxolitinib. J Am Acad Dermatol. 2017;76:​
Eur J Dermatol. 2009;19:341–344. 1054–1060.e1.
49. Bakis-Petsoglou S, Le Guay JL, Wittal R. A 64. Joshipura D, Alomran A, Zancanaro P, Rosmarin D.
randomized, double-blinded, placebo-controlled Treatment of vitiligo with the topical Janus kinase
trial of pseudocatalase cream and narrowband inhibitor ruxolitinib: A 32-week open-label extension
ultraviolet B in the treatment of vitiligo. Br J study with optional narrow-band ultraviolet B. J Am
Dermatol. 2009;161:910–917. Acad Dermatol. 2018;78:1205–1207.e1.
50. Naini FF, Shooshtari AV, Ebrahimi B, Molaei R. The 65. Joshipura D, Plotnikova N, Goldminz A et al.
effect of pseudocatalase/superoxide dismutase in the Importance of light in the treatment of vitiligo with
treatment of vitiligo: A pilot study. J Res Pharm Pract. JAK-inhibitors. J Dermatolog Treat. 2018;29:98–99.
2012;1:77–80. 66. Pasricha JS, Khaitan BK. Oral mini-pulse therapy
51. Sanclemente G, Garcia JJ, Zuleta JJ, Diehl C, Correa with betamethasone in vitiligo patients having
C, Falabella R. A double-blind, randomized trial of extensive or fast-spreading disease. Int J Dermatol.
0.05% betamethasone vs. topical catalase/dismutase 1993;32:753–757.
superoxide in vitiligo. J Eur Acad Dermatol Venereol. 67. Kim SM, Lee HS, Hann SK. The efficacy of low-
2008;22:1359–1364. dose oral corticosteroids in the treatment of vitiligo
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antioxidant versus excimer light alone for treatment H, Tanew A. Oral dexamethasone pulse treatment for
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69. Lee Y, Seo YJ, Lee JH, Park JK. High-dose prednisolone enhanced repigmentation in vitiligo patients. J
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in 36 patients with vitiligo. Clin Exp Dermatol. 81. Kim NH, Torchia D, Rouhani P, Roberts B,
2007;32:499–501. Romanelli P. Tumor necrosis factor-α in vitiligo:
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pulse therapy combined with narrow-band UVB 82. Webb KC, Tung R, Winterfield LS et al. Tumour
in non-segmental Vitiligo. Dermatology. 2016;​ necrosis factor-α inhibition can stabilize disease in
232(2):224–229. progressive vitiligo. Br J Dermatol. 2015;​173:641–650.
71. Kanwar AJ, Mahajan R, Parsad D. Low-dose oral 83. Rigopoulos D, Gregoriou S, Larios G, Moustou E,
mini-pulse dexamethasone therapy in progressive Belayeva-Karatza E, Kalogeromitros D. Etanercept
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72. Singh A, Kanwar AJ, Parsad D, Mahajan R. 84. Alghamdi KM, Khurrum H, Taieb A, Ezzedine K.
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active vitiligo vulgaris. Indian J Dermatol Venereol of vitiligo and new onset of halo naevi observed in
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73. El Mofty M, Essmat S, Youssef R et al. The role of 2013;26:370–372.
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of stable vitiligo: A randomized controlled trial. of vitiligo and onset of new psoriasiform dermatitis
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universalis: Role of melanocyte density, disease 87. Craiglow BG, King BA. Tofacitinib citrate for the
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75. Pardue SL, Fite KV, Bengston L, Lamont SJ, Boyle 88. Vu M, Heyes C, Robertson SJ, Varigos GA, Ross G.
ML 3rd, Smyth JR Jr. Enhanced integumental and Oral tofacitinib: A promising treatment in atopic
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77. Alghamdi K, Khurrum H. Methotrexate for the biloba for the treatment of vitilgo vulgaris: An open
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Surgical treatment of vitiligo
MUHAMMED RAZMI T., T. P. AFRA, and DAVINDER PARSAD
9
CONTENTS
Introduction 69 Conclusion 76
Patient selection 69 Acknowledgments 76
Recipient area preparation 69 References 76
Types of vitiligo surgery 69

INTRODUCTION lesions are preferred for tissue grafts, and those with
Vitiligo is the most common acquired depigmentation larger lesions are preferred for cellular grafts. Patients
disorder, with a reported worldwide prevalence of around with unrealistic expectations should be properly
2%. Cosmetically disfiguring depigmented patches counseled regarding surgical outcomes, including the
due to the loss of melanocytes cause great concern and possibility of a failed surgery.
psychological distress to affected patients.1 While medical
modalities address the stabilization of the patches followed RECIPIENT AREA PREPARATION
by repigmentation, surgical modalities may need to be Various methods of recipient area preparation have
employed to those patches that do not repigment with been described in the literature. These include the use
medical modalities. Inadequate residual melanocytes of liquid nitrogen, mechanical dermabrasion, diathermy
or inducible stem cells may be the reasons for lack of or chemical peeling–assisted dermabrasion, suction
repigmentation even after attaining stability. In vitiligo blisters, psoralen plus ultraviolet A (PUVA), and CO2
surgery, such resistant achromic patches are supplied and Er:YAG lasers. Lasers are very versatile and offer
with melanocytes or, recently, with additional melanocyte a precise depth of recipient bed at the cost of increase
precursors. Here, we highlight the different aspects of in expense. Mechanical dermabrasion devices are less
vitiligo surgery, including patient selection, recipient area costly and simpler to use, but may result in scarring with
preparation, and methodology of various types of vitiligo inexperienced hands. PUVA, suction blister, and liquid
surgery. nitrogen–based recipient area preparation increase the
procedural time for the surgery since it takes some time
PATIENT SELECTION to prepare the recipient bed.
Patient selection is an important aspect of successful Laser devices are largely used in resource-rich settings,
vitiligo surgery. Currently, a patch with at least 1 year and manual dermabrasion methods are commonly used in
lesional stability is best suited for a surgical intervention. 2 resource-poor settings. Acral skin and the skin previously
A minigraft test prior to the proposed surgery will help exposed to phototherapy are difficult to dermabrade. Local
to rule out microscopic lesional activity of the disease. infiltrative anesthesia is commonly used for the procedure.
Amelanotic lesions with sharp borders are best suited for General or regional anesthesia can be used for the surgery
surgery compared to hypopigmented lesions with poorly of large extensive patches or in the pediatric population.
defined borders. Regarding the type of vitiligo, segmental
vitiligo yields better repigmentation, followed by focal TYPES OF VITILIGO SURGERY
and common vitiligo, with acrofacial types giving a Different types of vitiligo surgery have been tabulated in
poorer repigmentation outcome. Repigmentation of Table 9.1. Tissue-based methods were the initial choices
lesions over hairy regions is better compared to lesions of surgery. Nowadays, cellular methods, especially
on nonhairy regions. Koebner sites like bony areas, noncultured epidermal cell suspensions, are increasingly
flexures, and eyelids also respond poorly. With the used for the surgery.
advent of cellular transplantation and combination
Tissue grafts
therapies, the definition of acral sites is being shifted
more distally, with acceptable repigmentation outcome The source of melanocytes here is epidermal-dermal
achieved nowadays proximal to the proximal phalanges. punches, ultrathin skin sheets, the epidermal roof
Even though the repigmentation outcome is good even in of a blister, and hair follicles. There will not be much
children, it’s prudent to wait until they become mature augmentation of donor-to-recipient area factor, but the
enough to endure the pain of the procedure and follow expected repigmentation is denser and diffuse compared
the postprocedure instructions. Patients with smaller to cellular transplantation methods. Postoperative

69
Table 9.1 Vitiligo surgery techniques
Method Efficacya Advantages Disadvantages
Tissue Grafts Full-Thickness Punch Varies from 50%–100% RP in Inexpensive. Cannot be expanded. Limited use in the
Grafts, 198327 38%–74.5% of patients in Easy to perform. Minimal equipment. treatment of large areas. Cosmetic
(mini-punch grafts) various studies28,29 Suitable for difficult locations such as complications like color mismatch,
the lips, palms, soles, and fingers.30,31 cobblestoning, speckled appearance,
and donor site scarring.29,31,32
Split-Thickness Skin Flip-Top Grafts, 19995 Rate of RP is 78%–91% 6,33–35 High rate of RP. Suitable for multiple or Requires a high degree of skill and
Grafts large areas and difficult areas, such as dexterity. Cosmetic damage to the
70 Surgical treatment of vitiligo

Theirsch-Ollier Seed/Smash the eyelid, inner canthus of the eyes, recipient and donor areas in case of
(0.125–0.275 mm Grafts, 20126 areola, nipples, and genitals. The donor thick grafts. Temporary milia-like cysts,
thick), 19733 site can be reused for subsequent partial loss of graft, and thick margins
or grafts.36 at the recipient site.33 Donor site
Ultrathin (0.08– scarring and hypopigmentation (less
0.15 mm thick), with ultrathin grafts). Not suitable for
19934 palms, soles, body folds, and
nonkeratinized mucosa.
Suction Blister Grafts, 1971,37 198838 50%–100% RP9 Safe, effective, easy, and inexpensive Time-consuming and painful procedure.
technique. Fast and uniform Cannot be expanded. Limited use in
repigmentation. No risk of scarring at the treatment of large areas and areas
the donor site, and donor sites can be such as the palms, soles, and body
used more than once. Suitable for folds. Repigmentation results are
difficult areas such as the eyelids, lips, inferior to split-thickness grafts and
and bony prominences. noncultured epidermal cell
suspensions.39 Cosmetic complications
are temporary hyperpigmentation of
the donor site and perigraft halo.40
Hair Follicle Tissue RP in 70% of grafts with a Suitable in hair-bearing areas and Cannot be expanded. Limited use in the
Grafts, 199841 mean diameter of patches with leukotrichia. treatment of large areas and non-hair-
repigmentation of 5 mm42 bearing areas. Scarring of the donor
site is common.
Cellular Cultured Grafts Cultured RP rate similar to noncultured Cover 100- to 500-fold the surface area Requires significantly greater resources
Grafts Epidermal epidermal of the original donor site. in terms of procedure cost, equipment,
Cellular Transplantation (more than and skilled personnel hours.
Suspensions, 198943,44 70%)10 Failure of the culture procedure.
Cultured 50%–90% RP46 Requires significantly less culture
Melanocyte medium and flasks, so less expense.
Cellular Being a cellular suspension, can be
Suspensions, 198745 used in the treatment of difficult areas,
such as irregularly shaped surfaces.
(Continued)
Table 9.1 (Continued) Vitiligo surgery techniques
Method Efficacya Advantages Disadvantages
Noncultured Grafts Noncultured, 48
RP rates varies from 69% to Five- to 10-fold greater surface area than Taking an ideal graft from donor site
Epidermal more than 95%49 the donor site can be treated. Can be requires skill and dexterity.
Cellular used on difficult-to-treat areas Specialized laboratory equipment and
Suspensions including the hands, feet, extensor trained personnel are needed. Not
(NCES), 199247 surfaces, eyelids, and genitalia with suitable for the palms and soles.
good results and color matching.50 Risk
of scarring at the donor site is low.
Noncultured RP outcomes inferior to Hair follicle–derived melanocytes are Though theoretically superior to
Outer Root noncultured epidermal more resistant to future noncultured epidermal grafts, studies
Sheath Hair suspension grafts17 depigmentation and are more have not shown similar results.
Follicle numerous compared to epidermal-
Suspensions derived melanocytes.
(NCORSHFS or FCS), 200915
Nongrafting Therapeutic Wounding RP rate is inferior to grafting No specialized training or supplies Limited efficacy, with similar or greater
Surgical techniques51 needed. risks of scarring in comparison to other
Techniques Improved efficacy with concomitant techniques.
photo/chemotherapy, use of
5-fluorouracil with an erbium
YAG-laser.52
Local Excision A quick technique for correcting a small Suboptimal cosmetic outcome such as
area of depigmentation if located in a anatomic deformation, persistent nerve
cosmetically acceptable location. injury, koebnerization, keloid
formation, dehiscence, or infection.
Micropigmentation A rapid method for providing persistent Risk of vitiligo reactivation, infection, the
camouflage that is recalcitrant to future pigment can occasionally induce
depigmentation by underlying vitiligo. phototoxic reactions, granuloma
formation, loss of hair, and keloid
formation.
a The reported efficacy is not directly comparable owing to differences in outcome measures and study design. RP, repigmentation.
Types of vitiligo surgery 71
72 Surgical treatment of vitiligo

immobilization plays an important role in the success of 1 week. The success of the graft can be ascertained by
surgery, which limits patient convenience. observing the pigmentation through the depigmented
epidermal hinge. Smash grafting, 6 a modification of
a. Split-thickness skin grafts: Here, a thin skin graft is har-
split-thickness grafting, cuts down split-thickness
vested using a skin-harvesting knife and transplanted
grafts into tiny pieces using scissors and transplants
over denuded recipient skin (Figure 9.1). If meshing
these pieces admixed with normal saline as a semisolid
is not done, the donor skin should be 10%–25% larger
preparation over the recipient dermal bed. Even though
than the recipient area owing to the dermal elastin con-
it is simple to perform and can cover a larger area than
tracture. A rapid and uniform repigmentation can be
ultrathin grafts, evidence for its efficacy is poor.
achieved with this method, but temporary milia-like
b. Mini-punch graft: Grafts are harvested from the donor
cysts, a partial loss of graft, and thick graft margins or
area (gluteal region) with the help of biopsy punches
scarring at the donor area are a possibility as well as a
and transplanted to the pits created in the recipient
lack of donor-to-recipient ratio augmentation. Behl3 has
depigmented patches (Figure 9.2). Punches measuring
demonstrated repigmentation of vitiligo patches with
1–3 mm in diameter can be placed at 5–10 mm gaps
autologous thin Thiersch’s grafts of 0.1–0.2 mm thick-
(dark skin) or 3–5 mm gaps (light skin) because of the
ness. Ultrathin skin grafts4 of 0.08–0.15 mm thickness
differential melanosome properties.7 The punches are
have now become the preferred tissue source for mela-
secured with tape dressing and removed after 1–2 weeks.
nocytes. For a successful outcome, Thiersch’s grafts of
The melanocytes in the donor punches start migrating
0.1–0.2 mm thickness should be engrafted to the recipi-
horizontally to the surrounding depigmented skin with
ent area, unlike ultrathin grafts, which are detached
the resultant production and transfer of melanin to the
from the recipient bed by 1–2 weeks after transferring
keratinocytes.8 Repigmentation starts by 3 weeks and an
melanocytes. Plucking or chemical epilation before sur-
adequate outcome can be expected by 4–6 months.
gery avoids graft lift-off after split-thickness grafting on
  Cobblestoning is a common adverse effect that can be
hair-bearing vitiligo patches.
prevented by adjusting the donor-to-recipient punch
  Various modifications of split-thickness grafts have
height-to-depth ratio by trimming excess fat in the
been proposed. In flip top grafting, 5 small pieces of
donor punch or creating deeper punches in the recipient
split-thickness grafts are placed under a hinge of raised
area. This is the simplest and cheapest method of vitiligo
epidermal flaps, which act as a natural dressing. The
surgery and can be done under any setting.
borders of the hinge are secured with cyanoacrylate glue,
c. Suction blister epidermal grafting: Epidermal roofs raised
and a transparent dressing is placed that is removed after
by applying negative pressure (300–500 mmHg) on the
pigmented donor skin are transected and transplanted
to the recipient de-epithelialized skin (Figure 9.3). Since
the blisters are raised above the lamina lucida level,
scarring at the recipient site is not a possibility. Dressings
are removed on day 7. Grafts may detach by this time
or some days later; however, the melanocytes will be
transferred from the donor epidermis to the recipient
bed. The patient should be well informed prior to surgery
to avoid erroneous interpretation of this as a graft failure
by the patient.
  Suction can be applied using a syringe attached to
a 50-cc syringe through a three-way rubber tubing
system, an oil rotary vacuum connected to a manometer,
or a manual suction unit with transparent plastic cups.
A modified suction-blister device has recently been
introduced to raise multiple blisters simultaneously.9 It
takes at least 3 hours to form a suction blister, or longer
Figure 9.1 Method of skin harvesting using straight artery during the winter. Injecting warm saline to the donor
forceps and disposable shaving blade. It is a common step in bed, use of a heat lamp or hair dryer, or placing blisters
split-thickness skin grafting as well as cultured and noncultured over bony prominences may hasten blister formation.
cellular transplantation. Applying petroleum jelly, using field Too much negative pressure that results in hemorrhagic
block anesthesia, and stretching the skin away and laterally blistering should be avoided to get “nonstressed”
from the donor area will help to get a uniform ultrathin graft. melanocytes. It is a simple office-based procedure with
Thinness of the graft can be ascertained by its ability to float minimal adverse effects and rapid repigmentation
in normal saline, ability to read the letters on the blade due to outcome. However, increased procedural time for the
its translucency, and absence of shrinking of the tissue (dermal initial blister raising, learning curve for final placement
elastin contraction). (Courtesy of Dr Rajsmita Bhattacharjee, of thin epidermal grafts, and a lower donor-to-recipient
MD, DNB.) augmentation are the limitations.
 Types of vitiligo surgery 73

Figure 9.2 Method of mini-punch grafting and repigmentation outcome. (a) Recipient area being punched to receive the donor
tissue. (b) Engrafted tissue punches at day 8. (c) Completely depigmented recipient area has now become partially pigmented at third
month due to melanocyte-melanin transfer from the grafted tissues. (Courtesy of Dr Amit Dalla, MBBS.)

Figure 9.3 Method of suction blister epidermal grafting. (a) Syringe with tubing and three-way cannula system to create a
negative suction pressure using 50-cc syringe. (b) Development of minute vesicles (after 2 hours) that later coalesce to form a single
large blister. Blister roofs will be detached at their peripherally attached borders using corneal scissors and placed on a glass slide
with their dermal side facing upward. Attached minimal dermal fibers will be scored and removed. The blister roof will now be placed
carefully on the dermabraded recipient bed by sandwiching the epidermal graft between the recipient bed and glass slide.

d. Hair follicle transplantation: Here, hair follicles including harvesting of skin, similar to ultrathin grafting, which is
the hair bulb are harvested either using the strip or later trypsinized using 0.25% trypsin-EDTA solution.
follicular unit extraction method, then punched into the
1. Cultured cellular grafts
recipient dermal bed. Since hair follicles contain various
a. Autologous, cultured epidermal cellular grafts:
immature melanocytes, stem cells, and melanocytes with
Keratinocytes and melanocytes obtained after
superior melanogenic properties and different antigen
trypsinization of tissue grafts are later cultured in
expression (compared to epidermal melanocytes), it
vitro for 15–30 days to produce large epidermal sheets
appears to be a good option for refractory vitiligo. A
expanding more than 100–500 times that of donor
mean diameter of repigmentation up to 5 mm has been
tissue. Once adequate cell lines have been achieved,
achieved with this method. This method is especially
the epidermal sheets are detached from the culture
useful for patches with leukotrichia.
plates using dispase and shrunk to half to two-
thirds of their original culture size. This shrinkage
Cellular transplantation increases the concentration of melanocytes per area
Individual cells from a tissue are transplanted to the of cultured sheets to 1000–2000 cells/mm2. Since
recipient depigmented patch in this method. It may be either the culture sheets are often fragile, these are made
a cultured or noncultured process. Both processes involve into cell suspensions before transplanting into the
74 Surgical treatment of vitiligo

recipient site. A recent study comparing cultured vs.

noncultured melanocyte transfer has documented a
similar repigmentation outcome.10
b. Autologous, cultured melanocyte grafts: Unlike
cultured epidermal cellular grafts, a pure isolate
of melanocyte population will be cultured to yield
cultured melanocyte grafts. During the culturing
process as described above, calcium is added to
remove keratinocytes and genticin is added to
remove fibroblasts.
  Cultured cellular grafting requires a sophisticated
laboratory setup, skilled personnel, and a 3-week
period for cell expansion. Even though the use of
12-tetradecanoylphorbol 13 acetate (TPA), a tumor
promoter, has been discarded nowadays, the use of
xenobiotics and growth factors still poses a concern
regarding its safety. However, no serious adverse
effects have been reported with the use of cultured
Figure 9.4 Method of noncultured epidermal cell
cellular grafts since their inception 25 years ago.
suspension preparation using a four-compartment technique.
2. Noncultured cellular grafts
Harvested ultrathin graft will be placed on the first chamber
a. Autologous noncultured epidermal cell suspension
containing trypsin-EDTA solution for 90 minutes under 37°C.
(NCES): In the noncultured epidermal cell suspen-
Excess trypsin is washed off using phosphate-buffered saline
sion method, individual melanocytes and keratino-
(PBS) in second and third chamber. An adequate amount of PBS
cytes are transplanted to the recipient de-epithelized
(based on recipient area size) is added to the fourth chamber
area concurrently, thus circumventing the costly
and dermal (left-hand side in the image) and epidermal (right-
and time-consuming step of culturing the cells. It
hand side in the image) sides of the graft will be separated
has similar repigmentation outcome to that of tis-
using forceps. Attached melanocytes from the dermal side will
sue grafts, with a donor-to-recipient augmentation
be separated and the remaining whitish dermal tissue will be
factor of 10.
discarded. Pipetting the cell containing the PBS solution using
 Ultrathin grafts are immersed in trypsin-
a 2-mL syringe yields a uniform epidermal cell suspension.
ethylenediaminetetraacetic acid (EDTA) solution
for 1 hour under 37°C (hot trypsinization) or for 18
hours under 4°C (cold trypsinization). Proteolytic was noted in more than half of the study population
dissociation of the tissue aided by mechanical as per the studies.13,14 At present, in the absence of a
dissociation with forceps leaves individual better alternative, such color mismatch is acceptable
cells in the solution (Figure 9.4). The resultant to the patient, provided there is a uniform coverage
solution is centrifuged to get a cell pellet, which of the repigmentation. Moreover, such a conclusion
is resuspended in phosphate buffer saline (PBS) cannot be made in the real-world scenario, as most
and mixed to get a thick cell suspension. The cell clinical trials are limited by a short trial period of 4–6
suspension is either injected into a blister raised on months, and we often observe improvement of color
the recipient area or spread on the de-epithelized match as time progresses.
recipient surface. After that, dressings are applied b. Autologous noncultured hair follicular cell
with collagen sheets, paraffin embedded mesh, suspension (FCS): Hair follicles as a source of better
absorbable gauze, transparent polyurethane melanocytes and various melanocyte precursors for
dressing, and elastic adhesive bandage, inside to vitiligo surgery were first reported by Vanscheidt
outside in that order. Dressings are removed after et al. through the plucked hair follicle method of
1 week. Various modifications of noncultured cell harvesting.15 Poor cell yield of this method
epidermal cell suspension have been described was rectified by Mohanty et al. by employing
(Table 9.2). follicular unit extraction followed by sequential
 Nowadays, vitiligo surgeons prefer this method trypsinization.16 It is estimated that one hair follicle
owing to its acceptable repigmentation outcome, is enough to provide melanocytes for a 1-cm2 area
better donor-recipient area augmentation and of depigmented skin. Melanocytes from the outer
procedural simplicity (Figure 9.5). PBS has now root sheath of hair follicles are extracted through
replaced melanocyte culture medium and trypsin a three-step trypsinization-neutralization process,
inhibitors, which were previously employed for NCES each having a duration of 20–30 minutes. This is
preparation.11 Optimal repigmentation (>75%) can be to avoid prolonged unopposed action of trypsin to
attained in more than two-thirds of patients as per a individual melanocytes shedding into the solution
number of clinical trials.12 However, color mismatch owing to the columnar shape of hair follicles.
 Types of vitiligo surgery 75

Table 9.2 Modifications of noncultured epidermal cell However, this complexity of the procedure was
suspension transplantation not translated to better repigmentation outcomes,
especially in acral areas. Even though there are
Study Modification
better melanocytes and stem cells with melanogenic
Gauthier et al.47 Pioneered the NCES method. Cold properties, the repigmentation outcome of this
trypsinization (under 4°C for 18 hours). method is comparable or inferior to NCES.17,18
Olsson and Hot trypsinization (60 minutes under c. Combined epidermal and follicular cell suspension:
Juhlin53 37°C). Cell suspension in melanocyte In this method, NCES and FCS are mixed in equal
culture media. proportion of cell numbers before transplanting into
van Geel et al.54 Addition of hyaluronic acid to the cell the depigmented skin. Such a combined cell suspension
suspension to increase viscosity and was found to have better repigmentation at acral areas
adherence to the recipient site. compared to NCES or FCS alone.19 In a randomized
Mulekar et al.55 Demonstrated repigmentation outcome clinical trial, this method was found to give quicker
with the ReCell-kit. and optimal repigmentation even in difficult-to-treat
Gho et al.56 Proposed the “six-well plate” technique vitiligo. This response was superior to that obtained
for the preparation of epidermal cell through NCES, the active control.20 Authors proposed
suspension. that better keratinocyte-derived growth factors and
Holla et al.11 Modifications addressing the cost OCT4+ stem cells found in NCES+FCS vs. NCES
reduction. Proposed the use of PBS in alone might be the reason for the superior outcome
place of melanocyte culture medium with the combined cell suspension.
and trypsin inhibitor. 3. Other methods
Sahni et al.57 Better repigmentation outcome by
Excision and primary closure can be employed for
suspending the melanocytes in the
small lesions. This method results in rapid correction
patients’ own serum.
of the depigmented patch, but at the cost of possible
scarring. 21 In micropigmentation, inert exogenous
Kumar et al.58 Proposed four-compartment method, a
pigments are inserted into the papillary dermis, similar
simple and clinic-based method of NCES
to tattooing, to impart a permanent camouflage. Even
preparation.
though it is rapid in concealing depigmentation,
Benzekri et al.59 Transepidermal transplantation of
there is a risk of infection and various tattoo
melanocytes using a 0.2-mm
reactions like granuloma formation and phototoxic
dermaroller system.
reactions. After years, the pigment starts to fade and
Razmi et al.20 Addition of noncultured hair follicular cell
sometimes is deposited into the dermis to give a bluish
suspension into the NCES to improve its
discoloration due to the Tyndall effect. In therapeutic
repigmentation outcome.
wounding, trauma is inflicted to the vitiligo patch so

Figure 9.5 Comparison of repigmentation outcome with mini-punch graft and noncultured epidermal cell suspension. (a)
Baseline image showing depigmented patches on the legs. (b) Repigmentation outcome after 1 month; mini-punch graft—upper
patch, and noncultured epidermal cell suspension—lower patch. (c) Repigmentation outcome at third month. In our experience, the
peri-graft halo on both the sites at this early follow-up usually repigments at a longer (1–2 year) follow-up. However, the speckled
appearance of mini-punch graft site persists for a long time. (Courtesy of Dr Amit Dalla, MBBS.)
76 Surgical treatment of vitiligo

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the depigmentation in a mouse model. 26 Tyrosinase- efficacy of cultured versus non cultured melanocyte
specific T-reg replenishment can be employed to halt transfer in the management of stable vitiligo. Med J
melanocyte destruction in active vitiligo. Armed Forces India. 2014;70:26–31.
11. Holla AP, Kumar R, Parsad D, Kanwar A. Modified
CONCLUSION procedure of noncultured epidermal suspension
Surgical options in vitiligo can be employed in carefully transplantation: Changes are the core of vitiligo
selected patches of stable vitiligo that do not respond surgery. J Cutan Aesthet Surg. 2011;4:44–45.
to medical modalities. To begin with, suction blister 12. Razmi TM, Parsad D. Cellular transplantation
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14. van Geel N, Ongenae K, De Mil M, Haeghen YV,
ACKNOWLEDGMENTS Vervaet C, Naeyaert JM. Double-blind placebo-
The authors thank Drs. Rajsmita Bhattacharjee, MD, controlled study of autologous transplanted
DNB, and Amit Dalla, MBBS, for their kind permission epidermal cell suspensions for repigmenting vitiligo.
to use the clinical and procedural images. Arch Dermatol. 2004;140:1203–1208.
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1989;21:257–264. 53. Olsson MJ, Juhlin L. Leucoderma treated by
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46. Chen YF, Yang PY, Hu DN, Kuo FS, Hung CS, Hung Modified technique of autologous noncultured
CM. Treatment of vitiligo by transplantation of epidermal cell transplantation for repigmenting
cultured pure melanocyte suspension: Analysis of vitiligo: A pilot study. Dermatol Surg. 2001;27:873–876.
120 cases. J Am Acad Dermatol. 2004;51:68–74. 55. Mulekar SV, Ghwish B, Al Issa A, Al Eisa A. Treatment
47. Gauthier Y, Surleve-Bazeille JE. Autologous grafting of vitiligo lesions by ReCell vs. conventional
with noncultured melanocytes: A simplified method melanocyte-keratinocyte transplantation: A pilot
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Dermatol. 1992;26:191–194. 56. Goh BK, Chua XM, Chong KL, de Mil M, van Geel
48. van Geel N, Goh BK, Wallaeys E, De Keyser S, NA. Simplified cellular grafting for treatment of
Lambert J. A review of non-cultured epidermal vitiligo and piebaldism: The “6-well plate” technique.
cellular grafting in vitiligo. J Cutan Aesthet Surg. Dermatol Surg. 2010;36:203–207.
2011;4:17–22. 57. Sahni K, Parsad D, Kanwar AJ, Mehta SD. Autologous
49. Mulekar SV. Long-term follow-up study of 142 noncultured melanocyte transplantation for
patients with vitiligo vulgaris treated by autologous, stable vitiligo: Can suspending autologous
non-cultured melanocyte-keratinocyte cell melanocytes in the patients’ own serum improve
transplantation. Int J Dermatol. 2005;44:841–845. repigmentation and patient satisfaction? Dermatol
50. Mulekar SV, Al Issa A, Al Eisa A. Treatment of Surg. 2011;37:176–182.
vitiligo on difficult-to-treat sites using autologous 58. Kumar R, Parsad D, Singh C, Yadav S. Four
noncultured cellular grafting. Dermatol Surg. compartment method: A simplified and cost-effective
2009;35:66–71. method of noncultured epidermal cell suspension
51. Toossi P, Shahidi-Dadras M, Mahmoudi Rad M, for the treatment of vitiligo. Br J Dermatol.
Fesharaki RJ. Non-cultured melanocyte-keratinocyte 2014;170:581–585.
transplantation for the treatment of vitiligo: A clinical 59. Benzekri L, Gauthier Y. The first transepidermal
trial in an Iranian population. J Eur Acad Dermatol transplantation of non-cultured epidermal
Venereol. 2011;25:1182–1186. suspension using a dermarolling system in vitiligo:
52. Anbar T, Westerhof W, Abdel-Rahman A, El-Khayyat A sequential histological and clinical study. Pigment
M, El-Metwally Y. Treatment of periungual vitiligo Cell Melanoma Res. 2017;30:493–497.
Phototherapy and lasers in the treatment
of vitiligo
10
VIKTORIA ELEFTHERIADOU

CONTENTS
Introduction 79 Narrowband ultraviolet B phototherapy and
Mechanism of action of phototherapy 79 carcinogenicity 80
Hospital and home phototherapy 79 Targeted phototherapy devices 80
Narrowband ultraviolet B and psoralen and Monochromatic excimer light 81
ultraviolet A phototherapy for vitiligo 80 Combination treatments with phototherapy 81
Narrowband ultraviolet B phototherapy side effects References 81
and contraindications 80

INTRODUCTION hormone. The latter enhances the proliferation and

Phototherapy is one of the well-known therapeutic migration of melanocytes in the outer root sheath of
modalities for the treatment of various skin diseases. The use hair follicles into depigmented lesions. In addition,
of ultraviolet light dates back to the early 1900s. Extensive NB-UVB induces tyrosinase enzyme activity and T-cell
research has expanded our understanding of various skin apoptosis.
disease pathophysiology. Advancements in technology have The above supports the fact that repigmentation usually
led to the development of UV devices that are more precise, begins around the hair follicle, that is, perifollicularly,
safer, and more effective for the treatment of a wide variety in vitiliginous lesions. Lack of hair follicles in areas
of dermatologic conditions, including vitiligo. such as hands and feet might explain poorer response to
In Egypt around 2000 bc, topical psoralens and sun phototherapy.4,5
exposure were used for treatment of vitiligo. Since then,
PUVA (topical or oral psoralen and UVA) and PUVAsol HOSPITAL AND HOME PHOTOTHERAPY
(topical or oral psoralen and ultraviolet A [UVA] sun Hospital UVB usually involves whole-body cabinets suitable
exposure) have been widely used to treat various skin for extensive cutaneous involvement, such as large or
conditions, including vitiligo and psoriasis. Although multiple lesions. During the session, the patient goes into a
PUVA phototherapy proved effective, it has several specially designed cabinet containing fluorescent light tubes
limitations, including phototoxic effects, nausea and (whole-body units). Usually the whole body is exposed to the
vomiting due to psoralens, and the potential risk for UVB for a short time (seconds to minutes). Hand and feet
skin cancer. In addition, systemic PUVA phototherapy is units for UVB are also available in some hospitals.6
contraindicated for children or pregnant women because of In recent years, targeted phototherapy has been
the systemic use of psoralen.1 Since narrow-band ultraviolet developed to overcome many of the limitations of full-body
B (NB-UVB) phototherapy was first reported to be effective cabinets. Terms such as microphototherapy, concentrated
for treatment of vitiligo in 1997, it has gradually taken the phototherapy, and focused phototherapy have been used
place of PUVA phototherapy. 2 NB-UVB phototherapy for targeted phototherapy.6,7 There are several benefits of
is also associated with adverse events such as erythema, using targeted phototherapy devices, such as sparing of
itching, and mild burning or pain, which are usually better uninvolved skin and treating areas not easily reached by
tolerated and spontaneously disappear a few hours after light, such as scalp and skin folds.
treatment in most cases.3 In addition, home phototherapy has gained popularity
In summary, the lack of a photosensitizer, the lower recently. Home phototherapy using whole-body units
cumulative dose, and fewer adverse effects are considered is available for the treatment of various dermatological
major advantages of NB-UVB over PUVA.2,3 conditions. A study comparing home versus hospital
whole-body phototherapy (NB-UVB) for psoriasis
MECHANISM OF ACTION OF PHOTOTHERAPY concluded that home phototherapy is equally effective and
The mechanism of action of NB-UVB is the inhibition implies no additional safety hazards compared to hospital
of cytokines and stimulation of melanocyte-stimulating phototherapy. Most of the participants said they would

79
80 Phototherapy and lasers in the treatment of vitiligo

prefer future phototherapy at home over the hospital.8 encouraged to enhance the treatment response, with the
Other benefits of home phototherapy include: greatest response anticipated on the face and neck.14
• Reduction in attendance at the hospital. Traditionally, In addition, Yones et al. demonstrated the superiority of
NB-UVB phototherapy to oral PUVA therapy. In their study,
patients receiving NB-UVB treatment would be required
the rate of more than 50% repigmentation was significantly
to attend the hospital 2–3 times per week.
• Cheaper cost and less opportunity cost for patients, such
higher in the NB-UVB group (64%) than in the PUVA group
(36%) after 6 months of treatment. In addition, repigmented
as traveling costs.
• Treatment can be provided at an early stage of their
skin showed excellent color match in all patients in the
NB-UVB group but only 44% of those in the PUVA group.14,15
disease, when the intervention might be more effective.6
Recurrence of vitiligo after discontinuation of NB-UVB
can occur. Relapses of previously repigmented lesions
have been reported in approximately 50% of patients
NARROWBAND ULTRAVIOLET B AND PSORALEN AND (44%–55%).16,17
ULTRAVIOLET A PHOTOTHERAPY FOR VITILIGO
Although several interventions are available to treat NARROWBAND ULTRAVIOLET B PHOTOTHERAPY SIDE
patients with vitiligo, there is no cure nor firm clinical EFFECTS AND CONTRAINDICATIONS
recommendations. 3 Phototherapy, including psoralen– Whole-body NB-UVB as well as targeted NB-UVB are well
UV-A (PUVA) and narrowband UV-B therapy, has been tolerated. The most common adverse events are dose- and
historically used for the management of generalized or skin type–dependent erythema occurring 12–24 hours post
extensive vitiligo, whereas targeted phototherapy, including treatment. Mild erythematous reaction in vitiliginous skin
lasers and various topical agents, are used to treat localized is generally considered a desirable outcome and indicates
disease. Management of vitiligo requires a long-term time adequate dosimetry.9
commitment and can be challenging. NB-UVB is absolutely contraindicated in patients
Currently there is no agreed protocol for NB-UVB in with xeroderma pigmentosum and lupus erythematosus.
vitiligo and therefore a variety of treatment regimens are used Relative contraindications include photodermatoses,
in different institutions and countries. Usually, NB-UVB is immunosuppression, and inability to stand still in a whole-
administered twice or thrice a week. Patients with vitiligo have body cubicle, among others. NB-UVB can be administered
traditionally been regarded as skin type 1 and consequently to children, pregnant and lactating women, and patients
were treated with doses between 150 and 250 mj/cm2 with with renal or hepatic diseases.9
increments of 10%–15% at each visit.9 However, minimal
erythema dose (MED) values in vitiligo skin are on average NARROWBAND ULTRAVIOLET B PHOTOTHERAPY AND
only 35% (95% confidence interval 31%–39%) lower than in CARCINOGENICITY
normal skin, suggesting photoadaptation.2,10–13 Total-body The issue of how great the risk of carcinogenicity is for
NB-UVB is suggested for vitiligo covering over 15%–20% of NB-UVB is unclear, as there is no good evidence to date.
the body surface area or for actively spreading vitiligo.9 Several studies were unable to detect any definite increased
A recently conducted meta-analysis of studies on risk of skin cancer following NB-UVB phototherapy.18–21 A
phototherapy for vitiligo included 35 studies (1428 larger study on 1380 participants also showed that UVB
patients). Randomized, nonrandomized, and open remains a relatively low-risk treatment for psoriasis.22
trials were included. Single-arm meta-analyses were A study performed on 1514 participants with vitiligo
performed for the NB-UVB and PUVA groups. The and 2813 participants with no vitiligo, showed that there
primary outcomes were mild (≥25%), moderate (≥50%), is a mutually exclusive relationship between susceptibility
and marked (≥75%) responses on a quartile scale. to vitiligo and susceptibility to melanoma, that is, vitiligo
This meta-analysis was conducted with the aim to patients may have protection against melanoma. 23
provide references to the expected treatment response However, there have been no trials performed on the risk
to phototherapy in the management of vitiligo. Mild of carcinogenicity of NB-UVB phototherapy on vitiligo
response to narrowband UV-B phototherapy occurred patients and the consensus is made mainly on data from
in 74% at 6 months and 75% at 12 months, and a psoriasis patients.
marked response was achieved in 19% at 6 months and
36% at 12 months. The face and neck achieved better TARGETED PHOTOTHERAPY DEVICES
repigmentation compared to the trunk and extremities.14 For localized vitiligo and in particular for small
The authors concluded that phototherapy requires at lesions of recent onset and childhood vitiligo, targeted
least 1 year to achieve a maximal treatment response phototherapies are indicated. In the management of
and suggested that at least 6 months of treatment are vitiligo, several different types of targeted phototherapy
required to determine the responsiveness to NB-UVB have been reported: excimer laser, monochromatic excimer
phototherapy. Moreover, overall treatment response to lamp, hand-held multichromatic incoherent UV sources,
PUVA phototherapy was inferior to that to NB-UVB, and low-level laser therapy.
although statistical comparisons were not conducted NB-UVB devices have a peak emission spectrum
in this study. Long-duration phototherapy should be between 311–313 nm. The first targeted NB-UVB device was
 References 81

described by Lotti et al. in 1999 (Bioskin).24 Other devices 17-butyrate cream and as monotherapy. Combination
have been reported since with similar efficacy results.25–27 therapy showed significantly higher repigmentation that
the laser alone for resistant head and neck lesions.35
MONOCHROMATIC EXCIMER LIGHT
Monochromatic excimer light (MEL) is a xenon chloride Topical cancineurin inhibitors and phototherapy
(XeCl) device, which emits a single 308-nm wavelength Good evidence exists that combination of topical calcineurin
either as a lamp or laser. MEL has shown therapeutic inhibitors (TCIs) (tacrolimus, pimecrolimus) with light
success in the treatment of various skin conditions such as therapy is more effective than monotherapy. TCIs showed
vitiligo, psoriasis, and mycosis fungoides. Various excimer encouraging results when combined with UVB phototherapy
lamp and laser devices are commercially available. The and laser.3,14 Concerns were expressed regarding possible
photobiologic effects of MEL are similar to those of 311– increased risk of carcinogenicity; a long-term follow-up of
313 nm. They include greater T-cell apoptosis and melanin 9813 tacrolimus-treated eczema patients showed no evidence
production from perifollicular dihydroxyphenylalanine of an increased risk of nonmelanoma skin cancer.36 However,
(DOPA)-depleted amelanotic melanocytes than traditional long-term data on vitiligo patients are still missing.
NB-UVB. 28,29 Treatment regimens studied included
Vitamin D analogues and phototherapy
excimer laser two to three times weekly for up to 36 weeks.
Patients commonly achieved >75% repigmentation. 30 A combination of vitamin D analogues and phototherapy
Differences between excimer lamp and laser include lower is not recommended due to contradictory results in trials.3,9
cost of excimer lamp, different hand pieces with various
Oral corticosteroids and narrowband ultraviolet B
spot sizes for excimer lamp compared to a fixed spot size
of excimer laser, and more expensive maintenance costs for One study comparing the combination of oral minipulse of
excimer laser. No significant difference in the effectiveness prednisolone (OMP) and NB-UVB versus OMP alone showed
of excimer laser and lamp have been found.29,31 that combination therapy was better.37 Expert consensus rec-
The optimal frequency and duration of treatment of ommends that the benefit of adding OMP for repigmenta­
excimer light are unclear. However, the success of the tion of stable vitiligo is not considered useful. Weekend OMP
excimer laser appears to vary by anatomical site similar to starting with a low dose (2.5 mg daily of dexamethasone) for
other sources of NB-UVB.32 fast-spreading vitiligo could be considered.9
Other targeted phototherapy devices include: In summary, light and laser therapies in combination
treatments with topical agents were shown to be statistically
• UVA device, Dualite (Theralight, Inc., USA), which significantly better at achieving over 75% repigmentation
emits at 330–380 nm. No trials with this device’s compared with monotherapies.3,9,14
UVA spectrum have been reported in the treatment of In conclusion, targeted phototherapy (including lasers)
vitiligo. is an emerging, effective form of phototherapy with
• Low-level laser devices, which emit at 600–1100 nm. advantages and limitations compared to conventional
These include ruby, gallium-aluminum-arsenide, and phototherapy. A recent shift toward using phototherapy
helium-neon lasers. Some evidence exists to support the earlier in the course of disease seems to be promising.
effectiveness of HeNe lasers.33,34 However, further trials are needed to definitively
In summary, targeted phototherapy is an emerging form demonstrate the effectiveness of various phototherapy
of phototherapy with advantages and limitations compared treatment modalities both as monotherapies and in
to whole-body phototherapy as described above. Targeted combination with topical treatments for vitiligo.
phototherapy is a safer option for both children and adults
with limited vitiligo covering up to 10% of the total body REFERENCES
surface. 1. Ling TC, Clayton TH, Crawley J et al. British
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COMBINATION TREATMENTS WITH PHOTOTHERAPY Photodermatology Group guidelines for the safe and
Several combination treatments have been proposed with effective use of psoralen-ultraviolet A therapy 2015.
the aim to enhance the effectiveness of phototherapy for Br J Dermatol. January 2016;174(1):24–55.
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of vitiligo with UV-B radiation vs topical psoralen
Topical steroids and phototherapy plus UV-A. Arch Dermatol. December 1997;133(12):​
European guidelines for the management of vitiligo 1525–1528.
recommend that the combination of topical steroids and 3. Whitton ME, Pinart M, Batchelor J, Leonardi-Bee
phototherapy (NB-UVB, excimer light or laser) may be J, González U, Jiyad Z, Eleftheriadou V, Ezzedine K.
promising, especially for difficult-to-treat areas such as Interventions for vitiligo. Cochrane Database Syst
bony prominences. Potent topical steroids applied once Rev. February 2015;24(2):CD003263.
a day can be used on vitiligo lesions for the first three 4. Weichenthal M, Schwarz T. Phototherapy: How does
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5. De Francesco V, Stinco G, Laspina S, Parlangeli 19. Weischer M, Blum A, Eberhard F et al. No evidence
ME, Mariuzzi L, Patrone P. Immunohistochemical for increased skin cancer risk in psoriasis patients
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UVB treatment in vitiligo. Eur J Dermatol. May phototherapy: a first retrospective study. Acta Derm
2008–June;18(3):292–296. Venereol. 2004;84(5):370–374.
6. Eleftheriadou V. Setting priorities and reducing 20. Man I, Crombie I, Dawe R, Ibbotson S, Ferguson J.
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The University of Nottingham; 2013. (TL-01) phototherapy: Early follow-up data. Br J
7. Mysore V. Targeted phototherapy. Indian J Dermatol Dermatol. April 2005;152(4):755–757.
Venereol Leprol. 2009;75:119–125. 21. Hearn R, Kerr A, Rahim K, Ferguson J, Dawe R.
8. Koek M, Buskens E, van Weelden H, et al. Home Incidence of skin cancers in 3867 patients treated
versus outpatient ultraviolet B phototherapy for with narrow-band ultraviolet B phototherapy. Br J
mild to severe psoriasis: Pragmatic multicentre Dermatol. September 2008; 159(4):931–935.
randomised controlled non-inferiority trial (PLUTO 22. Lim JL, Stern RS. High levels of ultraviolet B
study). Br Med J. 2009; 338:b1542. exposure increase the risk of non-melanoma
9. Taieb A, Alomar A, Böhm M et al. Vitiligo European skin cancer in psoralen and ultraviolet A-treated
Task Force. Guidelines for the management of vitiligo: patients. J Invest Dermatol. March 2005;124(3):​
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El-Khayyat MA. Evaluation of the effects of NB-UVB Genet. July 2010;42(7):576–578.
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Photomed. June 2006;22:157–163. segmental vitiligo. J Eur Acad Dermatol Venereol.
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33. AlGhamdi KM, Kumar A, Moussa NA. Low-level combination with topical hydrocortisone 17-butyrate
laser therapy: A useful technique for enhancing the cream in the treatment of vitiligo of the face and
proliferation of various cultured cells. Lasers Med Sci. neck. Br J Dermatol. October 2008;159:1186–1191.
January 2012;27:237–249. 36. Naylor M, Elmets C, Jaracz E, Rico JM. Non-
34. Yu HS, Wu CS, Yu CL, Kao YH, Chiou MH. melanoma skin cancer in patients with atopic
Helium–neon laser irradiation stimulates migration dermatitis treated with topical tacrolimus. J Dermatol
and proliferation in melanocytes and induces Treatm. July 2009; 16(3):149–153.
repigmentation in segmental-type vitiligo. J Investig 37. Rath N, Kar HK, Sabhnani S. An open labeled,
Dermatol. January 2003;120(1):56–264. comparative clinical study on efficacy and tolerability
35. Sassi F, Cazzaniga S, Tessari G, Chatenoud L, of oral minipulse of steroid (OMP) alone, OMP with
Reseghetti A, Marchesi L, Girolomoni G, Naldi PUVA and broad/narrow band UVB phototherapy
L. Randomized controlled trial comparing the in progressive vitiligo. Indian J Dermatol Venereol
effectiveness of 308-nm excimer laser alone or in Leprol. August 2008;74(4):357–360.
Emerging treatments for vitiligo
ANGELO MASSIMILIANO D’ERME and GIOVANNI BAGNONI
11
CONTENTS
Introduction 85 Emerging surgical treatments 87
Topical emerging treatments 85 Concluding remarks 87
Emerging phototherapies and lasers 85 References 87
Emerging systemic treatments 86

INTRODUCTION Clinical studies on Pigmerise are ongoing and recent

There are several safe and effective treatments that are results also seem to underline its efficacy in humans.
available for vitiligo. Existing treatments include topical Recently, an evaluation of the efficacy of topical piperine
and systemic immunosuppresants, phototherapy, and in combination with narrowband ultraviolet B (NB-UVB)
surgical techniques that, alone or together, may halt disease in patients with facial vitiligo was published. The authors
progression, stabilize lesions, and lead to repigmentation. reported that the combination therapy with NB-UVB/
The choice of the treatment depends on the type of the topical piperine had more influence on facial vitiligo than
disease, the percent of body area surface affected, the effect that of NB-UVB alone.10
on the quality of life, the compliance of the patient, and Piperine cream has the advantage of having fewer
the patient’s perception with regards to the risk-benefit adverse side effects than topical corticosteroids. The most
ratio.1–8 Currently, no treatment has been approved by the common side effect reported in daily practice and in the
U.S. Food and Drug Administration (FDA) for vitiligo. literature is a burning sensation and redness when applied
Topical treatments may be applied alone when a small on the skin. However, further studies on its clinical efficacy
area is involved, or together with phototherapy or systemic and pathogenic mechanisms are needed.
treatments when the area affected is more than 5%–10% or
there is a progression of the disease. Based on our current EMERGING PHOTOTHERAPIES AND LASERS
understanding of vitiligo pathogenesis, a successful The efficacy of UVR in the treatment of vitiligo has long
strategy to treat vitiligo should incorporate three distinct been a well-known therapy. Even today, phototherapies
approaches: reducing melanocyte stress, regulating are considered the first-line therapy, especially for
autoimmune response, and stimulating melanocyte extensive vitiligo, because of their good efficacy and
regeneration. Existing treatments partially address these tolerance. Phototherapy should be reserved for patients
needs; however, emerging therapies may do this in a more who have vitiligo covering more than 5%–10% of body
targeted way, and combination therapies may synergize to surface area (BSA) or patients who fail to respond to
produce a better overall response.1–8 topical therapy. Narrowband UVB light phototherapy
is superior to UVA light phototherapy for the treatment
TOPICAL EMERGING TREATMENTS of vitiligo.
Topical corticosteroids and calcineurin inhibitors are The monochromatic excimer laser is indicated as
common and effective first-line therapies. They can be used targeted treatment of specific lesions and yields better
as monotherapy or combined with phototherapy. results than conventional light therapy. Helium neon laser
An emerging topical treatment is a liposomal cream that therapy is effective for segmental vitiligo.
contains in high concentration a natural phytocomplex Within this context, some lasers have recently been
obtained from black pepper fruit (piper nigrum studied for the treatment of vitiligo, such as fractional
phytocomplex) (Pigmerise Fagron) (Figure 11.1). Piperine, erbium-YAG laser,11 fractional CO2 laser,12 and UVA1
the major alkaloid of black pepper, and its synthetic laser,13 with good results. However, more studies are needed
derivatives can stimulate pigmentation in the skin by before these lasers are recommended for vitiligo treatment.
inducing melanocyte proliferation and dendrite formation Despite being the most effective current treatment, patient
in vitro.9 In a sparsely pigmented mouse model, piperine and access to phototherapy is often difficult, and patients have
its analogues induced greater pigmentation than vehicle, to attend a specialized clinic two to three times weekly for
with additional exposure to ultraviolet radiation (UVR) months. Sun exposure, on the other hand, is an inexpensive
leading to darker pigmentation than did the compound or alternative to phototherapy, but nontherapeutic wavelengths
UVR alone, together with greater numbers of dihydroxy- of sunlight produce erythema and sunburn. To overcome
phenylalanine (DOPA) + melanocytes in skin histology.9 this limitation of sun exposure, a topical formulation of

85
86 Emerging treatments for vitiligo

(a) (b)

Figure 11.1 (a) Vitiligo lesions in an 8-year-old child; (b) rapid improvement in under 3 months of treatment of Pigmerise cream
in combination with tacrolimus ointment.

dimethicone 1% was recently produced with the ability immunomodulating, and photoprotective qualities and is
to permit therapeutic wavelengths in the NB-UVB range used to treat a variety of inflammatory and degenerative
(∼311 nm) to reach the skin and contemporaneously to block diseases.19
nontherapeutic wavelengths of sunlight below 300 nm. A The plant extract Polypodium leucotomos improved
first study found that sun exposure with application of this repigmentation responses to NB-UVB. Furthermore, in
cream was safe and effective at inducing repigmentation.14 subjects with or without vitiligo, it reduced the cutaneous
These promising results have to be confirmed in larger phototoxicity of PUVA and UVB phototherapies.19
clinical trials, opening new, easy, and more accessible Other studies revealed that the supplementation of an
methods of vitiligo treatment. However, UVA light is not antioxidant pool of alpha lipoic acid, vitamin C, vitamin E,
blocked by this cream, and thus this approach may not be and polyunsaturated fatty acids improved repigmentation
as safe as NB-UVB phototherapy. rates in combination with NB-UVB phototherapy but not
with PUVA.16
EMERGING SYSTEMIC TREATMENTS In conclusion, there is good evidence to support oral
Antioxidants/hormones antioxidant supplementation, specifically together with
Oxidative stress, including reduction of catalase enzyme, NB-UVB phototherapy. It is also likely a safe, widely
as well as elevated levels of reactive oxygen species (ROS) available, and inexpensive adjunct. However, defining
in lesional skin, has been implicated in the pathogenesis of dosing parameters, efficacy, and side effect profiles requires
vitiligo. These data prompted the hypothesis that treating further research.
patients with antioxidants or otherwise controlling ROS
might be an effective treatment strategy. Hormones
For example, methionine sulfoxide reductase (MSR), Afamelanotide, a synthetic analogue of alpha-
an important reducing agent, is less active and present melanocyte-stimulating hormone (α-MSH), has
in lower amounts in patients with vitiligo, leading to an recently been approved by the European Medicines
increase of melanocyte sensitivity to oxidative stress and Agency to mitigate photosensitivity in erythropoietic
cell death. protoporphyria. Afamelanotide also seems to improve the
Oral or topical natural health products, vitamins, and efficacy of NB-UVB in vitiligo. A randomized trial with
supplements have been suggested as possible therapies afamelanotide in combination with NB-UVB was carried
based on their elevated catalase activity, antioxidant, and out in adults with generalized vitiligo. The addition of
anti-inflammatory properties.1–8,15 afamelanotide resulted in faster and increased total
The herbal supplement gingko biloba has been tested in repigmentation compared to NB-UVB monotherapy,
two trials and reported to decrease disease progression of especially in patients with darker skin. The combination
vitiligo compared to placebo.16–18 therapy was somewhat well tolerated, although side
Polypodium leucotomos (PL) is a fern found in the effects including nausea and skin hyperpigmentation
American subtropics. The extract has antioxidant, were reported.20
 References 87

Immunosuppressants CTLA-4 agonists, such as abatacept (recently approved

Over the past decade, significant progress has been made in by the FDA for rheumatoid arthritis) or PD-1 ligand (PD-
the development of immunomodulators for inflammatory L1, a PD-1 agonist), are under development or in testing
skin disease, such as psoriasis and atopic dermatitis. The in trials for inflammatory diseases and may be effective,
identification of novel immune targets and pathways will especially for vitiligo patients.32
also help the development of new vitiligo treatments.1–8
EMERGING SURGICAL TREATMENTS
The IFN-γ/CXCL10 axis is emerging as a critical
signaling pathway required for both the progression Surgical treatment for vitiligo is invasive and not without
and maintenance of vitiligo. Interfering with the IFN-γ/ risks; however, it can be an excellent option for patients
CXCL10 chemokine axis may be an effective strategy to who fail nonsurgical therapy. There are several melanocyte
develop novel, targeted immunotherapies.21,22 transplant techniques available, including suction blister
A variety of antibodies and small-molecule inhibitors grafting, split-thickness grafting, punch grafting, and
have already been found to be efficacious and safe in melanocyte suspension. Surgical techniques are most
targeting components of this pathway in early-phase successful in late-stage segmental vitiligo, and they may
clinical trials for treatment of other autoimmune diseases. be considered in those with nonresponsive, stable vitiligo.
Recent findings in patients and a mouse model suggest that Noncultured epidermal melanocyte cell grafting
vitiligo patients may benefit in the future from these new demonstrates superior extent and quality of pigmentation
drugs.23,24 compared with other surgical techniques
Janus kinase (JAK)-signal transduction and transcrip- Adverse outcomes include scarring, graft failure,
tion (STAT) signaling, essential to transmitting extracel- koebnerization, infection, cobblestoning, and variegated
lular signals of many cytokines, including IFN-γ, to the pigmentation.
nucleus, has been studied in the last years.25 There are four Not so many surgical treatments have emerged for
members of the JAK family: JAK1, JAK2, JAK3, and tyro- vitiligo in recent years.
sine kinase 2 (TYK2), that are directly involved in IFN-γ Noncultured, extracted follicular outer root sheath
signaling, which activates STAT1 and thus induces the suspension (NC-EHF-ORS-CS) is a recently introduced
transcription of IFN-γ-induced genes, including CXCL10. technique for the treatment of stable vitiligo. Melanocytes
Several small-molecule JAK inhibitors with distinct are extracted from follicles from the occipital scalp and
selectivity have been tested in patients or are under incubated with trypsin-ethylenediaminetetraacetic acid
development for several autoimmune or autoinflammatory to separate outer root sheath cells, then reintroduced. This
diseases. Interestingly, significant repigmentation in technique is minimally invasive and promising for vitiligo.33
one patient with generalized vitiligo after the oral
CONCLUDING REMARKS
administration of tofacitinib (a Janus kinase inhibitor
[JAK 1/3])26 and in another patient with facial and At all stages of therapy, we should always keep in mind
trunk vitiligo at the beginning of treatment with oral that vitiligo can be a lifelong disease that may extensively
ruxolitinib [JAK 1/2 inhibitor])27 have been reported, damage one’s psychosocial sense of well-being. Thus,
opening new scenarios in the pathogenesis and treatment treatment in the future should also stress the use of
of vitiligo. However, the treatment response from these nonmedical treatment in helping patients to deal with the
inhibitors did not appear to be durable, as patients lost psychological disease burden.
the repigmentation after discontinuing treatment. Similar The correct use of proper camouflage, tattoos, cosmetic
to all other immunosuppressive drugs, adverse events agents, and psychological support will help patients to face
may limit their daily use. Topical formulations of these the psychosocial effects of vitiligo and also positively affect
drugs, however, may provide therapeutic benefit without disease progression.
increasing the risk of adverse events. Topical ruxolitinib Personalized nonmedical support is fundamental and
for 20 weeks resulted in 76% repigmentation of facial will be always more important in vitiligo treatment.
lesions in four patients and 23% improvement of all
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segmental vitiligo. Lasers Med Sci. 2017;32:1571–1577. and disease. J Immunol. 2015;194(1):21–27.
12. Kim HJ, Hong ES, Cho SH et al. Fractional Carbon 26. Craiglow BG, King BA. Tofacitinib citrate for the
Dioxide Laser as an “Add-on” treatment for vitiligo: treatment of vitiligo: A pathogenesis-directed
A meta-analysis with systematic review. Acta Derm therapy. JAMA Dermatol. 2015;151(10):1110–1112.
Venereol. 2018;98:180–184. 27. Harris JE, Rashighi M, Nguyen N et al. Rapid skin
13. Lotti T, Tchernev G, Wollina U et al. Successful repigmentation on oral ruxolitinib in a patient with
treatment with UVA 1 laser of non-responder coexistent vitiligo and alopecia areata (AA). J Am
vitiligo patients. Open Access Maced J Med Sci Acad Dermatol. 2016;74(2):370–371.
2018;6:43–45. 28. Rothstein B, Joshipura D, Sarayia A et al. Treatment
14. Goren A, Salafia A, McCoy J, Keene S, Lotti T. of vitiligo with the topical Janus kinase inhibitor
Novel topical cream delivers safe and effective ruxolitinib. J Am Acad Dermatol. 2017;76:1054–1060.
sunlight therapy for vitiligo by selectively filtering 29. Tufts Medical Center. ClinicalTrials.gov [Internet].
damaging ultraviolet radiation. Dermatol Ther. Bethesda (MD): National Library of Medicine (US);
2014;27(4):195–197. Topical Ruxolitinib for the Treatment of Vitiligo.
15. Shalbaf M, Gibbons NC, Wood JM et al. Presence of Available from https://clinicaltrials.gov/ct2/show/
epidermal allantoin further supports oxidative stress NCT02809976 NLM Identifier: NCT02809976 [2000-
in vitiligo. Exp Dermatol. 2008;17(9):761–770. [cited June 29, 2016]
16. Dell’Anna ML, Mastrofrancesco A, Sala R et al. 30. Moreland L, Bate G, Kirkpatrick P. Abatacept. Nat
Antioxidants and narrow band-UVB in the treatment Rev Drug Discov. 2006;5(3):185–186.
of vitiligo: A double-blind placebo controlled trial. 31. Weber J. Immune checkpoint proteins: A new
Clin Exp Dermatol. 2007;32(6):631–636. therapeutic paradigm for cancer—Preclinical
17. Parsad D, Pandhi R, Juneja A. Effectiveness of oral background: CTLA-4 and PD-1 blockade. Semin
ginkgo biloba in treating limited, slowly spreading Oncol. 2010;37(5):430–439.
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18. Szczurko O, Shear N, Taddio A, Boon H. Ginkgo and IDO to modulate immune responses in vitiligo.
biloba for the treatment of vitiligo vulgaris: An open Exp Dermatol. 2017;26:630–636.
label pilot clinical trial. BMC Complement Altern 33. Kumar P, Bhari N, Tembhre MK, Mohanty S, Arava S,
Med. 2011;11:21. Sharma VK, Gupta S. Study of efficacy and safety of
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Tuberous sclerosis complex
VESNA PLJAKOSKA, KATERINA DAMEVSKA, and NATASA TEOVSKA MITREVSKA
12
CONTENTS
Introduction 89 Angiofibromas 91
Clinical features 89 Shagreen patches 91
Cutaneous manifestations of tuberous Fibrous cephalic plaques 91
sclerosis complex 90 Ungual fibromas (Koenen tumors) 91
Hypopigmented macules 90 Treatment of cutaneous lesions 92
“Confetti”-like hypopigmentation 91 References 92

INTRODUCTION Table 12.1 Clinical criteria for the diagnosis of tuberous

Tuberous sclerosis complex (TSC) is a genetically sclerosis complex
determined autosomal disorder that causes substantial
Major criteria Minor criteria
complications in multiple organ systems.1 Benign tumor
growth represents the hallmark of the disease, with the Hypomelanotic macules (≥3, at “Confetti” skin lesions
central nervous system (CNS), the kidneys, and the skin least 5 mm diameter)
being the most commonly affected organs.1 Angiofibromas (≥3) or fibrous Dental enamel pits
The incidence of TSC may be as high as 1:5800 live cephalic plaque (≥3)
births.2 Population-based studies of TSC are rare. Studies Ungual fibromas (≥2) Intraoral fibromas (≥2)
in the United Kingdom reported a frequency of 1 in 12,000 Shagreen patch Retinal achromic patch
to 1 in 14,000 in children under 10 years of age.3
Tuberous sclerosis is caused by mutations in one of two Multiple retinal hamartomas Multiple renal cysts
tumor suppressor genes: TSC1 (9q34) and TSC2 (16p13.3), Cortical dysplasia Nonrenal hamartomas
which encode the proteins hamartin (TSC1) and tuberin Subependymal nodules
(TSC2). The hamartin-tuberin complex inhibits the
Subependymal giant cell
mammalian target of rapamycin pathway, which controls
astrocytoma
cell growth and proliferation.4
Cardiac rhabdomyoma
TSC can be diagnosed by the presence of clinical criteria
Lymphangioleiomyomatosis (LAM)
and by genetic testing. The identification of either a TSC1
or TSC2 pathogenic mutation in DNA from normal Angiomyolipomas (≥2)
tissue is sufficient to make a definite diagnosis of TSC.5–7 Source: Adapted from Northrup H, Krueger DA; International Tuberous
Disease-causing mutations can be detected in 75%–90% Sclerosis Complex Consensus Group. Pediatr Neurol. October
of patients who meet the diagnostic criteria.6 Therefore, 2013;49(4):243–54, with permission.
Definite diagnosis: Two major features or one major feature with two
negative genetic testing does not exclude the diagnosis of
minor features.
TSC.5 International TSC guidelines recommend obtaining
Possible diagnosis: Either one major feature or two minor features.
a three-generation family history to assess for additional
family members at risk for TSC.7 However, clinical features
continue to be the principal means of diagnosis.7,8 CLINICAL FEATURES
Updated clinical diagnostic criteria for TSC include 11 TSC is characterized by the development of a variety of
major and six minor features (Table 12.1).7 A definite TSC benign, noninvasive tumors in multiple organs, most
diagnosis requires identifying either two major symptoms commonly in the brain, heart, skin, eyes, kidneys, and
or one major and two or more minor symptoms.7 However, lungs, but also in the gastrointestinal tract, liver, and
a combination of lymphangioleiomyomatosis (LAM) and reproductive organs.4
angiomyolipomas without other features does not meet According to a recent national surveillance study in
criteria for a definite diagnosis. The classic TSC diagnostic Germany conducted using the current revised criteria for
triad of seizures, intellectual disability, and facial TSC, the three most common clinical features identified
angiofibromas (Vogt triad) occurs in less than one-third with TSC patients were central nervous system involvement
of patients with TSC.8 in 73.3% of patients (of these, 95.2% experienced seizures),

89
90 Tuberous sclerosis complex

cutaneous involvement in 58.1% of patients, and cardiac and psychological well-being. On occasion, the lesions may
rhabdomyoma. The annual incidence rate of TSC is bleed and become infected.13
estimated at a minimum of 1:17,785 live births.9
Central nervous system tumors are the leading cause of HYPOPIGMENTED MACULES
morbidity and mortality. They exhibit various neurological One of the terms used in the past to describe hypopigmented
symptoms, including epilepsy, seizures, developmental macules in tuberous sclerosis is white ash leaf spots; the
delay, intellectual disability, and autism, which are referred term is now discouraged from use since the macules can be
to as TSC-associated neuropsychiatric disorders.10 any shape or size (Figures 12.1 and 12.2). Hypopigmented
Other possible TSC symptoms include vascular macules of a certain size and shape are not indicative of a
anomalies, cardiovascular and pulmonary issues, definite TSC diagnosis.14
ophthalmologic problems such as multiple retinal
hamartomas, and retinal achromic patches. Dental enamel
pits and intraoral fibromas can occur in about 20%–50%
of individuals with TSC, appearing on the buccal or labial
mucosa and even the tongue.7
The management of TSC patients is very oppressive
in terms of time, and might increase healthcare costs
and the cost for the healthcare system. Management
options include conservative approaches, surgery,
pharmacotherapy with mammalian target of rapamycin
inhibitors, and recently proposed options such as therapy
with anti-EGFR antibodies and ultrasound-guided
percutaneous microwaves. However, no systematically
accepted strategy has been found that is both clinically
and economically efficient. Thus, decisions are tailored
to patients’ characteristics, resource availability, and the
clinical and technical expertise of each single center.8,11

CUTANEOUS MANIFESTATIONS OF TUBEROUS

SCLEROSIS COMPLEX
Cutaneous findings are the most common and readily
visible manifestation of TSC. More than 90% of patients Figure 12.1 Ash leaf spot.
with TSC have one or more skin lesions early in life,
although none are pathognomonic.4,12 It is important for
the pediatrician to be able to identify TSC-associated skin
manifestations to ensure prompt diagnosis, early treatment
initiation, and appropriate referral for follow-up of other
TSC-related sequelae.
The spectrum of cutaneous manifestation is wide and
includes:1,4,12,13
• Ash leaf macules, 90%
• Confetti macules, 67%
• Café au lait spots, 90%
• Angiofibromas, 73%
• Shagreen patch, 67%
• Fibrous plaque, 86%
• Periungual fibromas, 100%
• Poliosis, 100%
• Molluscum fibrosum pendulum, 100%
Ash leaf macules are the first to appear, usually at birth
or during infancy, and are present in more than 90% of
patients; shagreen patches and facial angiofibromas also
usually develop during childhood; angiofibromas typically
appear from 3–4 years of age and progressively worsen
as a patient gets older; ungual fibromas may develop
during adolescence or early adulthood. Skin lesions can Figure 12.2 Large hypopigmented macules with serrated
negatively impact a patient’s quality of life, confidence, margins.
 Ungual fibromas (Koenen tumors) 91

Hypopigmented macules are observed in about 90% of

patients with TSC and are usually elliptic in shape.13–15 In the
updated criteria,7 it was recommended that hypomelanotic
macules meet a size requirement of at least 5 mm in diameter
to distinguish hypomelanotic macules from smaller
and more numerous “confetti” lesions. Furthermore, it
is suggested to include polioses (circumscribed areas of
hypomelanosis of hair) in the hypomelanotic macule
count. While hypomelanotic macules are the more frequent
cutaneous presentation of TSC in children, they fade with
age and are detected less frequently in older patients.16
Minimally visible hypopigmented spots are more easily
visualized with a Wood’s lamp.
Congenital onset may help distinguish TSC-
related hypomelanotic macules from acquired causes
of hypopigmentation, such as vitiligo, idiopathic guttate
hypomelanosis, post-inflammatory hypopigmentation,
and hypopigmented scars.13,16,17
Treatment usually is not necessary, but is considered Figure 12.3 Shagreen patch.
for the cosmetically sensitive area of the face. An option
for this treatment can be topical mTOR inhibitors, but SHAGREEN PATCHES
long-term treatment may be necessary and the cost can be Shagreen patches are usually apparent before 10 years of
substantial.16,17 age and increase in number as a patient ages. Shagreen
patches are also a major symptom of TSC, seen most
“CONFETTI”-LIKE HYPOPIGMENTATION commonly over the lower back (Figure 12.3), in the form
“Confetti” skin lesions, another typical TSC symptom, of large plaques that have a bumpy or orange-peel surface.
are numerous 1-mm to 3-mm hypopigmented macules Smaller collagenomas on the trunk exhibit the same
scattered over regions of the body, such as the arms histologic changes as shagreen patches but are less specific
and legs. 7 This symptom is less common in children for TSC, since they may also occur as an isolated finding
with TSC but has over 50% overall prevalence. Confetti or in other genetic syndromes, including MEN1, BHD, and
skin lesions can appear any time from childhood to Cowden syndrome.21
adulthood.17–19
FIBROUS CEPHALIC PLAQUES
ANGIOFIBROMAS Histologically similar to angiofibromas, fibrous cephalic
Moreover, about 75% of TSC patients between ages 2 and plaques are regarded as the most specific skin finding
5 years develop angiofibromas on the malar regions of for TSC, present in about 25% of TSC patients.20 Initially
the face.8 Facial angiofibromas, sometimes erroneously referred to as forehead plaque, this symptom was renamed
referred to as adenoma sebaceum, are the most visually to fibrous cephalic plaque in order to increase awareness
apparent TSC-associated symptom. They are usually pink that fibrous plaques, although often located unilaterally
to red-brown papulonodules with a smooth, glistening on the forehead, may occur on other parts of the face
surface and are typically distributed symmetrically on the or scalp. If there is rapid progression of fibrous cephalic
face, at times mistaken for acne. Angiofibromas start small plaques, treatment options include surgical intervention
and gradually increase in size, with their growth being and sedation if necessary.15,20
augmented by puberty.17,20
To be regarded as a symptom of TSC, patients must UNGUAL FIBROMAS (KOENEN TUMORS)
exhibit at least three facial angiofibroma lesions, since one Ungual fibromas are smooth, firm, flesh-colored lumps
or two isolated sporadic lesions are often found among that emerge from the nail folds. Ungual fibromas are less
the general population. When there are only several common compared to other TSC-related skin findings,
angiofibromas, or if they are developed at a later age, a appearing with a frequency of about 20% overall, but
skin biopsy may be required. It is important to note that as high as 80% in older adults with TSC.15,20 They often
multiple facial angiofibromas have also been observed in develop during adolescence or adulthood and are more
Birt-Hogg-Dubé (BHD) syndrome and multiple endocrine commonly found on toenails. Longitudinal nail grooves
neoplasia type 1 (MEN1).20 without visible fibromas are also commonly seen. Less
Treatment options for facial angiofibroma could be frequent acral lesions include subungual red comets,
topical mTOR inhibitors, and there are benefits from splinter hemorrhages, and longitudinal leukonychia.20
various laser surgeries (vascular and ablative), using If lesions are symptomatic or larger than 3 mm, the
sedation with minimum surgical risks. Continual therapy treatment options include ablative laser or surgical
is necessary, because improvements are temporary.17 excision, and this treatment can be repeated if necessary.
92 Tuberous sclerosis complex

TREATMENT OF CUTANEOUS LESIONS genetics and management. J Am Acad Dermatol.

All individuals with TSC are at risk for life-threatening 2007;57:189–202.
conditions related to brain tumors, kidney lesions, or 9. Ebrahimi-Fakhari D, Mann LL, Poryo M et al.
LAM. Treatment options are aimed at managing the Incidence of tuberous sclerosis and age at first
symptoms of the disorder and often require input from diagnosis: New data and emerging trends from a
a multidisciplinary team. Continued monitoring by national, prospective surveillance study. Orphanet J
physicians experienced with TSC is crucial. Rare Dis. July 17, 2018;13(1):117.
Skin features are among the most prominent features of 10. de Vries PJ, Whittemore VH, Leclezio L et al.
TSC. Individuals diagnosed with TSC should undertake a Tuberous sclerosis associated neuropsychiatric
detailed dermatologic exam annually. Rapidly changing, disorders (TAND) and the TAND checklist. Pediatr
disfiguring, or symptomatic TSC-associated skin lesions Neurol. 2014;52(1):25–135.
should be treated as appropriate for the lesion and clinical 11. Kohrman MH. Emerging treatments in the
context, using approaches such as surgical excision, lasers, or management of tuberous sclerosis complex. Pediatr
possibly topical mTOR inhibitors. Sun protection is highly Neurol. May 2012;46(5):267–275.
recommended, since hypopigmented macules are susceptible 12. Roach ES, Gomez MR, Northrup H. Tuberous sclerosis
to sunburn, and ultraviolet-induced DNA damage may play a complex consensus conference: Revised clinical
role in the development of facial angiofibromas. Disfiguring diagnostic criteria. J Child Neurol. 1998;13:624–628.
lesions may improve with laser therapy and dermabrasion. 13. Webb DW, Clarke A, Fryer A, Osborne JP. The
Symptomatic or deforming dental lesions and oral fibromas cutaneous features of tuberous sclerosis: A population
should be treated with surgical excision or curettage. study. Br J Dermatol. 1996;135(1):1–5.
Limited data suggest that topical mTOR inhibitors such as 14. Northrup H, Koenig MK, Pearson DA et al. Tuberous
sirolimus are effective for the treatment of facial angiofibromas, Sclerosis Complex. July 13, 1999 [Updated July
ungual fibromas, and hypomelanotic macules.21,22 Long-term 12, 2018]. In: Adam MP, Ardinger HH, Pagon RA
and comparative studies between topical rapamycin and et al. eds. GeneReviews. Seattle (WA): University of
ablative techniques are required to establish which treatment Washington, Seattle; 1993–2018. Available from:
has a better outcome and a lower recurrence rate.23 https://www.ncbi.nlm.nih.gov/books/NBK1220/
Complication risks, adverse effects, cost, length of 15. Wataya-Kaneda M, Tanaka M, Hamasaki T,
treatment, and potential impact on TSC-associated Katayama I. Trends in the prevalence of tuberous
comorbidities should be considered when determining sclerosis complex manifestations: An epidemiological
the best treatment option. Management strategies should study of 166 Japanese patients. PLOS ONE.
be based on the clinical profile of each patient and on 2013;8:e63910.
evidence-based good practice guidelines. 16. Seibert D, Hong CH, Takeuchi F et al. Recognition
of tuberous sclerosis in adult women: Delayed
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CurrOpin Neurol. April 2000;13(2):115–119. 17. Cardis MA, DeKlotz CMC. Cutaneous manifestations
2. Osborne JP, Fryer A, Webb D. Epidemiology of of tuberous sclerosis complex and the paediatrician’s
tuberous sclerosis. Ann NY Acad Sci. 1991;615:125–127. role. Arch Dis Child. September 2017;102(9):858–863.
3. O’Callaghan FJ, Shiell AW, Osborne JP, Martyn CN. 18. Sehgal VN, Srivastava G. Hereditary hypo/de-pig­
Prevalence of tuberous sclerosis estimated by capture- mented dermatoses: An overview. Int J Dermatol.
recapture analysis. Lancet. 1998;351:1490. 2008;47:1041–1050.
4. Curatolo P, Bombardieri R, Jozwiak S. Tuberous 19. Jimbow K. Tuberous sclerosis and guttate
sclerosis. Lancet. 2008;23:372(9639):657–1468. leukodermas. SeminCutan Med Surg. 1997;16:30–35.
5. Rosset C, Netto CBO, Ashton-Prolla P. TSC1 and 20. Jozwiak S, Schwarz RA, Janniger CK et al. Skin
TSC2 gene mutations and their implications for lesions in children with tuberous sclerosis complex:
treatment in tuberous sclerosis complex: A review. Their prevalence, natural course, and diagnostic
Genet Mol Biol. 2017;40(1):69–79. significance. Int J Dermatol. 1998;37:911–917.
6. Caban C, Khan N, Hasbani DM, Crino PB. Genetics of 21. Wataya-Kaneda M, Ohno Y, Fujita Y et al. Sirolimus gel
tuberous sclerosis complex: Implications for clinical treatment vs placebo for facial angiofibromas in patients
practice. Appl Clin Genet. 2016;10:1–8. doi:10.2147/ with tuberous sclerosis complex: A randomized clinical
TACG.S90262 trial. JAMA Dermatol. July 1, 2018;154(7):781–788.
7. Northrup H, Krueger DA; International Tuberous 22. Sasongko TH, Ismail NF, Zabidi-Hussin Z. Rapamycin
Sclerosis Complex Consensus Group. Tuberous and rapalogs for tuberous sclerosis complex. Cochrane
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Oculocutaneous albinism
MIRA KADURINA, ANASTASIYA A. CHOKOEVA, and TORELLO LOTTI
13
CONTENTS
Introduction 93 Diagnosis 94
Epidemiology 93 Treatment 95
Etiology and pathogenesis 93 Prognosis 95
Clinical manifestations 93 References 95
Histology 94

INTRODUCTION made by the Greek Ctesis in 400 bc and the Roman Plini,
Albinism represents a large family of inherited disorders, four centuries later.7
characterized by enzyme defects, leading to impaired Nowadays, the incidence varies between racial groups, as
melanin production with decreased or absent melanin in the the highest morbidity has been found in Nigeria (1:1000), and
skin, hair, and eyes, resulting in hypo- or depigmentation, Cuna Indians in Panama (7:1000).7 Worldwide incidence
depending on the degree of lack of tyrosinase.1,2 The name of has been estimated around 1:20,000, but still varies for the
the disease comes from the Latin “albus,” meaning “white,” different phenotypes of the disease (Table 13.1). Males and
to emphasize the hallmark of its clinical manifestation. females are equally affected by this condition, although
In contrast to vitiligo, the number of melanocytes in the ocular albinism occurs primarily in males.2,3
skin is normal. This rare genetic condition can clinically
present affecting the pigmentation of the eyes only or ETIOLOGY AND PATHOGENESIS
the eyes as well as the skin and hair, resulting in ocular The variety of forms of this rare genetic condition is a
(OA) or oculocutaneous albinism (OCA), respectively. 3 result of lack or reduction of melanin in skin and eyes,
To date, seven types of nonsyndromic albinism have caused by mutations in genes involved in the biosynthesis
been described, and oculocutaneous albinism is the most of melanin pigment. Almost all of the forms are inherited
commonly presented form.1 Oculocutaneous albinism is in an autosomal recessive pattern, and they are classified
caused by a mutation in specific genes that inhibit melanin based on the identified gene defect. Mutations in genes
biosynthesis within melanocytes. The deficiency of melanin responsible for different types of oculocutaneous and
pigment causes the clinical presentations of albinism. ocular albinism include the tyrosinase gene (TYR) in
Albinism may be a clinical symptom in a variety of other OCA1. TYR hydroxylates l-tyrosine to l-DOPA and
syndromes, classified as “albinoid disorders.” Fifteen genes oxidates l-DOPA to DOPA quinone, while loss of this
are currently associated with different types of albinism, function leads to an inability to synthesize melanin.1,2
although new genes have recently been described in The product of the OCA2 gene in OCA2 is melanosome
association with autosomal recessive oculocutaneous transmembrane protein P, while the OCA3 gene in OCA3
albinism, which is phenotypically similar, but with diverse produces the tyrosinase-related protein-1 gene (TYRP1),
molecular origin.1,2,4 Clinical manifestation depends on the responsible for the stabilization and modulation of the
residual activity of tyrosinase, as well as on the underlying activity of tyrosinase and contributing to melanosome
genetic mutation, impairing different levels of melanin integrity. The SLC45A2 gene in OCA4 codes for a solute
production, accumulation, or melanosome function.1 Mild, carrier family 45, member 2 membrane-associated
moderate, or severe visual problems are associated with transport protein (MATP), associated with the transport
almost all of the clinical types of OCA.5 Other associated substances required for melanin biosynthesis into the
symptoms, such as mental retardation, anemia or bleeding, melanosome.1,4 The former separation between tyrosinase-
deafness, recurrent infections, and so on, should direct the positive and tyrosinase-negative types of albinism has been
clinician’s differential diagnostic plan toward the diagnosis replaced by a gene defect–based classification (Table 13.1).
of other syndromes. Hermansky-Pudlak syndrome,
Chediak-Higasi syndrome, and Griscelli syndrome are CLINICAL MANIFESTATIONS
thought to represent OCA with systemic manifestations The two main affected organs in albinism are the skin and
and will be described in detail in separate chapters.6 eyes. However, patients with ocular albinism may also have
skin problems, while patients with cutaneous albinism
EPIDEMIOLOGY show ocular findings quite often.7 The degree of hypo- and
The condition was first described in detail by Pearson et al. depigmentation varies widely between the different types of
in 1911, but the earliest description of this disorder was albinism based on the activity of tyrosinase. Patients with
93
94 Oculocutaneous albinism

Table 13.1 Prevalence and genetics of albinism

Worldwide Pattern of
Type of albinism prevalence Most commonly seen in inheritance Gene defect
OCA1 1:40,000 America, China AR The TYR gene; product: tyrosinase
OCA2 1:39,000 African Americans, AR OCA2 gene; product: OCA2 melanosome
Sub-Saharan Africa transmembrane protein P
OCA3 1: 8500 Southern Africa, Pakistan, AR The TYRP1 gene; product: tyrosinase-related
Germany, India, Japan protein 1
OCA4 1:100,000 Japan, Turkey, Korea, AR SLC45A2 gene codes for a solute carrier family
Morocco 45, member 2 membrane-associated transport
protein (MATP)
OCA5 Very rare Pakistan AR Not identified
OCA6 Very rare China, India SLC24A5 gene (solute carrier family 24, member
5) codes for a Na/K/Ca cation exchange
protein
OCA7 Very rare AR LRMDA gene (leucine-rich melanocyte
differentiation–associated protein)
Ocular albinism 1: 50,000 X-linked GPR143 gene
Source: Federico JR, Krishnamurthy K. Albinism. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; January 2018–July 28, 2018.

completely inactive tyrosinase are totally depigmented divided into refractive and nonrefractive errors, including
at birth with no melanin in irises and retina, leading to photophobia, foveal hypoplasia with lack of foveal reflex,
red reflex and severe ocular defects. Their hair is totally nystagmus, strabismus with binocular vision, reduced fine
white, and they never get darker or tanned. If there is some depth perception, and iris pigmentation and refractive
degree of functional tyrosinase, it may lead to some hair disorders such as astigmatism, myopia, pyperopia, and
color, seen in patients with the so-called OCA1-b form of so on. Pigmented disorders can also be presented as
albinism, where a mild degree of skin pigmentation may iris transillumination, yellow or orange retina due to
develop later in life. One extremely rare form of OCA1-B hypomelanosis of retinal epithelium with prominent
is the so-called “temperature-sensitive OCA1-b,” where choroidal vessels.2,10
tyrosinase is only active when the temperature is lower
than the body temperature, resulting in some degree of HISTOLOGY
peripheral pigmentation of the extremities.1,3,7 The histopathologic examination is not helpful. In contrast
OCA2 is the most common form among the tyrosinase- to vitiligo, normal melanocytes are present and skin defects
positive types of albinism. Although totally depigmented are not observed in hematoxylin and eosin staining. Special
at birth, patients develop some degree of pigmentation later melanin staining such as dopa oxidase or HMB45 could be
in life. The clinical findings in MATP-related albinism moderately positive. Specific histologic features could be
(OCA4) are almost similar. seen only in some of the albinoid disorders.7,11
In so-called “red albinism” (OCA3), patients have
tan skin and red-brown hair. The irises are pigmented. DIAGNOSIS
The condition most commonly affects dark-skinned The diagnosis of albinism is basically clinical. Skin
individuals (Africans and African Americans), and it is depigmentation at birth as a clinical finding should always
caused by defects in the P gene. The condition is known as include albinism in a differential diagnostic plan. Evaluation
“brown” or “rufous” OCA and it is often diagnosed because should focus on hair and skin color, presence of freckles and
of the associated ocular problems.1,7,8 ability to tan, evaluation of pigmented and nonpigmented
Ocular albinism is associated with mutations in the GPR143 melanocytic nevi, and ophthalmologic evaluation for eye
gene, resulting in dysfunctional melanosome biogenesis with visual acuity.1,2 The diagnosis is often made at birth as the
“macromelanosomes.” The pigment dysfunction is limited skin and hair color of the baby will be much lighter or paler
to the eyes, and the ocular problems are severe, including than the rest of the family. The presence of light patches on
nystagmus, foveal hypoplasia, and photophobia with the skin is a clue to the presence of albinism. The diagnostic
impaired visual acuity. Pale skin may be seen in addition. approach will include a physical examination, including
Almost all of the female carriers show X-inactivation with comparison of the pigmentation of the child with that of
pigmentary mosaicism in the retina, which is an important the parents and other members of the family.
diagnostic clue for affected male children.5,8,9 Further follow-up is also mandatory in order to assess
Importantly, ocular problems in all forms of albinism the potential residual pigmentation that can increase with
are the most concerning clinical findings. They may be time, mostly through pheomelanin. 5 Comparison with
 References 95

other family members may be also a helpful diagnostic 3. Oetting WS. Albinism. Curr Opin Pediatr.
tool. Ophthalmologic examination is also essential for 1999;11(6):565–571.
the correct diagnosis.12 As a number of vision-related 4. Suzuki T, Tomita Y. Recent advances in genetic
problems are often associated with albinism, a detailed analyses of oculocutaneous albinism types 2 and 4.
eye examination may be needed. The ophthalmologist J Dermatol Sci. 2008;51(1):1–9.
will assess the baby for nystagmus, strabismus, and 5. Kubasch AS, Meurer M. Oculocutaneous and ocular
photophobia. Electrodiagnostic testing in which small albinism. Hautarzt. 2017;68(11):867–875.
electrodes are placed on the scalp to test the connection of 6. Toro C, Nicoli ER, Malicdan MC, Adams DR,
the brain and eyes is also sometimes conducted.12 Introne WJ. Chediak-Higashi syndrome. In: Adam
Detailed directed evaluation for other associated MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH,
symptoms is essential, in order to exclude some of Stephens K, Amemiya A, ed. GeneReviews [Internet].
the albinoid disorders. Recurrent infections, mental Seattle (WA): University of Washington, Seattle;
retardation, anemia, or bleeding episodes should be a 1993–2018. March 3, 2009 [updated July 5, 2018].
diagnostic sign for an underlying syndromic albinism. 7. Ramrath K, Stolz W. Disorders of melanin pigmen­
Molecular genetic testing with multigene or com­ tation/amelanosis and hypomelanosis/albinism,
prehensive genome sequencing provide the highest Chapter 65. In: Burgdorf WHC, Plewig G, Wolf HH,
sensitivity for correct diagnosis and differentiation between Landthaler M. ed. Braun-Falco’s Dermatology. 3rd
the types of albinism.1,13 This method is expensive and not ed. Springer Verlag, Munchen, Germany; 2009, pp.
routinely applied worldwide. Prenatal diagnosis can be also 969–971.
helpful, if the genetic mutation is already identified among 8. Kamaraj B, Purohit R. Mutational analysis of
family members.1 oculocutaneous albinism: A compact review. Biomed
Res Int. 2014;2014:905472.
TREATMENT 9. Mártinez-García M, Montoliu L. Albinism in Europe.
There is no curative treatment for albinism and associated J Dermatol. 2013;40(5):319–24.
conditions. The most essential part of the patients’ 10. Khordadpoor-Deilamani F, Akbari MT, Karimipoor
education is to maximize light (ultraviolet radiation M, Javadi G. Sequence analysis of tyrosinase gene
A and B) protection with high sun protection factors, in ocular and oculocutaneous albinism patients:
protective clothing, and sunglasses. Collaboration with introducing three novel mutations. Mol Vis.
an experienced ophthalmologist is needed for optimal 2015;21:730–735. eCollection 2015.
management of the visual problems.12 Dermatologic 11. Dotta L, Parolini S, Prandini A, Tabellini G, Antolini
follow-up is crucial for the timely diagnosis and M, Kingsmore SF, Badolato R. Clinical, laboratory
management of cutaneous malignancies. Patients should and molecular signs of immunodeficiency in patients
be educated in self-skin examination with the melanoma with partial oculo-cutaneous albinism. Orphanet J
ABCDE rules.1 Recent clinical trials established that Rare Dis. October 17, 2013;8:168.
nitisinone (an inhibitor of 4-hydroxyphenylpyruvate 12. Kirkwood BJ. Albinism and its implications with
dioxygenase) can trigger tyrosine accumulation in blood, vision. Insight. 2009;34(2):13–166.
suggesting that it could improve pigmentation in OCA1B 13. Montoliu L, Grønskov K, Wei AH, Martínez-
patients.14 Potential gene therapy includes adeno-associated García M, Fernández A, Arveiler B, Morice-Picard
viruses’ vectors, introducing a functional copy of the F, Riazuddin S, Suzuki T, Ahmed ZM, Rosenberg
tyrosinase gene in OCA1 and OA1 patients, but clinical T, Li W. Increasing the complexity: New genes and
trials are still missing.1 new types of albinism. Pigment Cell Melanoma Res.
2014;27(1):11–18.
PROGNOSIS 14. Onojafe IF, Adams DR, Simeonov DR, Zhang J, Chan
The overall lifetime prognosis is not affected in OCA. The CC, Bernardini IM, Sergeev YV, Dolinska MB, Alur
mortality rate is due to a higher incidence of cutaneous RP, Brilliant MH, Gahl WA, Brooks BP. Nitisinone
malignancies. Although rare, albinism patients could improves eye and skin pigmentation defects in a
be also affected by melanoma, because of the preserved mouse model of oculocutaneous albinism. J. Clin.
melanocyte number and distribution.15 Squamous Invest. 2011;121(10):3914–3923.
cell carcinoma is the most commonly seen cutaneous 15. Emadi SE, Juma Suleh A, Babamahmoodi F,
malignancy among albinism patients (75%), with increased Ahangarkani F, Betty Chelimo V, Mutai B,
relative risk up to 1000 times, followed by basal cell Raeeskarami SR, Ghanadan A, Emadi SN. Common
carcinoma (23.4%) and melanoma (1.6%).16 malignant cutaneous conditions among albinos in
Kenya. Med J Islam Repub Iran. 2017;31:3.
REFERENCES 16. Mabula JB, Chalya PL, Mchembe MD, Jaka H, Giiti
1. Federico JR, Krishnamurthy K. Albinism. StatPearls G, Rambau P, Masalu N, Kamugisha E, Robert
[Internet]. Treasure Island, FL: StatPearls Publishing; S, Gilyoma JM. Skin cancers among albinos at
January 2018 – July 28, 2018. a university teaching hospital in Northwestern
2. Orlow SJ. Albinism: An update. Semin Cutan Med Tanzania: A retrospective review of 64 cases. BMC
Surg. 1997;16(1):24–29. Dermatol. 2012;12:5.
Hermansky-Pudlak syndrome, Chediak-
Chigasi syndrome, and Griscelli
14
syndrome
VESNA PLJAKOSKA, SILVIJA DUMA, and ANDREJ PETROV

CONTENTS
Hermansky-Pudlak syndrome 97 Griscelli syndrome 99
Chediak-Higashi syndrome 98 References 99

HERMANSKY-PUDLAK SYNDROME Initial clinical symptoms of HPS often include bleeding

Introduction diathesis (bleeding from the nose, gums, or surgical
wounds, especially in women during menstruation).
Hermansky-Pudlak syndrome (HPS) is an autosomal
Bleeding may become life-threatening, and aspirin may
recessive and a rare genetic group of disorders associated
deteriorate the bleeding.
with oculocutaneous albinism, bleeding diathesis,
In addition to prolonged bleeding, classic symptoms
granulomatous colitis, and highly penetrant pulmonary
of Hermansky-Pudlak syndrome include a lack of color
fibrosis in some subtypes.1–3 The disorder was initially
(pigmentation) in the skin, hair, and eyes, known as
identified in 1959 and was named after the two
oculocutaneous albinism, and the color may vary from very
Czechoslovakian pathologists, Hermansky and Pudlak, who
pale to almost normal coloring. Retinal hypopigmentation
were the first to identify patients with a unique combination
is characterized by reduced iris and retinal pigment
of oculocutaneous albinism and bleeding diathesis.
associated with a severe decline in visual acuity and
Prevalence and prognosis horizontal nystagmus. Tyrosinase-positive oculocutaneous
albinism implies that the eumelanin, that is, the brown/
Hermansky-Pudlak syndrome is a rare hereditary
black pigment, is absent from hair, eyes, and skin, while
disorder, with a worldwide prevalence of 1–9 in 1,000,000
pheomelanin or the yellow/orange pigment is present
individuals,4 though prevalence differs per subtype and
and builds up with age.7 It is important to note that the
region. The disorder is more commonly found in certain
degree of albinism varies and can be subtle in HPS patients,
populations of the world. For example, the prevalence of
potentially masked by use of hair-coloring products.
certain subtypes of HPS is significantly higher in Puerto
Pulmonary fibrosis occurs in HPS patients with subtypes
Rico.5 Individuals with HPS have also been identified in
1, 2, or 4, which may prove fatal in their 30s, 40s, or 50s.8
other regions, including China, India, South America,
The differential diagnosis of HPS includes Chediak-
and Western Europe. Although initial symptoms usually
Higashi syndrome, a recessive disorder that shares the
appear in infancy or early childhood, they may develop
features of mild albinism and bleeding.9
at an older age as well. The prognosis for patients with
HPS varies depending on the subtype. The course of
subtypes 3, 5, and 6, or HPS without pulmonary fibrosis as Diagnosis
a complication, is mild with no pulmonary involvement. The diagnosis of HPS is established by clinical findings of
Prognosis of subtypes 1, 2, and 4 is poor, as pulmonary hypopigmentation of the skin and hair, characteristic eye
fibrosis is fatal.4 findings, and demonstration of absent delta granules (dense
bodies) on whole-mount electron microscopy of platelets.10
Clinical features Furthermore, high-resolution computed tomography of
Depending on the genetic mutation that causes the the chest (HRCT) is used for diagnosing interstitial lung
disorder, there are 10 subtypes of human HPS identified disease.
to date. These mutations, observed in HPS patients, are Should clinical features prove inconclusive, the
known to cause impairment of the specialized secretory diagnosis is confirmed via identification of biallelic
cells, including melanocytes, platelets, and lung alveolar pathogenic variants in the protein coding genes associated
type II epithelial cells.6 Different symptoms are associated with the disorder.11 Genetic testing is recommended to
with the different subtypes of HSP. determine the specific disease subtype in individuals with

97
98 Hermansky-Pudlak syndrome, Chediak-Chigasi syndrome, and Griscelli syndrome

HPS10 (multigene panel containing the 10 genes associated Clinical features

with HPS). However, platelet transmission electron Eight known gene allele defects are associated with the
microscopy (PTEM), used to determine hereditary platelet Chediak-Higashi disorder.18 Patients with CHS exhibit
disorders, is currently available only in a limited number hypopigmentation, immunodeficiency and recurring
of laboratories. infections, mild coagulation defects, and different levels of
Management neurological dysfunction.19
The classical, early-onset CHS phase is known as the
HPS patients with oculocutaneous albinism are at an accelerated phase, with a mortality rate of 90% in the
increased risk of skin cancers, such as squamous and basal first decade of life. While this phase was initially thought
cell carcinomas, as well as melanoma. Recommendations to be caused by a malignancy, such as lymphoma, it is
toward the prevention of complications include protection now known to be hemophagocytic lymphohistiocytosis,
from the sun starting from a young age, as well as yearly associated with multiorgan inflammation. In addition to
screening examinations by a dermatologist. this classical, early-onset CHS phase, patients might also
Furthermore, HPS patients with bleeding diathesis have a later-onset form, known as atypical CHS phenotype.
should be evaluated and managed by a hematologist, They exhibit abnormal granules within leukocytes, with
and female patients should be also evaluated by neurodegeneration as the predominant symptom with
gynecologists if abnormally abundant menstrual bleeding only mild alterations in pigmentation, immune function,
is present. If present, gastrointestinal complications and reduced platelet-dense bodies with subtle bleeding
associated with ceroid deposition, such as gastroduodenitis, manifestations.16 These patients have subtle or absent
proctocolitis, or a granulomatous colitis, should be oculocutaneous albinism, as well as insignificant infections
addressed by gastroenterologists. In addition, patients or infections that become less frequent with age. Patients
with subtypes 1, 2, or 4 should be diagnosed and managed with this phenotype may be diagnosed after the third
by a pneumologist, due to the risk of developing severe decade of life.
pulmonary fibrosis. CHS patients often exhibit various neurological issues.
Neurological manifestations include strokes, coma, ataxia,
CHEDIAK-HIGASHI SYNDROME
tremor, motor and sensory neuropathies, and absent deep-
Introduction tendon reflexes.
Chediak-Higashi syndrome (CHS) is a rare autosomal In terms of partial oculocutaneous albinism, the
recessive disorder, characterized by partial oculocutaneous quantity of pigment dilution can vary from normal, partial,
albinism, immunodeficiency, recurring infections, mild or totally absent on skin, hair, and eyes. The classical form
bleeding tendency, and various neurological issues.12–14 of the disease is characterized by a metallic or “silvery”
This disorder was first reported by Beguez Cesar, a Cuban appearance of the hair, observable under a light microscope.
pediatrician, in 1943.15 A decrease in pigmentation of the iris leads to a decrease
in pigmentation of the retina. The visual acuity may be
Prevalence and prognosis affected, and patients can either have normal acuity or
With fewer than 500 cases reported worldwide, the exact exhibit some moderate impairment. Other ophthalmologic
prevalence of CHS is unknown.16 The disorder can appear symptoms include photophobia, increasing red reflex, and
in individuals of all age groups. There are two types of a horizontal or rotating nystagmus.
CHS: classic and late onset. Predominantly, the classical Skin infections and upper respiratory tract infections
accelerated CHS phase affects newborns and children are some of the most common infections associated with
under the age of 5. Generally, a mutation resulting in a CHS. Affected individuals often have recurring bacterial
loss of neurological function leads to a severe childhood and fungal infections with staphylococcal, streptococcal,
onset of the disease. Milder than the classic form, the late- pneumococcal, and beta-hemolytic species. Periodontitis
onset form occurs later in childhood or adulthood, and has been identified as an important indicator of immune
individuals experience minor pigmentation changes and dysfunction and can help in establishing the correct
are less likely to develop severe infections, but are at risk of diagnosis.
developing neurological problems. When it comes to bleeding tendency among individuals
It has been observed that the severity of the disease with CHS, epistaxis, mucosal, or gum bleeding are usually
correlates with the molecular phenotype, as well as the mild symptoms and generally do not require any medical
cellular phenotype. In terms of race or ethnicity, no intervention.
predilection is determined. The differential diagnosis for CHS should include other
CHS patients have poor prognosis if the disorder is left genetic conditions with oculocutaneous albinism, such as
untreated. Most children with the classic form die within Hermansky-Pudlak syndrome and Griscelli syndrome.
the first 10 years of their lives as a result of chronic infections
or organ failure. Patients with late-onset CHS may live Diagnosis
with the disorder into early adulthood, but typically have Clinical diagnosis can be given to patients with
shorter lifespans due to complications.17 immunodeficiency; pigment dilution of the skin, hair, or
 References 99

eyes; congenital or transient neutropenia; and signs of delayed development, intellectual disability, seizures, weak
unexplained neurologic symptoms or neurodegeneration. muscle tone (hypotonia), and eye and vision abnormalities.
Light microscopy and polarized microscopy of hair shafts Type II27 is caused by a mutation in the RAB27A gene, and
aids in the differential diagnosis of CHS.20 presents with hypopigmentation, combined with variable
Specific molecular genetic testing, which can include cellular immunodeficiency. Prone to recurring infec­
single-gene testing or multigene panel testing, can be tions, affected individuals may develop hemophagocytic
conducted in order to detect the biallelic variants in the lymphohistiocytosis, which manifests by overproduction
LYST gene.17 Molecular genetic testing is necessary for and infiltration of activated histiocytes (T lymphocytes
detecting the carrier status of the parents, since CHS and macrophages), which may damage various organs and
follows an autosomal recessive pattern of inheritance. The tissues, occasionally with a fatal outcome. Type III28 is also
best time for determining genetic risk is before pregnancy. characterized by hypomelanosis, but without neurological
or immunological manifestations. This type may result from
Management a mutation in melanophilin (MLPH) or the MIO5A gene.
CHS patients have poor prognosis if the disorder is left GS differs from Chediak-Higashi syndrome by
untreated. The hematological and immune deficiency the evident lack of observable giant granules in GS
associated with the accelerated phase, which usually granulocytes.
develops in the first 10 years of life, can only be cured with
an allogeneic hematopoietic stem cell transplantation Diagnosis
(HSCT), which should be performed as soon as the diagnosis Clinical diagnosis can be made in individuals who exhibit
is established.21 Nevertheless, neurological problems may symptoms caused by the mutations in the MYO5A or
occur despite the bone marrow transplantation. RAB27A gene. These include pigmentary dilution, such
Since individuals with CHS exhibit varying degrees of as granulomatous skin lesions, partial albinism, and
hypopigmentation, CHS patients should apply sunscreen generalized lymphadenopathy. The hair appears silvery
with a high protection factor to prevent skin cancers and gray, silvery, grayish golden, or dusty, and the skin is pale.
skin damage. The SPF is in direct correlation to the severity Similar to Chediak-Higashi syndrome, light microscopy
of the hypopigmentation. Furthermore, sunglasses should and polarized microscopy of hair shafts aids in the
be worn for protecting sensitive eyes against UV rays.22 differential diagnosis of Griscelli syndrome.20
Depending on the type, patients can also be diagnosed
GRISCELLI SYNDROME
by other internal organ abnormalities. Patients with
Introduction type II GS may exhibit hemiparesis, peripheral facial
Initially identified by Griscelli and Prunieras in 1978, palsy, spasticity, seizures, psychomotor retardation, and
Griscelli syndrome (GS) is a rare autosomal recessive severe retarded psychomotor development, as well as
disorder characterized by unusual hypopigmentation of hepatosplenomegaly and jaundice. Furthermore, partial
skin and hair, as well as immunodeficiency.23 ocular albinism has been observed in some patients, but
retinal degeneration has not been reported.
Prevalence and prognosis Since Griscelli syndrome is an autosomal recessive
The exact prevalence of GS is unknown. There are around disorder, genetic testing should be performed. Prenatal
100 cases reported worldwide, mostly from Turkish and diagnosis of type I and type II can be performed through
Mediterranean populations.24 The age and onset of the chorionic villus sampling by the sequencing of the MYO5A
disorder range between 4 months to 7 years, and there is or the RAB27A gene.
no sex predilection. In most patients, GS usually manifests
Management
between the ages of 4 months to 7 years, with the youngest
occurring at 1 month. type II appears to be the most The treatment and/or management of the disorder
common of the three known types of GS. depends on the subtype. There is no treatment for patients
The prognosis for patients with type I depends on the with type I, and their quality of life depends on the
severity of their neurological impairment, and there is no severity of their neurological impairment. For patients
cure. Bone marrow transplant extend survival for patients with type II, the only real preventive treatment against
with type II. the development of hemophagocytic lymphohistiocytosis
is early bone marrow transplant. Certain studies have
Clinical features used antibiotics and antiviral agents for treatment,
Griscelli syndrome is classified into three types, depending reporting mixed results.
on the gene mutation.25 Type I26 is due to MYO5A gene
mutations and is manifested by hypomelanosis, associated REFERENCES
with primary dysfunction of central nervous system. 1. Dessinioti C, Stratigos AJ, Rigopoulus D,
Patients with this type of GS exhibit silvery-gray sheen Katsambas AD. A review of genetic disorders of
of their hair and light-colored skin, as well as early and hypopigmentation: Lessons learned from the biology
severe psychomotor retardation. They typically have of melanocytes. Exp Dermatol. 2009;18:741–749.
100 Hermansky-Pudlak syndrome, Chediak-Chigasi syndrome, and Griscelli syndrome

2. Scheinfeld NS. Syndromic albinism: A review 16. Ajitkumar A, Ramphul K. Chediak Higashi syndrome.
of genetics and phenotypes. Dermatol Online J. [Updated June 10, 2018]. In: StatPearls [Internet].
December 2003;9(5):5. Treasure Island (FL): StatPearls Publishing; 2018.
3. Hermansky F, Pudlak P. Albinism associated with https://www.ncbi.nlm.nih.gov/books/NBK507881/
hemorrhagic diathesis and unusual pigmented 17. Toro C, Nicoli ER, Malicdan MC et al. Chediak-
reticular cells in the bone marrow: Report of two cases Higashi syndrome. In: Adam MP, Ardinger HH,
with histochemical studies. Blood. 1959;14:162–169. Pagon RA et al. eds. GeneReviewsSeattle (WA):
4. Data provided by Orphanet (www.orpha.net), the University of Washington, Seattle; 2009:1993–2018.
European website providing information about https://www.ncbi.nlm.nih.gov/books/NBK5188/
orphan drugs and rare diseases. 18. Solomons HD. Hermansky-Pudlak/Chediak-Higashi
5. “HPS most prevalent in persons from northwest syndromes. Cardiovasc J Afr. 2012;23(6):312.
Puerto Rico, where the disorder affects one of every 19. Dotta L, Parolini S, Prandini A et al. Clinical,
1.800 individuals,” according to the data published laboratory and molecular signs of immunodeficiency
by NORD, the National Organisation of Rare in patients with partial oculo-cutaneous albinism.
Disorders, https://rarediseases.org/rare-diseases/ Orphanet J Rare Dis. 2013;8:168. Published October
hermansky-pudlak-syndrome/ 17, 2013.
6. Berber I, Erkurt MA, Kuku I et al. Hermansky- 20. Valente NY, Machado MC et al. Polarized light
Pudlak syndrome: A case report. Case Rep Hematol. microscopy of hair shafts aids in the differential
2014;2014:249195–6. diagnosis of Chédiak-Higashi and Griscelli-
7. Ramsay M, Colman MA, Stevens G et al. The Prunieras syndromes. Clinics (Sao Paulo). August
tyrosinase-positive oculocutaneous albinism locus 2006;61(4):327–332.
maps to chromosome 15q11.2-q12. Am J Hum Genet. 21. Umeda K, Adachi S. Allogeneic hematopoietic stem
1992;51:879–884. cell transplantation for Chediak-Higashi syndrome,
8. Pierson DM, Ionescu D, Qing G et al. Pulmonary Pediatr Transplant. March 2016;20(2):271–275.
fibrosis in Hermansky-Pudlak syndrome: A case 22. Goding CR. Melanocytes: the new black. Int J
report and review. Respiration. 2006;73(3):382–395. Biochem Cell Biol. 2007;39:275–279.
9. El-Chemaly S, Young LR. Hermansky-Pudlak 23. Griscelli C, Prunieras M. Pigment dilution and
syndrome. Clin Chest Med. 2016;37(3):505–511. immunodeficiency: A new syndrome. Int J Dermatol.
10. Huizing M, Malicdan MCV, Gochuico BR et al. December 1978;17(10):788–791.
Hermansky-Pudlak syndrome. In: Adam MP, 24. Cağdaş D, Ozgür TT, Asal GT, Tezcan I, Metin A,
Ardinger HH, Pagon RA et al. eds. GeneReviews. Lambert N, de Saint Basile G, Sanal O. Griscelli
Seattle (WA): University of Washington, Seattle; syndrome types 1 and 3: Analysis of four new cases and
2000:1993–2018. https://www.ncbi.nlm.nih.gov/sites/ long-term evaluation of previously diagnosed patients.
books/NBK1287/ Eur J Pediatr. October 2012;171(10):1527–1531.
11. Oshima J, Martin GM, Hisama FM. Werner 25. Tardieu M, Rostasy K. Neurological expression of
syndrome. In: Adam MP, Ardinger HH, Pagon RA genetic immunodeficiencies and of opportunis-
et al., eds. GeneReviews. Seattle (WA): University of tic infections. In: Handbook of Clinical Neurology.
Washington, Seattle, 2002:1993–2018. https://www. 2013;112:1219–1227. doi:10.1016/B978-0-444-52910-
ncbi.nlm.nih.gov/books/NBK1514/ 7.00044-1.
12. Chediak MM. New leukocyte anomaly of 26. Ménasché G, Ho CH, Sanal O, Feldmann J, Tezcan I,
constitutional and familial character. Rev Hematol. Ersoy F, Houdusse A, Fischer A, de Saint Basile G.
1952;7:362–367. Griscelli syndrome restricted to hypopigmentation
13. Higashi O. Congenital gigantism of peroxidase results from a melanophilin defect (GS3) or a MYO5A
granules: The first case ever reported of qualitative F-exon deletion (GS1). J Clin Invest. 2003;112:450–456.
abnormity of peroxidase. Tohoku J Exp Med. 27. Bizario JC, Feldmann J, Castro FA, Ménasché G,
1954;59:315–332. Jacob CM, Cristofani L, Casella EB, Voltarelli JC, de
14. Sato A. Chédiak and Higashi’s disease: Probable Saint-Basile G, Espreafico EM. Griscelli syndrome:
identity of a new leucocytal anomaly (Chédiak) Characterization of a new mutation and rescue of
and congenital gigantism of peroxidase granules T-cytotoxic activity by retroviral transfer of RAB27A
(Higashi) Tohoku. J Exp Med. 1995;61:201–210. gene. J Clin Immunol. July 2004;24(4):397–410.
15. Beguez-Cesar AB. Neutropenia crónica maligna 28. Van Gele M, Dynoodt P, Lambert J. Griscelli
familiar con granulaciones atípicas de los leucocitos. ­synd­rome: A model system to study vesicular
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1943;15:900–922. 268–282.
Piebaldism
JOVAN LALOŠEVIĆ and MILOŠ NIKOLIĆ
15
CONTENTS
Introduction 101 Histopathology 103
Epidemiology 101 Differential diagnosis 103
Etiopathogenesis 101 Treatment 103
Clinical presentation 101 References 104

INTRODUCTION piebaldism.7 Patients with piebaldism that have no c-KIT

Piebaldism is an uncommon autosomal dominant disorder mutations are found to have heterozygous deletions in the
characterized by congenital white skin (leukoderma) SLUG coding region.8
and white hair (poliosis) on the frontal scalp, forehead,
ventral trunk, and extremities. This condition has been CLINICAL PRESENTATION
documented throughout history, from the ancient The most prominent characteristic is the white forelock
Egyptians to the slave plantations of South America. The (poliosis) (Figures 15.1 and 15.2) present in 80%–90% of
term piebald stems from the Latin word for magpie and is patients with piebaldism. The white forelock typically
used to describe animals whose bodies are covered in black appears in a triangular shape and the underlying skin of
and white patches.1 the scalp also is amelanotic (Figure 15.1). The eyebrows
and eyelashes may also be involved9 (Figure 15.1). Together
EPIDEMIOLOGY with poliosis, patients may have leukoderma, classically
Piebaldism is a rare genodermatosis. Its incidence is distributed on the central forehead and anterior trunk
estimated at less than 1/20,000 newborns.2 (Figure 15.3), with extension on the flanks, anterior
aspects of the medial arm, and leg regions (Figure 15.4).
ETIOPATHOGENESIS Sparing of the dorsal midline (Figure 15.3), hands, feet,
The mast cell growth factor (c-KIT), a tyrosine kinase and periorificial area is characteristic. Leukoderma is
receptor, is involved in melanoblast expansion, survival, commonly stable throughout life, although additional
and migration. Mutations leading to reduction in hyperpigmented macules (Figures 15.3 and 15.4) may
receptors impact the survival and migration of the neural develop at or within the margins of the white patches.10
crest-derived melanoblasts, resulting in failure of their Also, there are few reports on spontaneous repigmentation
colonization at anatomical sites most distant to the neural in infants, and even more sparse reports on repigmentation
crest. Another gene required for melanoblast migration in older children and adults.11,12
and/or survival is the SLUG gene (SNAIL), a zinc finger Not unusually, patients with piebaldism may also
neural crest transcriptional factor.3–5 develop hyperpigmented macules that are not within
Piebaldism results from inactivating mutations the boundaries of leukoderma (Figure 15.5). These
or deletions of the c-KIT gene, which is mapped on are café au lait macules (CALMs) and axillary and/or
chromosome 4q12, or of the SLUG gene, located on inguinal freckles.13,14 In contrast to depigmentation, the
chromosome 8q11. These mutations result in decreased pathogenesis and genetic mechanism for development
receptor tyrosine kinase signaling, impaired melanoblast of hyperpigmentation in piebaldism remain to be
development, and a decrease in melanogenesis. 3 The elucidated. One group of authors has postulated that
number and functionality of the c-KIT depends on the mutation in the KIT proto-oncogene in piebaldism leads
type and extent of the mutations. Frameshift mutations to inadequate phosphorylation of Sprouty-related, Ena/
that result in a null gene product produce melanoblasts vasodilator-stimulated phosphoprotein homology-1
with half as many c-KIT receptors and therefore a domain-containing protein 1 (SPRED1), a protein that is
milder form of the disorder. By contrast, point missense defective in patients with neurofibromatosis 1 (NF1)-like
mutations, specifically in the tyrosine kinase domains, syndrome, leading to the loss of function. This induces
produce a nonoperational gene product, which reduces the the development of CALMs and intertriginous freckles.15
signal transduction capability to one-fourth and results In contrast to depigmentation, hyperpigmented lesions
in a more severe phenotype.6 Point missense mutations like CALMs and freckles are not constant features of
in the KIT ligand-binding domain have been identified piebaldism and their severity does not parallel the severity
in patients and present with extremely mild forms of of the depigmentation. If a patient with piebaldism has

101
102 Piebaldism

Figure 15.1 (a,b) Characteristic white forelock (poliosis) and underlying triangularly shaped leukoderma on the forehead.

Figure 15.2 (a–c) Mother and daughter with different phenotypes. Mother with a more prominent poliosis and the daughter
with a more noticeable frontal leukoderma.

Figure 15.3 (a) Amelanotic macules on the anterior part of the arms and trunk with distinctive hyperpigmented macules within
the margins of leukoderma. (b) The characteristic sparring of the dorsal midline.
 Treatment 103

DIFFERENTIAL DIAGNOSIS
There are several genetic disorders that feature either
poliosis and/or leukoderma. Waardenburg syndrome (WS)
is characterized by poliosis and leukoderma in WS types
1–4, heterochromatic irises in types 1 and 2, sensorineural
hearing loss in types 1–4, dystopia canthorum in types 1
and 3, musculoskeletal abnormalities of the upper limbs
in type 3, and Hirschsprung disease in type 4.18 Tietze
syndrome is also a rare autosomal dominant disorder
characterized by congenital deafness and stable congenital
leukoderma and poliosis, but no heterochromatic irises.19
Hypopigmented macules and rarely poliosis have been
described in patients with tuberous sclerosis. Even
though poliosis occurs in only 20% of patients with
tuberous sclerosis, it may be one of the earliest signs of the
disease.20 The previously reported Ziprkowski-Margolis
or Woolf syndrome, characterized by hypomelanosis,
deafness, and mutism, has now been included in the
Figure 15.4 Large leukodermatous patches on the anterior albinism-deafness syndrome and the gene has been
aspects of the legs. localized to Xq26.3–q27.1, but not identified.21,22 There are
reports of piebaldism phenotype associated with Marfan
syndrome, ganglioglioma, glycogen storage disease 1a,
and Rubinstein-Taybi syndrome.23–26
Poliosis and leukoderma can also be present in
certain acquired conditions. They have been commonly
associated with vitiligo, more frequently in patients
with the segmental form, with eyebrows being most
commonly affected.27 Vogt-Koyanagi-Harada syndrome
is a rare multisystem autoimmune disease that affects
tissues containing melanin, including the eye, inner
ear, meninges, and skin. The disease is characterized
by bilateral uveitis associated with vitiligo, poliosis,
aseptic meningitis, tinnitus, dysacusis, and alopecia. 28
Alezzandrini syndrome is a condition characterized by
unilateral degeneration of the retina, unilateral vitiligo,
poliosis, and hearing abnormalities.29 White hair is often
noted with early hair regrowth in alopecia areata (AA).
Pigmented hairs are selectively affected in AA and may
result in sudden whitening of a salt-and-pepper scalp.30,31
In sarcoidosis, poliosis can be present on the eyelashes, in
the setting of uveitis.32 Also, it can be a manifestation of
chronic blepharitis.33
There are single reports on hypopigmented hair
arising from an underlying neurofibroma or a melanoma.
Figure 15.5 Café au lait macule (black arrow) arising In the case of melanoma, it was postulated that the
outside the leukoderma margins on the trunk. depigmentation was probably due to immune destruction
of the melanocytes by cytotoxic lymphocytes. In case of
neurofibroma, the authors postulated that pathogenesis
CALMs and intertriginous freckling, this does not of poliosis is either due to cytotoxic T cells targeting
necessarily represent a coexistence of NF1, regardless of neurofibroma cross-reacting with the melanocytes of the
the sufficient clinical criteria for the diagnosis of NF1.16,17 hair bulbs, or due to neurochemical mediators secreted by
neurofibroma, cytotoxic to melanocytes.34,35
HISTOPATHOLOGY
Melanocytes are absent or considerably reduced in TREATMENT
depigmented patches both by light and electron microscopy. Piebaldism is a disease in which depigmented skin
The hyperpigmented macules are characterized by an areas are unresponsive to topical or light treatment. The
normal number of melanocytes with plenty of melanosomes nonpigmented patches are at an increased risk of sunburn
in them and in keratinocytes.9 and skin cancer related to excessive sun exposure; therefore,
104 Piebaldism

sunscreen should be used frequently. Topical treatments 12. Frances L, Betlloch I, Leiva-Salinas M, Silvestre
with makeup or artificial pigmenting agents, for example, JF. Spontaneous repigmentation in an infant with
dihydroxyacetone (the ingredient used in sunless tanning piebaldism. Int J Dermatol. 2015;54(6):e244–e246.
products) that causes the skin to turn brown/dark by 13. Spritz RA, Itin PH, Gutmann DH. Piebaldism
polymerizing the amino acids and amino groups, could be and neurofibromatosis type 1: Horses of very
used in patients who are still not old enough for grafting different colors. J Invest Dermatol. 2004;122(2):​
procedures.36 xxxiv–xxxv.
Depigmented areas may be treated with autografting 14. Sarma N, Chakraborty S, Bhanja DC, Bhattachraya
of normal skin or melanocytes into amelanotic areas, SR. Piebaldism with non-intertriginous freckles:
either by thin split-thickness grafts and minigrafting or What does it mean? Indian J Dermatol Venereol
with in vitro cultured epidermis and suction epidermal Leprol. 2014;80(2):163–165.
grafting. 37,38 A large retrospective study concluded that 15. Chiu YE, Dugan S, Basel D, Siegel DH. Association
stable types of leucoderma, that is, segmental vitiligo of piebaldism, multiple cafe-au-lait macules, and
and piebaldism, responded in most cases with 100% intertriginous freckling: Clinical evidence of a
repigmentation, regardless of the surgical method that common pathway between KIT and Sprouty-
was used.39 Phototherapy alone is insufficient, but could related, Ena/vasodilator-stimulated phosphoprotein
be used to prepare the recipient site before cell suspension homology-1 domain containing protein 1 (SPRED1).
transplantation or after the transplantation to enhance Pediatr Dermatol. 2013;30(3):379–382.
melanocyte migration.38,40 16. Jia WX, Xiao XM, Wu JB et al. A novel missense
KIT mutation causing piebaldism in one Chinese
REFERENCES family associated with cafe-au-lait macules and
1. Huang A, Glick SA. Piebaldism in history—“The intertriginous freckling. Ther Clin Risk Manag.
Zebra People.” JAMA Dermatol. 2016;152(11):1261. 2015;11:635–638.
2. Debbarh FZ, Mernissi FZ. Piebaldisme: A rare 17. Nagaputra JC, Koh MJA, Brett M, Lim ECP, Lim
genodermatosis. Pan Afr Med J. 2017;27:221. HW, Tan EC. Piebaldism with multiple cafe-au-lait-
3. Dessinioti C, Stratigos AJ, Rigopoulos D, like hyperpigmented macules and inguinal freckling
Katsambas AD. A review of genetic disorders of caused by a novel KIT mutation. JAAD Case Rep.
hypopigmentation: Lessons learned from the biology 2018;4(4):318–321.
of melanocytes. Exp Dermatol. 2009;18(9):741–1269. 18. Pingault V, Ente D, Dastot-Le Moal F, Goossens
4. Perez-Losada J, Sanchez-Martin M, Rodriguez- M, Marlin S, Bondurand N. Review and update of
Garcia A et al. Zinc-finger transcription factor SLUG mutations causing Waardenburg syndrome. Hum
contributes to the function of the stem cell factor c-kit Mutat. 2010;31(4):391–406.
signaling pathway. Blood. 2002;100(4):1274–1286. 19. Smith SD, Kelley PM, Kenyon JB, Hoover D. Tietz
5. Tomita Y, Suzuki T. Genetics of pigmentary syndrome (hypopigmentation/deafness) caused by
disorders. Am J Med Genet C Semin Med Genet. mutation of MITF. J Med Genet. 2000;37(6):446–448.
2004;131c(1):75–81. 20. Sleiman R, Kurban M, Succaria F, Abbas O. Poliosis
6. Spritz RA. The molecular basis of human piebaldism. circumscripta: Overview and underlying causes. J
Pigment Cell Res. 1992;5(5 Pt 2):340–343. Am Acad Dermatol. 2013;69(4):625–633.
7. Fleischman RA, Gallardo T, Mi X. Mutations in 21. Jacob AN, Kandpal G, Gill N, Kandpal RP. Toward
the ligand-binding domain of the kit receptor: expression mapping of albinism-deafness syndrome
An uncommon site in human piebaldism. J Invest (ADFN) locus on chromosome Xq26. Somat Cell Mol
Dermatol. 1996;107(5):703–706. Genet. 1998;24(2):135–140.
8. Sanchez-Martin M, Perez-Losada J, Rodriguez- 22. Shiloh Y, Litvak G, Ziv Y et al. Genetic mapping of
Garcia A et al. Deletion of the SLUG (SNAI2) gene X-linked albinism-deafness syndrome (ADFN) to
results in human piebaldism. Am J Med Genet A. Xq26.–q27.I. Am J Hum Genet. 1990;47(1):20–27.
2003;122a(2):125–132. 23. Bansal L, Zinkus TP, Kats A. Poliosis with a rare
9. Agarwal S, Ojha A. Piebaldism: A brief report and association. Pediatr Neurol. 2018;83:62–63.
review of the literature. Indian Dermatol Online J. 24. Ghoshal B, Sarkar N, Bhattacharjee M, Bhattacharjee
2012;3(2):144–147. R. Glycogen storage disease 1a with piebaldism.
10. Oiso N, Fukai K, Kawada A, Suzuki T. Piebaldism. J Indian Pediatr. 2012;49(3):235–236.
Dermatol. 2013;40(5):330–335. 25. Herman KL, Salman K, Rose LI. White forelock in
11. Arase N, Wataya-Kaneda M, Oiso N et al. Marfan’s syndrome: An unusual association, with
Repigmentation of leukoderma in a piebald patient review of the literature. Cutis. 1991;48(1):82–84.
associated with a novel c-KIT gene mutation, G592E, 26. Herranz P, Borbujo J, Martinez W, Vidaurrazaga C,
of the tyrosine kinase domain. J Dermatol Sci. Diaz R, Casado M. Rubinstein-Taybi syndrome with
2011;64(2):147–149. piebaldism. Clin Exp Dermatol. 1994;19(2):170–172.
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27. Hann SK, Lee HJ. Segmental vitiligo: Clinical 36. Suga Y, Ikejima A, Matsuba S, Ogawa H. Medical
findings in 208 patients. J Am Acad Dermatol. pearl: DHA application for camouflaging segmental
1996;35(5 Pt 1):671–674. vitiligo and piebald lesions. J Am Acad Dermatol.
28. Greco A, Fusconi M, Gallo A et al. Vogt-Koyanagi- 2002;47(3):436–438.
Harada syndrome. Autoimmun Rev 2013;12(11):​ 37. Thomas I, Kihiczak GG, Fox MD, Janniger CK,
1033–1038. Schwartz RA. Piebaldism: An update. Int J Dermatol.
29. Andrade A, Pithon M. Alezzandrini syndrome: 2004;43(10):716–719.
Report of a sixth clinical case. Dermatology. 38. Njoo MD, Nieuweboer-Krobotova L, Westerhof W.
2011;222(1):8–9. Repigmentation of leucodermic defects in piebaldism
30. Elston DM, Clayton AS, Meffert JJ, McCollough ML. by dermabrasion and thin split-thickness skin
Migratory poliosis: A forme fruste of alopecia areata? grafting in combination with minigrafting. Br J
J Am Acad Dermatol. 2000;42(6):1076–1077. Dermatol. 1998;139(5):829–833.
31. Jalalat SZ, Kelsoe JR, Cohen PR. Alopecia areata 39. Olsson MJ, Juhlin L. Long-term follow-up of
with white hair regrowth: Case report and review of leucoderma patients treated with transplants
poliosis. Dermatol Online J. 2014;20(9). of autologous cultured melanocytes, ultrathin
32. Lett KS, Deane JS. Eyelash poliosis in association with epidermal sheets and basal cell layer suspension. Br J
sarcoidosis. Eye (Lond). 2005;19(9):1015–1017. Dermatol. 2002;147(5):893–904.
33. Bernardes TF, Bonfioli AA. Blepharitis. Semin 40. Lommerts JE, Meesters AA, Komen L et al.
Ophthalmol. 2010;25(3):79–83. Autologous cell suspension grafting in segmental
34. Dunn CL, Harrington A, Benson PM, Sau P, James vitiligo and piebaldism: A randomized controlled
WD. Melanoma of the scalp presenting as poliosis trial comparing full surface and fractional CO2
circumscripta. Arch Dermatol. 1995;131(5):618–619. laser recipient-site preparations. Br J Dermatol.
35. Kwon IH, Cho YJ, Lee SH et al. Poliosis circumscripta 2017;177(5):1293–1298.
associated with neurofibroma. J Dermatol.
2005;32(6):446–449.
Waardenburg syndrome
CARMEN MARIA SALAVASTRU, STEFANA CRETU, and GEORGE SORIN TIPLICA
16
CONTENTS
Introduction 107 SOX10 108
Genetic background 107 EDN3 and EDNRB 108
PAX3 107 Clinical findings 108
Microphthalmia-associated transcription factor 107 Cutaneous features 109
SNAI2 108 References 110

INTRODUCTION PAX3
Waardenburg syndrome (WS), a genetic condition first Most of the cases of WS type I, if not all, are the result of
described in 1951 by the Dutch ophthalmologist Petrus heterozygous PAX3 mutations. Homozygous or compound
Johannes Waardenburg,1 is classified into four subtypes, heterozygous PAX3 mutations are responsible for severe
with several genes involved.2 Multiple studies have found cases of the WS type III, occasionally resulting in death in
that the prevalence of the disease ranges between 1 in early infancy or in utero. Mutations can either be inherited
20,000 and 1 in 42,000.1,3–7 The inheritance pattern in in an autosomal dominant manner or occur de novo.10
WS is usually autosomal dominant, although autosomal In the developing embryo, PAX3 expression coincides
recessive cases have been described.7 with the formation of somites and is switched off as the
The syndrome associates disabling features, such as somites dissociate. It is also expressed in the undifferentiated
hearing loss, found more frequently in WS type II; limb mesenchyme of the limb buds, explaining the presence of
abnormalities in type III; or life-threatening features, as are phenotypes such as those seen in WS type III.7 In addition
associated with Hirschsprung disease in type IV. Although to their involvement in the development of the melanocyte
they are not the main cause of disability, cutaneous findings lineage, PAX3 genes are important for the formation of
are present in all types of WS and their recognition, either craniofacial cartilage and bones, hence the reason dystopia
in the patients or their family members, can aid in rapidly canthorum is seen in WS type I, but not in type II, as
establishing the correct diagnosis.1–8 microphthalmia-associated transcription factor (MITF) is
very important for the melanocytic lineage, but not for cell
GENETIC BACKGROUND precursors of the cranial cartilage and bones.9,13,14
The neural crest was first described over 150 years ago.9 In order for a neural crest cell to follow the pathway
WS is a typical neurocristopathy and its characteristics to become a melanocyte, PAX3 and MITF need to be
are due to mutations affecting neural crest cells. These expressed,14 with the MITF expression being regulated by
multipotent embryonic cells migrate from the dorsal PAX3;13 the expression of the PAX3 gene is required for
part of the neural tube and are precursors for several melanoblast proliferation, whereas the expression of MITF is
cell lineages: melanocytes, peripheral and enteric important in their survival during and after their migration.14
neurons and glia, craniofacial chondrocytes, osteoblasts,
adrenal chromaffin cells, intermediate cells of the stria MICROPHTHALMIA-ASSOCIATED TRANSCRIPTION
vascularis in the cochlea, and certain cells of the heart FACTOR
and thymus.10–12 All melanocytes, except for those of Approximately 15% of WS type II cases are the result of
the retina (derived from the optic cup of the brain), are mutations in the MITF gene. Individuals are heterozygotes
derived from cells of the neural crest.9,12 The function of and the mutations can be inherited in an autosomal
the protein products of the mutated genes can be absent or dominant manner or occur de novo. Microphthalmia-
diminished compared to the wild-type gene, depending associated transcription factor controls the development
on the mutations present and on how much of the original and differentiation of melanocytes, osteoclasts, and
protein was altered.13 The features present in WS are the mastocytes.10,15 Mutations involving this gene lead to
result of a reduced level of expression (haploinsufficiency) pigmentation loss, microphtalmia, deafness, failure
of different transcription factors.12 This results in of secondary bone resorption, and a small number of
anomalies of the proliferation, survival, migration, and mast cells. The promoter of MITF-M, one of the five
differentiation of the cells derived from the neural crest. known isoforms of MITF, is functional only in cells of
These cells, at key moments in their development, express the melanocyte lineage. This promoter is upregulated
specific genes. by other transcription factors like PAX3 and SOX10. In

107
108 Waardenburg syndrome

addition, one of the control mechanisms for the activity is able to interact with all three members of the EDN
and degradation of MITF-M is through c-KIT signaling.15 family; however, murine studies have suggested that the
EDN3 protein is its main ligand.10,18 The genes encoding
SNAI2 EDN3 and EDNRB are important in the proliferation,
The SNAI2 gene encodes for a zinc-finger transcription factor migration, and differentiation of cell lineages derived
and is expressed in neural crest cells as they migrate from from the neural crest.19 During embryogenesis, EDNRB
their original site, important in the migration of these cells, is expressed for the first time in the cells at the dorsal tip
not in their development. In vivo, it also interacts with KIT. of the neural tube and then in cells of the neural crest.10
Mutations in this gene are also responsible for WS type II. Afterward, it is only expressed by the cells that follow
In these cases, although MITF is present and transactivates the dorso-ventral migration pathway and then in most of
the promoter for SNAI2, the downstream cellular events can the cellular types derived from them, such as the enteric
no longer follow their usual path, resulting in the phenotype ganglia. Heterozygous mutations of these genes lead to
being consistent with WS type II.16 aganglionic megacolon, a feature of WS type IV. Patients
suffering from this condition develop life-threatening
SOX10 functional bowel obstruction.18,20 Although the genes
SOX10 is a transcription factor responsible for the involved in the pathogenesis of WS have been extensively
development and preservation of melanocytes, Schwann studied, there are still cases in which the phenotype
cells, and enteric ganglion cells, all of which derive from cannot be explained on the basis of mutations to any of
the neural crest cells.17 The gene is expressed in the the known genes. This is the case for approximately 70%
developing embryo in neural crest cells that contribute of WS type II and 35% of WS type IV, as opposed to the
to the formation of the peripheral nervous system and majority of WS type I and III cases, where the findings
transiently in melanoblasts. In later stages of development, are due to mutations to the PAX3 gene.10,21 Mutations
it is also expressed in the central nervous system, reaching of the EDNRB gene are estimated to be the cause of
a maximum level of expression at this site in the adult life. 5%–6% of mutations in WS type II. In homozygotes,
Among the transcription factors modulated by SOX10 the mutated genes have complete penetrance, leading
are PAX3 and MITF.13 Individuals with WS and SOX10 to severe phenotypes, whereas in heterozygotes, they
mutations are heterozygotes. In the homozygous state, have an autosomal dominant mode of transmission,
SOX10 mutations are lethal in early infancy or in utero.10 with incomplete penetrance leading to no changes or to
partial phenotypes. 22 These are summarized in Table 16.1.
EDN3 AND EDNRB
Endothelins (EDNs) are a family of three proteins CLINICAL FINDINGS
(EDN1, EDN2, EDN3) functioning as ligands for the When the syndrome was first described, Waardenburg
endothelin receptor (EDNR). The EDNRB subtype characterized it by the following aspects: (1) congenital

Table 16.1 WS subtypes and their mode of inheritance

Genetic
mutations Mode of
Type involved Gene product inheritance
I PAX3 PAired boX 3 transcription factor AD
II MITF Melanocyte Inducing Transcription Factor AD
SNAI2 (SLUG) SNAIL homolog 2 protein AD
SOX10 Sry 10 bOX transcription factor AD
EDNRB ENDothelin AD
Receptor type B
III PAX3 PAired boX 3 transcription factor AD
IV SOX10 Sry 10 bOX transcription factor AD
EDN3 ENDothelin 3 AR
EDNRB ENDothelin Receptor type B AR
Sources: Farrer LA et al. Am J Hum Genet. May 1992;50(5):902; Tamayo ML et al. Am J Med Genet A. April 15,
2008;146(8):1026–1031; Milunsky JM. Waardenburg syndrome type I. InGeneReviews® [Internet]
2017 May 4. University of Washington, Seattle. Available from: https://www.ncbi.nlm.nih.gov/
books/NBK1531/, accessed on December 2018; Hageman MJ, Delleman JW. Am J Hum Genet.
September 1977;29(5):468; Read AP, Newton VE. J Med Genet. August 1, 1997;34(8):656–665; U.S.
National Library of Medicine, National Institutes of Health. Genetics Home Reference: Your guide to
understanding genetic conditions. Available from: https://ghr.nlm.nih.gov/condition/waardenburg-
syndrome, accessed on December 2018; Pingault V et al. Hum Mutat. April 2010;31(4):391–406;
Pilon N. Rare Dis. January 1, 2016;4(1):4483–4496.
 Cutaneous features 109

Table 16.2 Variation in clinical features in WS tuberous sclerosis complex.23,24 Skin findings in WS usually
present as hypopigmented macules and patches on the face,
Percentage of
trunk, or limbs. The periphery of the lesions may appear
Site of affected
hyperpigmented.5,23 Upon Wood lamp examination, the
involvement Clinical findings individuals
lesions appear hypopigmented, unlike chalk-white in
Cranio-facial High nasal root 52%–100% vitiligo. The hypopigmented lesions of TSC appear early
anomalies Dystopia canthorum 98%–100% in the course of the disease, and a thorough evaluation
Hearing loss Bilateral or unilateral 47%–58% should be performed. Lisch nodules of NF1 can be easily
(>100 dB) sensorineural hearing loss differentiated from iris pigmentary anomalies of WS by
Hair Synophrys 63%–73% ophthalmologic examination.23,24 Severe depigmentation
White forelock 43%–48% associated with upper limb defects and other clinical
Early graying 23%–38% features are the result of homozygous mutations or
Skin Leukoderma 22%–38%
compound heterozygous mutations of the PAX3 gene.10
Also, this can be found in cases with particular SOX10
Eyes Heterochromic irides 15%–31%
variants. Watanabe et al. reported a patient with extensive
Hypoplastic blue irides 15%–18%
hypopigmentation carrying a deletion type mutation to
Sources: Farrer LA et al. Am J Hum Genet. May 1992;50(5):902; Tamayo this gene.25
ML et al. Am J Med Genet A. April 15, 2008;146(8):1026–1031;
Milunsky JM. Waardenburg syndrome type I. InGeneReviews®
Hair depigmentation
[Internet] 2017 May 4. University of Washington, Seattle.
Available from: https://www.ncbi.nlm.nih.gov/books/ With age and as a consequence of oxidative stress,
NBK1531/, accessed on December 2018. newly formed hair follicles are devoid of melanocytes,
because their stem cell precursors become dysfunctional,
deafness or partial (unilateral) deafness; (2) circumscribed undergoing apoptosis; the process involves the reduction
albinism of the frontal head hair (white forelock); (3) lateral of Bcl-2 gene expression levels in the melanocyte stem
displacement of the medial canthi and lacrimal points cells. This is a proto-oncogene, interacting with other
(dystopia canthorum); (4) partial or total heterochromia key genes, including MITF.26 Hair depigmentation in WS
iridum; (5) hyperplasia of the medial portions of the includes the presence of a white forelock, usually in the
eyebrows; and (6) a hyperplastic, broad, and high nasal root.1 medial part of the forehead and extending toward the
Several investigator groups have studied the penetrance posterior, or patches of white hair located in other areas of
of clinical features found in affected individuals, and a the scalp.10,27 The underlying scalp skin and forehead may
detailed description is available in Table 16.2. Genotype/ appear hypopigmented.5 These features are not present in
phenotype correlations are difficult to establish across the all cases.
different types of WS, as phenotypes vary greatly even Other clinical findings are early hair graying, usually
between members of the same family.10 before the age of 30, and white eyebrows and/or eyelashes.10
Both early graying and the white forelock are considered,
CUTANEOUS FEATURES by some authors, forms of partial hair albinism.28
Skin depigmentation
Congenital leukoderma in a child can be the consequence Synophrys
of many processes (Figure 16.1). WS is an uncommon Medial confluence of the eyebrows above the nasal bridge
condition in comparison to other diseases such as vitiligo is also called synophrys. It is a feature of several genetic
or other genodermatoses, like neurofibromatosis type I or syndromes, as well as a normal variation.29 In WS, it is the

Figure 16.1 (a) Partial/segmental heterochromia; (b) hair hypopigmentation; (c) hypopigmentation of the skin. (Courtesy of
Carmen Maria Salavastru.)
110 Waardenburg syndrome

result of pathological migration of the cells from the neural in cases of life-threatening bowel involvement or in those
crest to the medial region of the face.28 with sensorineural deafness.

Diagnosis REFERENCES
Diagnosis is in most cases clinical, based on major and 1. Waardenburg PJ. A new syndrome combining
minor criteria, detailed in Table 16.3, with cutaneous developmental anomalies of the eyelids, eyebrows
findings being present in all four types.2–4,7 and noseroot with pigmentary anomalies of the
The diagnosis for WS type I is established in the iris and head hair and with congenital deafness;
presence of two major criteria or one major and two Dystopia canthi medialis et punctorum lacrimalium
minor. For WS type II, two major criteria are necessary lateroversa, hyperplasia supercilii medialis et radicis
and dystopia canthorum is excluded. In WS type III, nasi, heterochromia iridum totaliis sive partialis,
also called Klein-Waardenburg, diagnosis is established albinismus circumscriptus (leucismus, polioss) et
based on the same criteria as WS I plus musculoskeletal surditas congenita (surdimutitas). Am J Hum Genet.
findings. The diagnosis for WS type IV, also known as September 1951;3(3):195.
Shah-Waardenburg, is based on the same criteria as type I 2. Zaman A, Capper R, Baddoo W. Waardenburg
plus Hirschsprung disease.2–5,7 syndrome: More common than you think! Clin
Family members of the patient can present with features Otolaryngol. February 2015;40(1):44–48.
of the syndrome and their examination can prove useful in 3. Farrer LA, Grundfast KM, Amos J, Arnos KS, Asher
cases with few clinical findings, especially in very young JH, Beighton P, Diehl SR, Fex J, Foy C, Friedman
children and where the diagnosis is difficult to establish. TB, Greenberg J. Waardenberg syndrome (WS)
Also, gene testing can prove useful for diagnosis of such type I is caused by defects at multiple loci, one of
cases. which is near ALPP on chromosome 2: First report
of the WS consortium. Am J Hum Genet. May
Treatment 1992;50(5):902.
No specific treatment is available. 4. Tamayo ML, Gelvez N, Rodriguez M, Florez S,
As with many other conditions, a rapid diagnosis is Varon C, Medina D, Bernal JE. Screening program
very important in the prognosis of the patient, especially for Waardenburg syndrome in Colombia: Clinical
definition and phenotypic variability. Am J Med
Genet A. April 15, 2008;146(8):1026–1031.
Table 16.3 Diagnostic criteria of WS 5. Milunsky, JM. Waardenburg syndrome type I.
InGeneReviews® [Internet] 2017 May 4. University
Major criteria Minor criteria
of Washington, Seattle. Available from: https://
Congenital sensorineural hearing loss Congenital www.ncbi.nlm.nih.gov/books/NBK1531/, accessed
leukoderma on December 2018.
White forelock, hair hypopigmentation Synophrys and/or 6. Hageman MJ, Delleman JW. Heterogeneity in
medial eyebrow Waardenburg syndrome. Am J Hum Genet. September
flare 1977;29(5):468.
Abnormal pigmentation of the iris: Broad/high nasal 7. Read AP, Newton VE. Waardenburg syndrome.
• Complete heterochromia iridum root, low-hanging J Med Genet. August 1, 1997;34(8):656–665.
• Partial/segmental heterochromia columella 8. U.S. National Library of Medicine, National Institutes
• Hypoplastic or brilliant blue irides of Health. Genetics Home Reference: Your guide to
Dystopia canthorum, W index > 1.95a Underdeveloped understanding genetic conditions. Available from:
alae nasi https://ghr.nlm.nih.gov/condition/waardenburg-
First-degree relatives with specific Premature gray hair syndrome, accessed on December 2018.
clinical findings 9. Bronner ME, LeDouarin NM. Development and
evolution of the neural crest: An overview. Dev Biol.
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Farrer LA et al. Am J Hum Genet. May 1992;50(5):902; Tamayo
June 1, 2012;366(1):2–9.
ML et al. Am J Med Genet A. April 15, 2008;146(8):1026–1031; 10. Pingault V, Ente D, Dastot-Le Moal F, Goossens
Milunsky JM. Waardenburg syndrome type I. InGeneReviews® M, Marlin S, Bondurand N. Review and update of
[Internet] 2017 May 4. University of Washington, Seattle. mutations causing Waardenburg syndrome. Hum
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NBK1531/, accessed on December 2018; Read AP, Newton VE. 11. Pilon N. Pigmentation-based insertional mutagenesis
J Med Genet. August 1, 1997;34(8):656–665. is a simple and potent screening approach for
a The W index is calculated using the inner canthal distance (a), inter-
identifying neurocristopathy-associated genes in
pupillary distance (b), outer canthal distance (c) and the following
formula:
mice. Rare Dis. January 1, 2016;4(1):4483–4496.
W index = X + Y + a/b, where 12. Takeda K, Takahashi NH, Shibahara S. Neuroendocrine
X = (2a-(0.2119c + 3.909))/c functions of melanocytes: Beyond the skin-deep
Y = (2a-(0.2479b + 3.909))/b melanin maker. Tohoku J Exp Med. 2007;211(3):201–221.
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13. Bondurand N, Pingault V, Goerich DE, Lemort 21. Bergeron KF, Nguyen CM, Cardinal T, Charrier B,
N, Sock E, Caignec CL, Wegner M, Goossens M. Silversides DW, Pilon N. Upregulation of the Nr2f1-
Interaction among SOX10, PAX3 and MITF, three A830082K12Rik gene pair in murine neural crest
genes altered in Waardenburg syndrome. Hum Mol cells results in a complex phenotype reminiscent of
Genet. August 12, 2000;9(13):1907–1917. Waardenburg syndrome type 4. Dis Model Mech.
14. Wang Q, Fang WH, Krupinski J, Kumar S, 2016 Nov 1;9(11):1283–93.
Slevin M, Kumar P. PAX genes in embryogenesis 22. Issa S, Bondurand N, Faubert E et al. EDNRB
and oncogenesis. J Cell Mol Med. December 1, mutations cause Waardenburg syndrome type II in the
2008;12(6a):2281–2294. heterozygous state. Hum Mutat. 2017, 38(5):581–593.
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T, Watanabe KI, Saito H, Takahashi K. sign of systemic disease. Indian J Dermatol Venereol
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regulation. In Journal of Investigative Dermatology disorders of the eyes and skin. Clin Dermatol. March
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Alezzandrini syndrome, Margolis
syndrome, Cross syndrome, and other
17
rare genetic disorders
ATHANASIOS I. PAVLIDIS and ANDREAS D. KATSAMBAS

CONTENTS
Introduction 113 Differential diagnosis 115
Epidemiology 113 Treatment 115
Pathophysiology 113 References 115
Clinical presentation 114

INTRODUCTION skin and hair. GS was first described by Griscelli and

Alezzandrini syndrome is a condition of unknown etiology Siccardi in 1978.12
first described by Alezzandrini and Casala in 1959.1
This syndrome is a rare group of ipsilateral pigmentary EPIDEMIOLOGY
changes characterized by poliosis, facial vitiligo, unilateral Alezzandrini syndrome is a rare disorder with an unknown
degenerative retinitis, an atrophic iris, reduced visual prevalence instead of mortality rate. Most patients initially
acuity, and occasionally deafness.2 present when they are 12–30 years, and it is not limited to
Ziprkowski-Margolis syndrome is a condition also known a certain race. Only a few clinical cases in world literature
as X-linked albinism-deafness syndrome characterized by have been described.13
congenital neural deafness and a severe or extreme piebald- The incidence of Ziprkowski-Margolis syndrome is
like phenotype with extensive areas of hypopigmentation. unknown. Few cases are published to date.
This syndrome was first identified by both Ziprkowski and The prevalence of Cross syndrome in consanguineous
Margolis in 1962, in an Israeli Jewish family of Sephardic families is in favor of an autosomal recessive inheritance,
origin.3,4 and it has been suggested that it maps to chromosome
Cross syndrome was first identified by Cross et al. in 3q27.1q29.14
1967. This syndrome is characterized by hypopigmentation Hermansky-Pudlak syndrome is a rare form of albinism.
involving skin and hair, intellectual disability, The prevalence of HPS worldwide is 1 in 500,000–1,000,000
microcephaly, and neurologic and ocular disorders.5 individuals, and it is likely to occur in all ethnic groups, as
Hermansky-Pudlak syndrome (HPS) was first described sporadic cases have been reported in several ethnicities,
by Hermansky and Pudlak in 1959 in two unrelated including Japanese, Finnish, Mexican, and Sri Lankan.15
patients.6 This syndrome is a rare autosomal recessive The incidence of Vici syndrome is unknown, and it is
genetic disorder characterized by oculocutaneous likely to be rare but probably underdiagnosed. Since the
albinism and prolonged bleeding diathesis due to platelet original description, an increasing number of patients have
dysfunction. In some individuals, it is related to pulmonary been reported, with around 50 genetically confirmed cases
fibrosis, granulomatous colitis, or immunodeficiency.7,8 published to date.16
Vici syndrome, first described by Dionisi-Vici and The first case of Chediak-Higashi syndrome was
colleagues in 1988,9 is a severe congenital multisystem reported in 1943. For the past 20 years, less than 500 cases
disorder characterized by callosal agenesis, cataracts, have been reported worldwide. In China, no more than 50
oculocutaneous hypopigmentation, cardiomyopathy, and cases have been reported over the past decades.11
a combined immunodeficiency.10 The incidence of Griscelli syndrome is unknown. GS
Chediak-Higashi syndrome is a rare autosomal usually manifests in persons aged 4 months to 4 years,
recessive disorder characterized by variable degrees of though the youngest reported is 1 month with no sex
oculocutaneous albinism, recurrent infections, a tendency predilection.17
for mild bleeding, progressive neurologic deterioration,
and hemophagocytic lymphohistiocytosis (HLH).11 PATHOPHYSIOLOGY
Griscelli syndrome (GS) is a rare autosomal recessive Alezzandrini syndrome has an unknown etiology. Many
disorder with characteristic pigmentary dilution of the theories have been proposed regarding viral or autoimmune

113
114 Alezzandrini syndrome, Margolis syndrome, Cross syndrome, and other rare genetic disorders

processes. As known, melanocytes that originate in the unilateral appearance of facial vitiligo, poliosis, and
neural crest migrate to the skin, leptomeninges, retinas, hearing abnormalities.13
uvea, cochleae, and vestibular labyrinths. Any disorder In Ziprkowski-Margolis syndrome, males in the
that destroys the melanocytes in the skin also affects same Jewish family showed congenital subtotal nerve
other organs and systems such as the eye, ear, and central deafness and piebaldness. Their skin was characterized by
nervous system.13 alternating achromatic and hyperpigmented patches, with
Margolis syndrome or X-linked albinism-deafness sharply delineated areas (“leopard skin”), and their hair
syndrome (ADFN) probably affects the migration of was white.18
neural crest–derived precursors of melanocytes. A locus at The clinical features of patients with Cross syndrome
Xq26.3-q27.I has been suggested. The perceptive deafness could include skin hypopigmentation silver-gray/white
could be explained by the failure of the nerve cells to hair, ocular anomalies, microcephaly, hypotonia, ataxia,
migrate from the neural crest to the cochlea.18 spasticity, developmental delay/intellectual disability,
Cross syndrome, also known as oculocerebral brain malformation, growth retardation, recurrent uri-
hypopigmentation syndrome (OCHS), is assumed to be nary tract infections/malformations, heart malforma-
autosomal recessive, with its genetic cause still unknown. tions, vertebral anomalies, osteoporosis, and acetabular
OCHS maps to chromosome 3q27.1q29.14 hypoplasia. 5,24,25
Hermansky-Pudlak disorder is classified into different Hermansky-Pudlak syndrome (HPS) is characterized
subtypes (HPS1–HPS10) based on genetic mutations in dif- by oculocutaneous albinism including reduced iris
ferent genes. The primary defect in HPS is disruption in the and retinal pigment, foveal hypoplasia with significant
biogenesis of lysosomes and lysosome-related organelles reduction in visual acuity, nystagmus, and a bleeding
(LROs). LROs include melanosomes, PDG, lamellar bod- diathesis that can result in variable bruising; epistaxis;
ies of type II pneumocytes, and granule proteins of cyto- gingival bleeding; postpartum hemorrhage; colonic
toxic and suppressor T cells and NK cells. Identification of bleeding; and prolonged bleeding with menses or after
biallelic pathogenic variants in AP3B1, AP3D1, BLOC1S3, tooth extraction, circumcision, and other surgeries. Hair
BLOC1S6, DTNBP1, HPS1, HPS3, HPS4, HPS5, or HPS6 color in HPS ranges from white to brown; skin color
confirms the diagnosis using molecular genetic testing if ranges from white to olive and is usually a shade lighter
clinical features are inconclusive.19 than that of other family members. Type 1 HPS is the most
Vici syndrome pathogenesis is caused due to recessive common and most severe variant and leads to high-risk
mutations in the ectopic P granules protein 5 (EPG5) cases of pulmonary fibrosis, more common among female
gene on chromosome 18q12.3 organized in 44 exons and patients, a restrictive lung disease due to accumulation of
encoding EPG5. EPG5 is a protein of 2579 amino acids, ceroid-lipofuscin in the pulmonary alveolar macrophages
originally known as KIAA1632, initially identified among and presented by dispnea. Granulomatous colitis is severe
a group of genes found to be mutated in breast cancer tissue in about 15% of affected individuals.7,26
before its implication in Vici syndrome in 2013. To date, Vici syndrome is one of the most extensive inherited
around 40 EPG5 mutations have been identified in families human multisystem disorders reported to date, presenting
with Vici syndrome, distributed throughout the entire invariably in the first months of life. The five principal
EPG5 coding sequence without clear genotype-phenotype diagnostic findings include callosal agenesis, cataracts,
correlations.20 cardiomyopathy, hypopigmentation, and combined
In Chediak-Higashi syndrome (CHS), the genetic immunodeficiency; additionally, any organ system can
defect was identified in 1996 and was mapped to human be involved. 23 Profound developmental delay, acquired
chromosome 1q42–44. 21 The CHS gene was originally microcephaly, and marked failure to thrive have recently
called LYST, which contains 53 exons with an open emerged and are, although nonspecific, as consistently
reading frame of 11,406 bp, and encodes for a 3801–amino associated as the five main diagnostic features and highly
acid protein, CHS1. Although the exact function of CHS1 supportive of the diagnosis.20
remains unknown, it has been thought to play a role in Chediak-Higashi syndrome is classified into three
regulating lysosome-related organelle size, fission, and phenotypes. Based on clinical symptoms are childhood,
secretion.22 adolescent, and adult forms, with 80%–85% being the
In Griscelli syndrome, the three different subtypes childhood form.27 It is characterized by frequent severe
are caused by mutations in the Myosin Va (MyoVa) infections and massive hemophagocytic lymphohistiocy-
(GS1, Elejalde), small GTPase protein RAB27A (GS2), or tosis due to inappropriate cytotoxic activity, which leads
melanophil MLPH (GS3) genes, respectively. The protein to the impaired downregulation of immune responses and
complex formed by these is essential for the capture and sustained activation and proliferation of cytotoxic T lym-
movement of melanosomes in the actin-rich cell periphery phocytes and NK cells. HLH often occurs following initial
of melanocytes.23 exposure to EBV and has a high mortality rate.28
Griscelli syndrome includes three types (GS1, GS2,
CLINICAL PRESENTATION and GS3). GS1 has characteristic albinism with central
Alezzandrini syndrome is characterized by unilateral nervous system dysfunction without immunological
tapetoretinal (retinal pigment epithelia) degeneration, involvement. GS2, the most common, is associated with
 References 115

albinism and a severe immunological impairment and The main treatment for CHS focuses on three fields:
commonly develops hemophagocytic lymphohistiocytosis supportive management of disease-derived complications,
and recurrent infections. In GS3, patients are associated treatment of the accelerated phase or HLH, and
with partial albinism only.29,30 hematopoietic stem cell transplantation (HSCT), which
has been recognized as the most effective treatment for
hematologic and immune defects caused by CHS. The only
DIFFERENTIAL DIAGNOSIS
treatment is allogenic HSCT, but the prognosis is poor.28
The relationship between Alezzandrini syndrome and
other syndromes involving vitiligo and eye pathology is REFERENCES
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syndrome, characterized by bilateral decoloration of the unilateral con retinitis pigmentaria y hypoacusia.
skin, eyebrows, eyelashes, alopecia, chronic uveitis, and Arch Argent Dermatol. 1959;9:449.
meningoencephalitis. 2. Alezzandrini AA. Unilateral manifestations of
In Margolis syndrome, similar conditions not associated tapeto-retinal degeneration, vitiligo, poliosis,
with deafness should lead to consideration of Chediak- grey hair and hypoacousia. Ophthalmologica.
Higashi syndrome. 1964;147:409–419.
Hermansky-Pudlak syndrome should be included in 3. Ziprkowski L, Krakowski A, Adam A et al. Partial
the differential diagnosis of patients with inflammatory albinism and deaf-mutism due to a recessive sex-
bowel disease and interstitial lung disease, particularly linked gene. Arch Derm. October 1962;86:530–539.
in the presence of bleeding diathesis and albinism like
4. Margolis E. A new hereditary syndrome: Sex-linked
oculocutaneous albinism (OCA), X-­linked ocular albinism deaf-mutism associated with total albinism. Acta
(XLOA), Chediak-Higashi syndrome, and Griscelli Genet. 1962;12:12–19.
syndrome. 5. Cross HE, McKusick VA, Breen W. A new oculocer-
The differential diagnosis of Vici syndrome includes a ebral syndrome with hypopigmentation. J Pediatr.
number of syndromes with overlapping clinical features, March 1967;70:398–406.
neurological and metabolic disorders with similar CNS 6. Hermansky F, Pudlak P. Albinism associated with
abnormalities, and primary neuromuscular disorders hemorrhagic diathesis and unusual pigmented
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Higashi syndrome, Hermanksy-Pudlak syndrome type 2, 7. Pierson DM, Ionescu D, Qing G et al. Pulmonary
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8. Christensen S, Wagner L, Colema MM. et al. The
from the other two autosomal recessive transmission
lived experience of having a rare medical disorder:
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2017;13(1):62–72.
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9. Vici CD, Sabetta G, Gambarara M et al. Agenesis of
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the corpus callosum, combined immunodeficiency,
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In Griscelli syndrome, the absence of giant granules in brothers. Am J Med Genet. January 1988;29(1):1–8.
the nucleated cells makes it possible to differentiate from 10. Cullup T, Kho AL, Dionisi-Vici C et al. Recessive
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multisystem disorder with defective autophagy. Nat
TREATMENT Genet. January 2013;45(1):83–87.
For all syndromes and genetic disorders, patients with 11. Kaplan J, De Domenico I, Ward DM. Chediak-
vitiligo should use a sunscreen to prevent sunburn and Higashi syndrome. Curr Opin Hematol. January
subsequent skin cancer. Topical steroids and tacrolimus 2008;15(1):22–29.
may be tried on localized areas of vitiligo.31 12. Griscelli C, Durandy A, Guy-Grand D et al. A
In cases with widespread depigmentation, treatment ­syndrome associating partial albinism and immu-
with psoralen plus ultraviolet A (PUVA) can be provided nodeficiency. Am J Med. October 1978;65:691–702.
but with great caution in patients with anterior uveitis 13. Andrade A, Pithon M. Alezzandrini syndrome:
because PUVA therapy might aggravate the ocular Report of a sixth clinical case. Dermatology. February
inflammatory disorder.32 2011;222(1):8–9.
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aimed at alleviating the effects of extensive multisystem to chromosome 3q27.1q29. Dermatology. 2011;223(4):​
involvement.16 306–310.
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15. Asztalos ML, Schafemak KT, Gray J et al. Hermansky- 24. Pollazzon M, Grosso S, Papa FT et al. A 9.3 Mb
Pudlak syndrome: Report of two patients with microdeletion of 3q27.3q29 associated with psy-
updated genetic classification and management chomotor and growth delay, tricuspid valve dys-
recommendations. Pedriatr Dermatol. November plasia and bifid thumb. Eur J Med Genet. March
2017;34(6):638–646. 2009–June;52(2–3):131–133.
16. Byrne S, Dionisi-Vici C, Smith L et al. Vici syndrome: 25. De Jong G, Fryns JP. Oculocerebral syndrome with
A review. Orphanet J Rare Dis. February 29, 2016;11:21. hypopigmentation (Cross syndrome): The mixed
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2006;47(1):20–27. genotype-phenotype correlation in childhood,
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defects and clinical characteristics of patients with Am J Med Genet. February 2002;108(1):16–22.
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Mosaic hypopigmentation
IRENE LATOUR-ÁLVAREZ and ANTONIO TORRELO
18
CONTENTS
Definition and mechanisms of mosaicism 117 Diagnosis 124
Classic patterns of cutaneous mosaicism 118 Follow-up and treatment 124
Clinical manifestations of mosaic hypopigmentation References 124
diseases 118

DEFINITION AND MECHANISMS OF MOSAICISM phenotypically abnormal). Nonlethal dominant

A “mosaic” is an organism composed of two or more cell mutations appear under this form of mosaicism
lines that are genetically different, derived from a genetically (e.g., segmental neurofibromatosis or segmental
homogenous zygote.1,2 Some mosaic skin disorders tuberous sclerosis).1 Recessive mutations may also
exclusively occur sporadically because the underlying rarely mimic type 1 mosaicism, in case the embryo is
mutation, when present in the fertilized egg, is incompatible heterozygous for the recessive mutation and a second
with life, and then the mutation can only survive in the mutation during embryo development will show a
form of mosaicism (e.g., McCune-Albright syndrome3 and segmental manifestation of the disease.
CLOVES syndrome4) in close vicinity to the population • In type 2 mosaicism, an individual heterozygous
of normal cells. The hypothesis of lethal genes surviving for a dominant disease (and hence manifesting a
by mosaicism has been proved on molecular grounds in dominant disease), may exhibit a more intense
several diseases.1,5 The distinction between mosaicism of expression of the disease in one segment because
lethal (e.g., Proteus syndrome6) from nonlethal postzygotic of an early event of loss of heterozygosity in the
mutations (e.g., neurofibromatosis type 1,7 tuberous affected gene. The individual will show homo­
sclerosis8) is important because the clinical expression of zygosity in this segment, whereas they will remain
the mosaic state can be modified. Other factors, such as the heterozygous in the germline.11 There are several
timing of mutation during embryo development and the cells mechanisms of loss of heterozygosity, including
affected by the mutation, are also key factors in determining second hit mutations, gene conversion, mitotic
the depth of mosaicism and its clinical expression. nondisjunction, mitotic recombination, and point
Mosaicism can affect autosomes and X chromosomes mutation deletion.12
and can be classified into two major categories,1 genomic 2. Epigenetic or functional mosaicism: This is due to changes
and epigenetic mosaicism: in gene expression (gene activation or silencing).
• Lyonization: In women, functional mosaicism occurs
1. Genetic mosaicism (genomic): This type of mosaicism is due to random X chromosome inactivation; this
related to changes in the DNA sequence due to mutations mechanism may produce cutaneous manifestations
(somatic mutation) or chromosomal alterations (half- of diseases whose responsible genes are located in
chromatid mutation, chromosomal nondisjunction, or the X chromosome. In X-linked recessive diseases,
chimerism). In these postzygotic mutations (somatic inactivation of the normal allele will produce a linear
mosaicism), the mutation occurs de novo during skin disease in females that is often compatible with
embryonic development. Some authors claim that the life, whereas the areas of the skin where the mutated
term somatic is not totally correct. In fact, these mosaic X chromosome is inactivated will remain normal. In
manifestations carry an implicit risk of transmission some cases, carrier females may appear completely
to the next generation because of simultaneous mosaic normal or have minimal manifestations of the
involvement of the gonads (gonadal mosaicism). 5,9 disease (e.g., in hypohidrotic ectodermal dysplasia).
Therefore, the term postzygotic mutation is preferable. Furthermore, some genes in the X chromosome skip
  Two mechanisms exist for the segmental expression of inactivation and in this case, carrier females will not
nonlethal, autosomal traits10 (Figure 18.1): show any manifestations (e.g., X-linked ichthyosis).
• In type 1 mosaicism, a postzygotic mutation However, if the mutation is transmitted to a male
occurs in a normal embryo (wild type); therefore, embryo, he will suffer a nonsegmental disease
the cutaneous changes are seen only in a localized affecting the germline.
segment, corresponding to cells carrying the mutation   In X-linked dominant conditions, most males
(only in this segment, the individual is heterozygous, with only one X chromosome die before birth (e.g.,

117
118 Mosaic hypopigmentation

Somatic mosaicism of nonlethal, dominant mutations

Type 1 mosaicism Type 2 mosaicism

Normal
Loss of
Mutation heterozygosity
heterozygous

Heterozygous

Normal germline genotype Abnormal germline genotype

Phenotype normal Abnormal phenotype
Segmental phenotype abnormal More severely affected area

Figure 18.1 Mechanisms for the segmental expression of nonlethal, autosomal disorders.

incontinentia pigmenti) and females will show a mesodermal components of the skin, but, not rarely,
segmental skin disease on the areas where the wild- pigmentary mosaicism follows this pattern.
type allele was inactivated. Males can survive in the • Type 3: Phylloid pattern. Streaks and round or oval
form of mosaics as a result of extra X chromosome asymmetric lesions mimicking leaves appear. This
donation (XXY karyotype—Klinefelter syndrome) pattern is exclusive to hyper- or hypopigmentation
or due to mosaic postzygotic mutation in the disorders, and some cases of phylloid hypopigmentation
X chromosome or hypomorphic or half-chromatid are due to mosaicism of trisomy 13.
mutations.2,12 • Type 4: Garment-like patterns, with large patches
• Epigenetic modification: This is due to a switch in without midline separation. This is typically a
gene expression, including cytosine methylation migrational patterning that is mostly restricted to
and histone modification.13 This mechanism has, so melanocytic nevi.
far, not been demonstrated in humans. • Type 5: Lateralization affecting only one side of the body,
with midline demarcation. This pattern is typical, but
CLASSIC PATTERNS OF CUTANEOUS MOSAICISM not restricted to, X-linked mutations.
In 1901, Alfred Blaschko described segmental cutaneous
lesions following linear patterns as S-figures on the CLINICAL MANIFESTATIONS OF MOSAIC
anterior and lateral trunk, linear streaks on extremities, HYPOPIGMENTATION DISEASES
and a V-shape on the central back.14 These lines are called
There are several conditions that can produce a mosaic
Blaschko lines after him. Happle, in 2001, described these
hypopigmentation. In this chapter, we summarize briefly
lines on the cephalic and cervical regions15 (Figure 18.2).
the most prevalent and important cutaneous manifestations
Mosaic skin lesions can be clinically recognized because
due to a mosaic that can manifest as a hypopigmentation
they follow fixed patterns described by Happle.16 These are
(Table 18.1).
as follows (Figure 18.3):
• Type 1: Blaschko lines. This is the most common type a. Hypomelanosis following the lines of Blaschko
that mirrors the embryonic development of many of the This is the most frequent presentation of
components of the epidermis. Two types of Blaschko hypopigmented mosaicism in children. Various
lines are recognized: terms have been used to describe this type of
• Type 1a: Narrow Blaschko lines. Some pigmentary dyspigmentation, including hypomelanosis of
disorders and incontinentia pigmenti are examples Ito,17 nevus achromicus (Figure 18.4), nevus
of this type. depigmentosus,18 and blaschkoid dyspigmentation;
• Type 1b: Broad Blaschko lines. These frequently however, the term linear hypomelanosis is preferred
appear in segmental pigmentation disorder and in here. Small round or oval patches of hypopi­ g­
McCune-Albright syndrome. men­tation (also called achromic nevus or nevus
• Type 2: Blocks, flags, segments, or “checkerboard depigmentosus) most likely represent late-stage
patterns.” Alternate areas of skin changes with midline mosaicism.
demarcation appear. Examples of this are Becker’s   Linear hypomelanosis is a congenital
nevus or capillary malformations, among many others. nonprogressive disorder characterized by
This pattern often represents the expansion pattern of hypopigmented skin lesions following Blaschko
 Clinical manifestations of mosaic hypopigmentation diseases 119

Figure 18.2 Blaschko lines on (a) the body and (b) the head and neck. (From Blaschko A. Die Nervenverteilung in der Haut in ihre
Beziehung zu den Erkrankungen der Haut. Vienna, Austria, and Leipzig, Germany: Wilhelm Braunmuller; 1901. Happle R. Mosaicism in
human skin. Understanding Nevi, Nevoid Skin Disorders, and Cutaneous Neoplasia. Springer; 2014. With permission. Happle R, Assim A.
J Am Acad Dermatol. 2001;44:6125. With permission.)

lines, without a preceding inflammatory phase rather than the chalk-white color typical of vitiligo.
(Figure 18.5). The hypopigmentation may be evident Histopathology studies revealed melanin was
at the time of birth and remain stable throughout decreased in epidermal layers of the hypopigmented
life. However, if the skin is very light, it can be noted lesion compared with perilesional normal skin;
later during infancy when the child is exposed to however, the number of melanocytes varied
sun.1,19,20 Lesions appear off-white under Wood lamp depending on the reports (normal or decreased).19,21
120 Mosaic hypopigmentation

Type 1a: Narrow lines Type 1b: Broad lines Type 2: Checkerboard

Type 1: Blaschko lines

Type 3: Phylloid Type 4: Large patches without Type 5: Hemibody lateralization

midline separation

Figure 18.3 Patterns of mosaicism.

  This disorder is sometimes associated with megalencephaly and hypopigmentary linear

extracutaneous defects, including variable neur­ mosaicism in skin.24
ologic and eye findings. 22 Nevertheless, most b. Segmental hypomelanosis arranged in a checkerboard
patients attended in dermatology consultations pattern
showed no association with systemic disease or This entity, sometimes named “flag-like hypo­
neurological abnormalities; thus, children with melanosis,” consists of a unilateral patch of
linear hypomelanosis are unlikely to develop serious variable shape, with serrated borders, arranged in
extracutaneous involvement, especially when a checkerboard pattern (Figure 18.6). Leucotrichia
lesions are limited to one single segment. Children may be present when the hypopigmentation appears
with linear hypomelanosis who are developing in rich region of terminal hair, in contrast to linear
normally and appear normal by the age of 3 usually hypomelanosis. Molecular findings are so far not
will not show any related neurologic manifestation available.25
of disease. 20 Karyotyping from peripheral blood c. Epidermal nevus
lymphocytes and skin fibroblasts may detect The term epidermal nevus includes a heterogeneous
abnormalities in patients with and without group of mosaic lesions and can result as a mutation in
extracutaneous manifestations. The chromosomes many genes including KRT1, KRT10, NRAS, HRAS,
involved in the investigated cases of pigmentary BRAF, and FGFR2, among others.26,27 Clinically,
mosaicism were 2, 3, 4, 5, 7, 9, 10, 12–16, 18, 20–22, most patients with epidermal nevus will show a
and the sex chromosomes.23 Mosaic mutations of linear arrangement of brown, velvety papules. One or
mTOR have been reported in children with diffuse multiple lines of Blaschko may be involved. Rarely,
Table 18.1 Comparison of the principal diseases of mosaic hypopigmentation

Segmental
hypomelanosis
Linear arranged in a Conradi- Goltz syndrome
hypomelanosis checkerboard Incontinentia Pallister-Killian Phylloid Hünermann- (focal dermal
in narrowbands pattern Epidermal nevi pigmenti syndrome hypomelanosis Happle syndrome hypoplasia)

Mutation Miscellanea Not available KRT1, KRT10, NRAS, X-linked dominant Extra Trisomy or Mutation in EBP gene X-linked dominant
Abnormal HRAS, PIK3CA, disorder, mutation isochromosome tetrasomy 13 or disorder, mutation
cytogenetic FGFR2, FGFR3 in NEMO gene 12p, limited to 13q in PORCN gene
studies fibroblasts
Mutation mTOR
Distribution of the Blaschko lines Checkboard Blaschko lines Hypopigmented lines “Atypical” Blaschko Phylloid pattern Blaschko lines Blaschko lines
hypopigmentation pattern lines or any
pattern
Skin surface Smooth Smooth Smooth or warty Smooth Smooth Smooth Mild scaling Smooth
Atrophoderma Dermal atrophy
Skin features Nonprogressive, Leucotrichia Hyper- or Four consecutive Streaks and spots of Asymmetrical First weeks of life: Dermal atrophy, fat
without hypopigmentation, stages of the linear hypopigmentation round or oval linear areas of herniations into the
inflammatory even skin lesions: lesions inflammation and dermis
phase pink or yellow 1) Vesicles hyperkeratosis “Raspberry-like”
2) Verrucous Later: atrophy and papules in lips and
3) Hyperpigmented hypopigmentation, anogenital region
4) Hypopigmented follicular
atrophic lines atrophoderma on
without eccrine the scalp, scarring
gland and hair alopecia
follicles
Systemic ± Neurologic ± Neurologic ± Neurologic Ectodermal Dysmorphic Neurologic Sectorial cataracts, Eyes, teeth, bones
manifestations abnormalities features, mental defects (absence epiphyseal stippling
(tooth, ocular, and retardation of the corpus
neurologic) callosum)
Clinical manifestations of mosaic hypopigmentation diseases 121
122 Mosaic hypopigmentation

Figure 18.4 Nevus achromicus.

Figure 18.7 Hypopigmented epidermal nevus. Note the

hypopigmented lines along the right buttock and velvety
papules distributed along the Blaschko lines.

epidermal nevi appear as hypopigmentation along

the lines of Blaschko, the so-called hypopigmented
epidermal nevus (Figure 18.7). Histopathology will
Figure 18.5 Linear hypomelanosis. show a moderate degree of acanthosis. Epidermal nevi
can appear isolated or associated with extracutaneous,
mostly neurologic, abnormalities. Developmental
delay, epilepsy, intellectual disability, and focal motor
deficits are the principal manifestations observed.
When neurological manifestations are present, the
epidermal nevus usually affects the scalp or the
face; however, it can appear on other skin regions. A
careful history should provide information in case of
systemic involvement.28
d. Incontinentia pigmenti
Incontinentia pigmenti (IP) is an X-linked dom­inant
disorder caused by mutations in IKBKG (inhibitor
of Kappa light polypeptide gene enhancer in B cells,
Kinasa gamma), also known as NEMO (NF-kB
essential modulator) located at Xq28. This mutation
results in failure to activate NF-kB, which normally
protects against TNF-α-induced apoptosis;29 then,
cells with mutations in NEMO are not protected
from apoptosis. IP is considered a type of ectodermal
dysplasia, with a likelihood of associated tooth, eye,
and neurologic involvement.
 The Blaschko-linear pattern of the cutaneous
manifestations ref lects functional mosaicism
Figure 18.6 Hypomelanosis in a checkerboard pattern. because of lyonization. IP typically has four
 Clinical manifestations of mosaic hypopigmentation diseases 123

consecutive stages: (1) linear erythema and vesicles e. Pallister-Killian syndrome

during the first weeks of life, (2) verrucous linear Pallister-Killian syndrome (PKS) is caused by
plaques, (3) hyperpigmented swirls and streaks along somatic mosaicism of an extra chromosome, limited
lines of Blaschko, and (4) from puberty onward, to fibroblasts and not present in lymphocytes. 31
hypopigmented atrophic lines without eccrine gland PKS is a rare genetic disorder caused by tissue-
and hair follicles30 (Figures 18.8 and 18.9). limited mosaicism tetrasomy of the short arm of
chromosome 12, which usually cytogenetically
presents as an extra isochromosome 12p.32
 The clinical phenotype of PKS includes dys­
morphic features (brachycephaly, temporal balding
the first years of life, short nose with flat bridge,
microstomia, progressive macroglossia, small
mandible, and short neck), mental retardation, and
other severe systemic manifestations.32,33 Skin lesions
consist of streaks and spots of hypopigmentation
along “atypical” Blaschko lines, whereas other
lesions do not follow any pattern.1
f. Phylloid hypomelanosis (mosaic trisomy 13)
Most cases of phylloid hypomelanosis are caused
by mosaic forms of trisomy (or tetrasomy) 13 or
13q.1,34 A neurocutaneous syndrome consisting
of a phylloid pattern of skin pigmentation
associated with neurological defects (especially
absence of the corpus callosum), colobomas,
conductive hearing loss, craniofacial anomalies,
and digital malformations has been reported. The
hypomelanosis consists of round or oval lesions and
large asymmetrical areas reminiscent of the leaves
of a begonia, as well as pear-shaped areas or oblong
macules.35
Figure 18.8 Incontinentia pigmenti stage 4. Note g. Conradi-Hünermann-Happle syndrome (X-linked
hypopigmented atrophic lines without hair follicles. dominant chondrodysplasia punctata)
Conradi-Hünermann-Happle syndrome is caused
by mutations in a gene that encodes emopamil
binding protein, EBP (beta-hydroxysteroid-
delta 8, delta 7-isomerase), an enzyme involved
in cholesterol biosynthesis. 36 This syndrome
includes skin lesions along the Blaschko lines,
sectorial cataracts, asymmetric shortening of the
proximal limbs, and asymmetric bone defects
(epiphyseal stippling). In the first weeks of life, the
patient shows linear areas of inflammation and
hyperkeratosis; later, these lesions are followed by
atrophy and hypopigmentation with rather mild
scaling. Scarring alopecia on the scalp following the
Blaschko lines and follicular atrophoderma on the
scalp, wrists, and hands are also common.1
h. Goltz syndrome
Goltz syndrome, also called focal dermal hypoplasia,
is a rare genetic X-linked dominant disorder affecting
ectodermal and mesodermal structures. It is caused
by mutations in PORCN gene, which encodes an
O-acyltransferase, which is a regulator of Wnt, an
important morphogen in ecto-mesodermal tissue
devolopment.37 The phenotype is variable depending
on the proportion and distribution of cells expressing
Figure 18.9 Incontinentia pigmenti stage 4. Linear the mutant X chromosome. Clinically, mutation on
hypopigmented bands. PORCN is expressed in the eyes (e.g., colobomas,
124 Mosaic hypopigmentation

microphtalmia, cataracts), teeth (e.g., hypodontia, 6. Lindhurst MJ, Sapp JC, Teer JK et al. A mosaic
vertical grooving), bones (e.g., limb malformations, activating mutation in AKT1 associated with the
osteopathia striata), and skin. The skin lesions are Proteus syndrome. N Engl J Med. 2011;365:611–619.
characterized by linear streaks along the lines of 7. Lara-Corrales I, Moazzami M, García-Romero MT
Blaschko, with dermal atrophy, fat herniations et al. Mosaic neurofibromatosis type 1 in children:
into the dermis, and hypo- or hyperpigmentation. A single-institution experience. J Cutan Med Surg.
Erythematous (“raspberry-like”) papules may appear 2017;21:379–382.
in any location, but the anogenital region and lips are 8. Bessis D, Malinge MC, Girard C. Isolated and
the most common.2 unilateral facial angiofibromas revealing a type
1 segmental postzygotic mosaicism of tuberous
DIAGNOSIS sclerosis complex with c.4949_4982del TSC2
mutation. Br J Dermatol. 2018;178:e53–e54.
Genetic mosaicism is detected by comparing affected with
9. Nagao-Watanabe M, Fukao T, Matsui E et al.
unaffected tissue from the same individual. In mosaic
Identification of somatic and germline mosaicism
cutaneous disease, genetic analysis of the affected skin
for a keratin 5 mutation in epidermolysis bullosa
can reveal the presence of the mutation, which is not
simplex in a family of which the proband was
present in normal skin. Sometimes, the mosaic can be
previously regarded as a sporadic case. Clin Genet.
expressed in a low percentage of blood cells, especially if
2004;66:236e8.
the mutation occurs early in embryogenesis. Selection of
10. Happle R. Segmental forms of autosomal dominant
the appropriate unaffected control tissue is thus important,
skin disorders: Different types of severity reflect
and in cutaneous mosaic disorders, blood, buccal swabs, or
different states of zygosity. Am J Med Genet. 1996;​
saliva are usually employed.38
66:241–242.
11. Happle R. The concept of type 2 segmental mosaicism,
FOLLOW-UP AND TREATMENT
expanding from dermatology to general medicine.
Although mosaic skin hypopigmentation is usually an J Eur Acad Dermatol Venereol. 2018;32:1075–1088.
isolated manifestation, patients must be followed up in order 12. Siegel DH. Cutaneous mosaicism: A molecular and
to rule out association with internal organ involvement. It is clinical review. Adv Dermatol. 2008;24:223–244.
important to recognize mosaic hypopigmentation because 13. Geiman TM, Robertson KD. Chromatin remodeling
it may be the first manifestation of a systemic disease. histone modifications, and DNA methylation-
Especially in linear hypopigmentation, if the cutaneous how does it all fit together? J Cell Biochem.
lesions are very extensive, the patient must be examined 2002;87:117–125.
by an ophthalmologist and neurologist. 14. Blaschko A. Die Nervenverteilung in der Haut in
Mosaic conditions are usually not heritable. However, ihre Beziehung zu den Erkrankungen der Haut.
the mutation can affect not only the skin but also the gonads Vienna, Austria and Leipzig, Germany: Wilhelm
(germinal or gonadal mosaicism), and in this case, the Braunmuller; 1901.
mutations can be inherited and expressed constitutionally 15. Happle R, Assim A. The lines of Blaschko on the head
by subsequent generations.38,39 Genetic counseling may and neck. J Am Acad Dermatol. 2001;44:6125.
thus be difficult.40 16. Happle R. Mosaicism in human skin. Understanding
Nowadays, unfortunately, there is no effective treatment the patterns and mechanisms. Arch Dermatol.
for mosaic hypopigmented conditions. 1993;129:1460–1470.
17. Ito M. Studies of melanin XI. Incontinentia pigmenti
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1. Happle R. Mosaicism in human skin. Understanding systematicus bilateralis. Tohoky J Exp Med 1952;​
Nevi, Nevoid Skin Disorders, and Cutaneous Neoplasia. 55(Suppl):57–59.
Springer; 2014. 18. Lee HS, Chun YS, Hann SK. Nevus depigmentosus:
2. Celia Moss. Mosaicism and linear lesion. In: Bolognia Clinical features and histopathologic characteristics
JL, Jorizzo JL, Schaffer JV. Dermatology. Vol 1. 4th ed. in 67 patients. J Am Acad Dermatol. 1999;40:21–26.
Elsevier; 2018:1004–1025. 19. Kim SK, Kang HY, Lee ES, Kim YC. Clinical and
3. Happle R. The McCune Albright syndrome: A histopathologic characteristics of nevus depigmen­
lethal gene surviving by mosaicism. Clin Genet. tosus. J Am Acad Dermatol. 2006;​55:423–428.
1986;29:321–324. 20. Cohen J 3rd, Shahrokh K, Cohen B. Analysis of
4. Kurek KC, Luks VL, Ayturk UM et al. Somatic mosaic 36 cases of Blaschkoid dyspigmentation: Reading
activating mutations in PIK3CA cause CLOVES between the lines of Blaschko. Pediatr Dermatol.
syndrome. Am J Hum Genet. 2012;90:1108–1115. 2014;31:471–476.
5. Happle R. The molecular revolution in cutaneous 21. Hogeling M, Fieden IJ. Segmental pigmentation
biology: Era of mosaicism. J Invest Dermatol. disorder. Br J Dermatol. 2010;162:1337–1341.
2017;137:e73–e77.
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22. Nehal KS, PeBenito R, Orlow SJ. Analysis of 54 32. Karaman B, Kayserili H, Ghanbari A, Uyguner ZO,
cases of hypopigmentation and hyperpigmentation Toksoy G, Altunoglu U, Basaran S. Pallister-Killian
along the lines of Blaschko. Arch Dermatol. syndrome: clinical, cytogenetic and molecular
1996;132:1167–1170. findings in 15 cases. Mol Cytogenet. 2018;11:45.
23. Kromann AB, Ousager LB, Ali IKM, Aydemir N, Published online August 17, 2018. doi:10.1186/
Bygum A. Pigmentary mosaicism: A review of s13039-018-0395-z.
original literature and recommendations for future 33. Wilkens A, Liu H, Park K, Campbell LB, Jackson M,
handling. Orphanet J Rare Dis. 2018;13:39. Kostanecka A, Pipan M, Izumi K, Pallister P, Krantz
24. Mirzaa GM, Campbell CD, Solovieff N et al. ID. Novel clinical manifestations in Pallister-Killian
Association of MTOR mutations with developmental syndrome: Comprehensive evaluation of 59 affected
brain disorders, including megalencephaly, focal individuals and review of previously reported cases.
cortical dysplasia, and pigmentary mosaicism. JAMA Am J Med Genet A. 2012;158A:3002–3017.
Neurol. 2016;73:836–845. 34. Dhar SU, Robbins-Furman P, Levy ML, Patel A,
25. Torchia D, Happle R. Segmental hypomelanosis and Scaglia F. Tetrasomy 13q mosaicism associated with
hypermelanosis arranged in a checkerboard pattern phylloid hypomelanosis and precocious puberty. Am
are distinct naevi: Flag-like hypomelanotic naevus J Med Genet A. 2009;149A:993–996.
and flag-like hypermelanotic naevus. J Eur Acad 35. Happle R. Phylloid hypomelanosis and mosaic trisomy
Dermatol Venereol. 2015;29:2088–2099. 13: A new etiologically defined neurocutaneous
26. Asch S, Sugarman JL. Epidermal nevus syndromes: syndrome. Hautarzt. 2001;52:3–5.
New insights into whorls and swirls. Pediatr 36. Braverman N, Lin P, Moebius FF et al. 1999. Mutations
Dermatol. 2018;35:21–29. in the gene encoding 3 beta-hydroxysteroid-delta 8,
27. Garcias-Ladaria J, Cuadrado Rosón M, Pascual- delta 7-isomerase cause X-linked dominant Conradi-
López M. Epidermal nevi and related syndromes— Hünermann syndrome. Nat. Genet. 22:291–294.
Part 1: Keratinocytic nevi. Actas Dermosifiliogr. 37. Clements SE, Mellerio JE, Holden St et al. PORCN
2018;109:677–686. gene mutation and the protean nature of focal dermal
28. Laura FS. Epidermal nevus syndrome. Handb Clin hypoplasia. Br J Dermatol. 2009;160:1103–1109.
Neurol. 2013;111:349–368. 38. Lim YH, Moscato Z, Choate KA. Mosaicism in
29. Fusco F, Bardaro T, Fimiani G et al. Molecular cutaneous disorders. Annu Rev Genet. 2017;​51:123–141.
analysis of the genetic defect in a large cohort of IP 39. Bachoo S, Gibbons RJ. Germline and gonosomal
patients and identification of novel NEMO mutations mosaicism in the ATR-X syndrome. Eur J Hum Genet.
interfering with NF-kappaB activation. Hum Mol 1999;7:933–936.
Genet. 2004;13:1763–1773. 40. Sachdev NM, Maxwell SM, Besser AG, Grifo JA.
30. Greene-Roethke C. Incontinentia pigmenti: A Diagnosis and clinical management of embryonic
summary review of this rare ectodermal dysplasia mosaicism. Fertil Steril. 2017;107:6–11.
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31. Peltomäki P, Knuutila S, Ritvanen A et al. Pallister-
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Skin disorders causing
post-inflammatory hypopigmentation
19
POLYTIMI SIDIROPOULOU, DIMITRIOS SGOUROS, and DIMITRIS RIGOPOULOS

CONTENTS
Introduction 127 Management 128
Etiology 127 Course and prognosis 129
Pathogenesis 127 Disorders involving hypopigmentation 129
Clinical features 128 Conclusion 132
Histological features 128 References 132
Diagnosis 128

INTRODUCTION A large number of inflammatory dermatoses, such as

Post-inflammatory hypopigmentation (PIH) is a common psoriasis (Figure 19.1), seborrheic or atopic dermatitis,
cause of acquired partial or diffuse loss of skin pigmentation. pityriasis alba, and lupus erythematosus, may induce
It can occur in all skin types as a result of cutaneous PIH. Sarcoidosis, lichen sclerosus, mycosis fungoides,
inflammation, injury, or dermatological interventions. and scleroderma may all present with hypopigmented
However, it is more prominent in dark-skinned or tanned lesions, as may Hansen disease. In addition, external skin
individuals, possibly because of the color contrast with the injuries from severe scratching, burns, and irritants, as
surrounding normal skin.1–3 well as dermatological and cosmetic procedures (e.g.,
Hypopigmentation secondary to cutaneous inflammation chemical peels, dermabrasion, cryotherapy, laser ablation,
covers a wide array of etiologies. Several dermatoses, intralesional steroid injections) can also lead to PIH.1–7
including psoriasis, seborrheic or atopic dermatitis, and
PATHOGENESIS
pityriasis alba, tend to induce PIH. Atypical presentation of
classic diseases such as mycosis fungoides and sarcoidosis The underlying mechanisms governing the pathogenesis
may also involve hypopigmentation. Moreover, cutaneous of PIH remain elusive. The variation in individual
injuries (e.g., burns, chemical peels, cryotherapy) represent
other examples of post-inflammatory leukoderma.1–7
Causal diagnosis of PIH is often clinically straight­
forward by determining the distribution and configura-
tion of the primary lesions, if present. Nevertheless, some
situations require further investigation, and sometimes a
biopsy should be performed.1–3,6 The most important key
to management is to identify and treat the primary cause.
Most cases of PIH resolve spontaneously with treatment of
the underlying condition; however, it can be permanent as
a result of complete destruction of melanocytes.1,2,4,8
In this review, the origin, pathogenesis, clinical features,
differential diagnosis, and treatment options for PIH are
discussed. “Disorders Involving Hypopigmentation”
toward the end of this chapter briefly covers some of the
common entities involving a hypopigmented phenotype.
A detailed description of trauma-induced and iatrogenic
hypopigmentation is beyond the scope of this chapter and
is not discussed.

ETIOLOGY
PIH can occur following cutaneous inflammation, injury,
or dermatological interventions. It covers a broad spectrum
of etiologies, thus including a wide differential diagnosis. Figure 19.1 PIH with fine scaling due to psoriasis.

127
128 Skin disorders causing post-inflammatory hypopigmentation

melanocyte response to trauma or inflammation is not well DIAGNOSIS

understood.2,8 The term “inherited individual chromatic Since the causes of PIH are different and heterogeneous,
tendency” has been proposed to describe this variation.9 establishing the correct diagnosis requires a thorough
Melanocytes can react to cutaneous inflammation or history and physical examination, the use of special
trauma with normal, increased, or decreased melanin lighting techniques, such as Wood’s lamp, and sometimes
production. People with melanocytes susceptible to a biopsy of the abnormally pigmented skin.1,10–12
damage are more prone to develop hypopigmentation.2,8,9 Apart from the aforementioned clinical features, the
Melanogenesis is a complex process involving various presence of other morphological signs, such as scaling,
steps that determine the skin color (melanosome biogene- epidermal atrophy, alopecia, induration, and infiltration,
sis, melanin production, melanosome transport, and trans- may address the underlying condition. The presence of
fer to keratinocytes). It is controlled by multiple mediators epidermal changes is a clue toward skin diseases that
(e.g., growth factors, cytokines) acting directly or indirectly disrupt the normal turnover of the epidermis. The presence
on melanocytes, keratinocytes, and fibroblasts. Through of fine scaling may be suggestive of pityriasis alba. If
dysregulation of these processes, cutaneous inflammation hypopigmentation is related to epidermal atrophy, LS,
can induce abnormal melanocyte-keratinocyte interac- morphea, and the hypopigmented variant of MF are to be
tions, leading to hypopigmentation.2,4 considered. If induration occurs, it indicates the presence
It has been suggested that hypopigmentation is usually of dense collagen, which characterizes LS and morphea.2,3,12
associated with a decrease, but not absence, of pigment.2,4 Further investigation is determined by the suspected
As tumor necrosis factor (TNF)-α and IL-17 are known diagnosis. Wood’s lamp testing can be used to further
to synergistically suppress pigmentation-related signaling refine the diagnostic approach and differentiate between
and melanin production, it is possible to represent a hypopigmented and depigmented skin. Wood’s lamp
potential mechanism by which inflammatory dermatoses accentuates depigmented lesions (complete pigment loss)
such as psoriasis are complicated by hypopigmentation.7 but does not enhance hypopigmented lesions (partial
However, when there is severe local inflammation, loss or pigment loss). 2,7,12 Confocal laser scanning microscopy
even death of functional melanocytes occurs, resulting in may further facilitate distinction between different
permanent pigmentary changes.2,4 hypomelanotic conditions based on the melanin content
and distribution patterns. Melanophages are present in
CLINICAL FEATURES PIH, but undetectable in vitiligo and nevus depigmentosus.
PIH may appear in a localized or diffuse pattern.1,3,10 However, the contents of melanin and dermal papillary
The disorders described in this chapter can initially be rings vary with the degree of the inflammation.2
localized; however, the distribution of hypopigmentation A skin biopsy is not always mandatory to establish the
often progresses to involve multiple body surfaces. diagnosis. In some cases, histology is less specific and the
The distribution and morphology of hypopigmented diagnosis is made primarily on a clinical basis. In certain
lesions usually reflects the area affected by the primary dermatoses, however, there may be some histopathological
inflammatory condition, and the color ranges from evidence that can reveal the primary cause of PIH, such as
hypopigmentation to depigmentation (reduced or absent in MF, LE, and sarcoidosis. Hypopigmentation associated
melanin skin content).1,2,8 Complete depigmentation is most with epidermal changes (e.g., atrophy), induration, sensory
commonly seen in the setting of severe atopic dermatitis changes, alopecia, or refractory to conventional treatment
(AD) and discoid lupus erythematosus (DLE), especially should be considered for biopsy. Pathology can also be of
in dark-skinned individuals. Whether this represents value in eliminating entities that can be confused with
koebnerization of vitiligo into areas of inflammation versus common hypopigmentary disorders such as vitiligo.2,4,6,12
the consequence of severe inflammation is controversial.2,4
Hypomelanosis usually follows or coexists with the MANAGEMENT
original inflammatory lesions, making the diagnosis Identifying and controlling or preventing the underlying
straightforward on clinical grounds. However, in some etiology is the key step in managing PIH. Once the primary
cases, the inflammatory phase is not present, and inflammatory condition is effectively treated, PIH usually
hypopigmentation may be the only feature. Examples resolves over time. Current treatment modalities include
include mycosis fungoides (MF), lichen sclerosus (LS), topical medications, phototherapy, laser, surgical grafting
morphea (localized sleroderma), systemic sclerosis techniques, and cosmetic camouflage.1,2,4,12
(generalized scleroderma), and sarcoidosis.2–4 Topical corticosteroids and/or calcineurin inhibitors
have been found to be beneficial in treating PIH when
HISTOLOGICAL FEATURES lesions are limited. Although the exact mechanisms of
In general, histopathology of PIH is rarely diagnostic. action remain elusive, those agents may affect inflamma-
A skin biopsy of the hypopigmented lesions shows tory cells. Sun or ultraviolet (UV) exposure (UVA or UVB
nonspecific findings, including decreased epidermal phototherapy, PUVA) may lead to repigmentation if mela-
melanin, superficial lymphohistiocytic infiltration, and nocytes in the affected areas are still functional and may
presence of melanophages in the upper dermis.2,12 be of value when lesions are widespread. Overexposure,
 Disorders involving hypopigmentation 129

however, may accentuate the color contrast due to tan- predisposition are strongly implicated in the development
ning of the surrounding skin. Both the 308-nm excimer of PA. Clinically, the condition is characterized by ill-
laser and the ablative fractional CO2 laser have been used defined, round to oval, slightly scaly macules and patches
to stimulate melanogenesis with favorable outcomes. with mild to moderate hypopigmentation. The lesions vary
However, regular subsequent treatment is usually needed in size from 0.5 to 3 cm, but larger lesions can also occur.
to maintain the results. In cases of amelanotic leukoderma The face, especially the malar region, is the most frequent
with total melanocyte loss, transplantation techniques site of involvement, but lesions can occasionally develop on
such as epidermal or melanocyte grafting may be con- the neck, trunk, and extremities. This dermatosis is usually
sidered and seem to be the most promising procedures to asymptomatic, but some patients complain of itching and
repigment extensive hypopigmented areas. In addition, burning. Under Wood’s lamp examination, the lesions
cosmetic cover-ups for camouflage, including high-cover- are enhanced. Histopathology of the affected skin reveals
age makeup, tanning products, and tattooing, may be an subacute spongiotic dermatitis along with reduced numbers
alternative option in order to decrease the color disparity of active melanocytes and a decrease in the number and size
with the normal skin. However, all therapeutic approaches of melanosomes. Topical corticosteroids may be beneficial,
are hampered by the fact that the pathophysiology of PIH but emollients seem to be equally effective. Recent data
remains poorly understood.2,4,8,12 reported perfect results with topical calsineurin inhibitors
Sun protection, including the use of a broad-spectrum (pimecrolimus, tacrolimus) as well as calcipotriol. Sun
sunscreen, can be of great value depending on the protection is of the utmost importance. The hypopigmented
underlying disease. In some cases, hypopigmented lesions patches often remain stable for several months or years and
are susceptible to sun damage and will become more may become more apparent during the summer period
obvious with tanning of the surrounding normal skin. On when the surrounding skin is tanned. The condition usually,
occasion, however, hypopigmentation may improve with but not always, resolves spontaneously after puberty.4–6,10,13
sun exposure, as happens in the context of psoriasis.12
Dermatitis/eczema
COURSE AND PROGNOSIS
PIH is frequently seen in association with atopic dermatitis, as
The severity of pigment loss is related to the extent and well as with other forms of eczema, especially in patients with
degree of the inflammation. PIH is usually self-limited colored skin. Although AD or atopic diathesis is occasionally
and improves or resolves spontaneously within a few related to vitiligo vulgaris, patients may also develop PIH
weeks or months if the primary cause is ceased. However, manifested as ill-defined white patches with eczema (Figure
depigmentation induced by severe inflammation (e.g., LE, 19.2a,b). The decrease in pigmentation can be attributed to a
scleroderma) may require years to become repigmented, disruption in melanogenesis secondary to the inflammatory
and may become permanent due to irreversible melanocyte process or to the application of potent topical corticosteroids.
destruction.2,4,8 In the latter case, pigmentary changes are more common
and intense.12,14 An extremely inflammatory form of vitiligo,
DISORDERS INVOLVING HYPOPIGMENTATION
called vitiligo with inflammatory raised border, can also arise
Pityriasis alba as a consequence of severe AD.15 Interestingly, the severity
Pityriasis alba (PA), a common benign condition, typically of AD seems to be higher if leukoderma occurs. The levels
occurs during childhood and adolescence, affecting 1% of of eosinophil counts, SCORAD, CCL17/TARC, and LDH
the general and 9.9% of the pediatric population. Although tend to be higher in AD cases with associated leukoderma
its pathogenesis remains unknown, it is included among PIH compared to nonleukoderma patients, indicating that the
disorders. Excessive sun exposure, skin dryness, and atopic incidence of leukoderma may be dependent on the severity

Figure 19.2 (a, b) PIH following resolution of AD eruption. (a) Localized leukoderma on the dorsum of the right shin in a 9-year-old
girl. (b) Post-inflammatory hypopigmented vitiligo-like lesions on the bilateral antecubital region in a 12-year-old boy with eczema.
130 Skin disorders causing post-inflammatory hypopigmentation

of AD.14 Seborrheic dermatitis is another common and often Lichen sclerosus

difficult-to-treat cause of PIH, particularly in patients with Lichen sclerosus is a common cause of PIH and typi-
darker skin phototypes.16 cally affects middle-aged women in their 50s and 60s.
This chronic mucocutaneous disorder of unclear etiol-
Lupus erythematosus ogy is delineated by violaceous erythema and ivory- or
Hypopigmentation or depigmentation is commonly ­porcelain-white depigmentation, mainly involving the
seen in LE as a result of the destruction of the basal genitals. However, the inflammatory phase may be clini-
layer homing melanocytes. In discoid LE, skin lesions cally undetectable, and hypopigmentation can be the sole
begin as dull-red macules or indurated plaques that feature. The pathogenesis of LS-associated leukoderma
develop pigment changes. Hypomelanosis favors the remains unknown, but it results in hypomelanotic or
center of the lesions and is usually surrounded by an amelanotic keratinocytes. Three possible mechanisms have
irregular rim of hyperpigmentation. Cutaneous atrophy been suggested: reduced melanin production, melanocyte
and scarring almost always coexist (Figure 19.3a–c). In decrease or loss, and blocked transfer of melanosomes to
chronic scarring DLE cases, the pigmentary changes keratinocytes. LS manifests with anogenital and extra-
are persistent. Histologically, in addition to decreased genital features. Typical lesions consist of well-demarcated
epidermal melanocytes, features that help to establish porcelain-white patches or plaques with irregular bor-
the diagnosis include epidermal atrophy, basal vacuolar ders, and varying degrees of sclerosis (Figure 19.4a–c).
degeneration, a dense inflammatory infiltration consisting Additional changes include epidermal atrophy, follicular
mainly of CD123+ plasmacytoid dendritic cells, pigmentary plugging, and, in the anogenital region, purpura. On occa-
incontinence, and fibrosis. Hypopigmentation is also sion, extragenital LS can present as guttate leukoderma.
frequently encountered in the center of annular lesions of Genital involvement may cause pruritus, dysuria, dyspa-
subacute LE, but is usually reversible.1,4,10,17 reunia, and a burning sensation, while extragenital lesions

Figure 19.3 (a–c) Clinical appearance of leukoderma in DLE lesions. Well-demarcated hypopigmented slightly atrophic patches
with atrophy involving the face and scalp of a 58-year-old woman (a), the back of a 27-year-old woman (b), and the neck and upper
chest area of a 46-year-old woman (c).

Figure 19.4 (a–c) LS-associated leukoderma presenting irregular ivory- or porcelain-white penile patches and plaques in three
male patients.
 Disorders involving hypopigmentation 131

are often asymptomatic. If LS is left untreated, scarring and individuals, especially of South African origin, with a
progression to squamous cell carcinoma (SCC) can occur. female-to-male ratio of approximately 2:1. Skin lesions
LS should be considered in any patient with genital vitil- consist of circumscribed or poorly marginated, irregular,
igo-like depigmentation. Although the clinical evaluation hypochromic papules or plaques distributed extensively
usually provides a straightforward diagnosis, a histologic on limbs and trunk, and they may not be indurated. In
confirmation may be sought to rule out SCC and its precur- addition, hypomelanosis surrounding dermal nodules
sors. Ultra-high-potency topical corticosteroids represent may be seen. The lesions are asymptomatic, favor the
the mainstay of treatment and can achieve complete reso- extremities, and display no other secondary changes.
lution of skin texture and color. Male circumcision can be Histopathology is similar to classic sarcoidosis, with
curative in some patients. Surgical referral is necessary if noncaseating granulomas expanding in the dermis. By
complications occur (e.g., phimosis, meatal stenosis, ure- electron microscopy, a vacuolated appearance in some
thral stricture), or with symptoms refractory to treatment. melanocytes as well as a decreased number of melanosomes
Long-term follow-up every 6–12 months is highly recom- within keratinocytes is observed.3,4,6
mended to monitor for disease recurrence, progression, or
development of malignancy.1,3,4,6,12 Mycosis fungoides
Although typical MF (erythematous patches, plaques,
Scleroderma and nodules) can induce PIH, there is a variant in which
Hypopigmentation is not uncommon in lesions of morphea hypomelanotic lesions are the only or main characteristic.
and systemic sclerosis (SS). Hypomelanotic changes This type of MF prevails in the juvenile setting,
described in the setting of SS include a mixture of hypo- especially in patients with dark skin, and in the pediatric
and hyperpigmentation in areas of chronic sclerosis, for population. Hypopigmented MF (HMF) presents with
example, the hands, and a characteristic vitiligo-like scaly hypomelanotic patches that may be pruritic with
phenotype in both sclerotic and nonsclerotic skin. The latter loss of hair of the affected skin and develop on the trunk
early feature of SS is characterized by circumscribed areas and extremities (Figure 19.5). Typical MF lesions such as
of depigmentation with perifollicular pigment retention, erythema and slight infiltration are usually, but not always,
forming a “salt-and-pepper” appearance. The epidermal present concurrently. Histologically, epidermotropism of
melanocytes disappear in the interfollicular regions but atypical T lymphocytes is seen, a picture similar to that of
are retained in the near vicinity of hair follicles. This classic MF. Electron microscopy demonstrates decreased
peculiar leukoderma resembles repigmenting vitiligo and numbers of melanosomes within epidermal keratinocytes,
usually involves the retro-auricular region, scalp, forehead,
chest, and/or trunk. When such leukoderma presents,
SS must be excluded, as it is only known to occur in two
other settings: overlap syndromes (that may include SS)
and scleromyxedema. Hypopigmented lesions may also
be seen in morphea or localized scleroderma. In a subset
of children, early juvenile localized scleroderma (JLS) or
hypopigmented morphea manifests with depigmented
lesions that mimic, both clinically and histologically,
vitiligo, resulting in a protracted diagnosis and treatment.
A reciprocal distribution of CD34+ and FXIIIa+ cells (i.e.,
significant decrease or absence of FXIIIa+ and CD34+
cells in the papillary and reticular dermis, respectively,
and increased FXIIIa+ cells in areas of fibrosis) can
help distinguish early JLS from vitiligo. The origin and
pathogenesis of scleroderma-associated pigmentary
disturbances are elusive. Early diagnosis and adequate
treatment are pivotal in preventing disfiguring progression
and require a multidisciplinary a­ pproach.1,3,4,10,12

Sarcoidosis
The skin is one of several organs potentially affected by
sarcoidosis, a multisystem idiopathic disease characterized
by noncaseating granulomas. Cutaneous involvement
is protean and occurs in up to one-third of patients
(25%–30%). Although the true incidence of leukoderma
in sarcoidosis is unknown, hypopigmented patches are Figure 19.5 Hypopigmented MF showing macular
one of the less typical presentations. Hypopigmented hypomelanosis with ill-defined borders expanding on the legs
sarcoidosis is mainly reported in darkly pigmented with characteristic concomitant focal hair loss.
132 Skin disorders causing post-inflammatory hypopigmentation

whereas numerous morphologically normal melanosomes 7. Disturbances of Pigmentation. In: James W, ed.
are present in melanocytes. This finding is suggestive of Andrews’ Diseases of the Skin: Clinical Dermatology,
a defect in melanosomal transfer. Clinically, HMF may 12th ed. China: Elsevier; 2016:856, 870.
mimic vitiligo, PA, leprosy, and pityriasis versicolor. In a 8. Hartmann A, Bröcker EB, Becker JC. Hypopigmentary
high level of suspicion, such a diagnosis should be carefully skin disorders: Current treatment options and future
considered in any young patient presenting with persistent directions. Drugs. 2004;64:89–107.
hypopigmented patches, especially over the trunk and 9. Ruiz-Maldonado R, Orozco-Covarrubias ML. Post­
sun-protected areas. Assessment of lymph nodes and inflammatory hypopigmentation and hyperpigmen-
routine histology and immunophenotyping may guide tation. Semin Cutan Med Surg. 1997;16:​36–43.
diagnosis. Successful treatment, including photo(chemo) 10. Mollet I, Ongenae K, Naeyaert JM. Origin, clinical
therapy or topical nitrogen mustard, usually results in presentation, and diagnosis of hypomelanotic skin
repigmentation.3,4,6,12,18–20 disorders. Dermatol Clin. 2007;25:363–371, ix. doi:
10.1016/j.det.2007.04.013.
CONCLUSION 11. Plensdorf S, Livieratos M, Dada N. Pigmentation
This chapter addresses PIH, a significant disease group disorders: Diagnosis and management. Am Fam
among pigmentary skin disorders that can be particularly Physician. 2017;96:797–804.
distressing for cosmetic reasons and may also be associated 12. Tey HL. A practical classification of childhood
with underlying malignancies or systemic disease. hypopigmentation disorders. Acta Derm Venereol.
Enhancing dermatologists and other clinicians’ experience 2010;90:6–11.
in recognizing the key clinical features can greatly improve 13. Engin RI, Cayir Y. Pigmentation disorders: A
diagnostic accuracy, reduce unnecessary interventions, short review. Pigment Disord. 2015;2:6. doi:
and prevent disabling complications. 10.4172/2376-0427.1000189.
14. Kuriyama S, Kasuya A, Fujiyama T et al. Leukoderma
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1. Saleem MD, Oussedik E, Picardo M et al. Acquired 2015;42:215–218.
disorders with hypopigmentation: A clinical approach 15. Sugita K, Izu K, Tokura Y. Vitiligo with inflammatory
to diagnosis and treatment. J Am Acad Dermatol. raised borders, associated with atopic dermatitis. Clin
2019;80:1233–1250.e10. doi: 10.1016/j.jaad.2018.07.070 Exp Dermatol. 2006;31:80–82.
2. Vachiramon V, Thadanipon K. Postinflammatory 16. Lopez I, Ahmed A, Pandya AG. Topical PUVA for
hypopigmentation. Clin Exp Dermatol. 2011;36:708– post-inflammatory hypopigmentation. J Eur Acad
714. doi: 10.1111/j.1365-2230.2011.04088.x. Dermatol Venereol. 2011;25:742–743.
3. Tey HL. Approach to hypopigmentation disorders 17. Connective tissue diseases. In: James W, ed. Andrews’
in adults. Clin Exp Dermatol. 2010;35:829–834. doi: Diseases of the Skin: Clinical Dermatology, 12th ed.
10.1111/j.1365-2230.2010.03853.x. China: Elsevier; 2016:153–162.
4. Passeron T, Ortonne J. Vitiligo and other disorders 18. Amorim GM, Niemeyer-Corbellini JP, Quintella DC
of hypopigmentation. In: Callen J, ed. Dermatology et al. Hypopigmented mycosis fungoides: A 20-case
by Jean L. Bolognia, Julie V. Schaffer, and Lorenzo retrospective series. Int J Dermatol. 2018;57:306–312.
Cerroni, 4th ed. China: Elsevier; 2018:1103–1106. 19. Castano E, Glick S, Wolgast L et al. Hypopigmented
5. Nicolaidou E, Katsambas AD. Pigmentation disorders: mycosis fungoides in childhood and adolescence:
Hyperpigmentation and hypopigmentation. Clin A long-term retrospective study. J Cutan Pathol.
Dermatol. 2014;32:66–72. 2013;40:924–934.
6. Patel AB, Kubba R, Kubba A. Clinicopathological 20. Furlan FC, Sanches JA. Hypopigmented mycosis
correlation of acquired hypopigmentary disorders. fungoides: A review of its clinical features and
Indian J Dermatol Venereol Leprol. 2013;79:376–382. pathophysiology. An Bras Dermatol. 2013;88:954–960.
Infectious and parasitic causes
of hypopigmentation
20
SERENA GIANFALDONI, ALEKSANDRA VOJVODIC, NOOSHIN BAGHERANI,
BRUCE R. SMOLLER, BALACHANDRA ANKAD, LEON GILAD, ARIEH INGBER,
FABRIZIO GUARNERI, UWE WOLLINA, and TORELLO LOTTI

CONTENTS
Pityriasis versicolor 133 Treponematoses 139
Leprosy 135 References 141
Onchocerciasis 139

PITYRIASIS VERSICOLOR Cell-mediated immunity plays an important role

Introduction in the skin equilibrium of Malassezia species. 7,16
Monocyte-derived dendritic cells play a great role in
Pityriasis versicolor (PV) is a common benign superficial
binding and phagocytizing virulent fungal organisms
fungal skin disease,1–3 characterized by scaly hyper- and
in immunocompetent cases.14 It seems that in cases with
hypopigmented skin lesions 4. It is caused by lipophilic
recurrent and disseminated pityriasis versicolor (RDPV),
yeasts from the genera Malassezia (previously named
an underlying reduced cellular immunity can be a
Pityrosporum orbiculare), which are members of the skin
predisposing factor in development of disease.7
microflora.1–7
The role of humoral-mediated immunity against
Epidemiology Malassezia infections is debatable. In a study on patients
with atopic dermatitis, the role of Malassezia in promoting
PV affects up to 40% of the population, especially
production of T helper 2 (Th2)-type cytokine profile,
in tropical regions. Teenagers and young adults are
including interleukin 4 (IL-4) and IL-10 and expression of
frequently afflicted.7–12 Malassezia colonies on the skin
Malassezia-specific IgE antibodies, was demonstrated.17
begin immediately after birth and increase with age 4
The pathogenesis of hypopigmented lesions is different
and Malassezia is seen as normal skin flora in 75%–98%
from that of hyperpigmented ones. The former is caused
of healthy adults. 5 Distribution of various species of
by damage of melanocytes, inhibition of tyrosinase by
Malassezia shows differences based on geographical
Malassezia-produced dicarboxylic acid and inflammation.14
situation,4,13 seasonal variation,9 ethnicity,13–14 body site,
Activation of complement factors via direct and alternative
age, gender,4,12,15 different sampling techniques, and culture
pathways plays a role in production of the inflammation.16
media.12
Etiopathogenesis Clinical features
Malassezia yeasts are the causative factor for developing PV is a superficial pigmentary noninf lammatory
PV. These are divided into about 14 species, among dermatosis. 4 It is characterized by hypopigmented,
which M. furfur, M. globosa, M. sympodialis, M. slooffiae, hyperpigmented, or erythematous scaly, oval, and round
M. restricta, and M. obtuse have been isolated from the macules and patches (Figures 20.1 through 20.3).1,4,8,14 The
skin of patients with PV.4 M. globosa is the most common follicular type of PV has been described18 (Figure 20.4).
species cultured from PV lesions.3,4,12,14,15 Its color ranges from white to brown and black. 3,16 The
PV is associated with increased activity of sebaceous term “versicolor” refers to these various colors, which can
glands.8 Malassezia species are dimorphic fungi which be seen simultaneously in the same patient. These lesions
upon conversion from yeast to mold or mycelial phase can coalesce, forming irregular and large patches. 8,14
can result in their penetration and invasion of the stratum Gentle scraping produces a mild scaling, which helps in
corneum, with consequent PV. 4,5 Individual factors establishing the diagnosis.14
include genetic predisposition, hyperhidrosis, long-term The lesions of PV are mostly asymptomatic, but
corticosteroid administration, 8,11,14,16 broad-spectrum pruritus has been reported in some cases.11,16 The trunk,
antibiotic therapy,11 occlusive dressing,8 administration of including the chest and upper back, neck, proximal upper
topical oily agents, malnutrition, chronic infections, and extremities,2,11 abdomen, and inguinal areas are the sites
pregnancy.14 that are most commonly involved by this disease.

133
134 Infectious and parasitic causes of hypopigmentation

Figure 20.3 Pityriasis versicolor with pink scaly patches.

(Courtesy of Prof. Balachandra Ankad; Department of
Dermatology, SN Medical College, Rajiv Gandhi University of
Figure 20.1 Pityriasis versicolor with hypopigmented Health Sciences, Bengaluru, India.)
patches with fine scaling, more evident by stretching the
skin. (Courtesy of Prof. Balachandra Ankad; Department of
Dermatology, SN Medical College, Rajiv Gandhi University of
Health Sciences, Bengaluru, India.)

Figure 20.4 Follicular variant of PV showing hypopigmented

macules with follicular distribution. (Courtesy of Prof. Balachandra
Ankad; Department of Dermatology, SN Medical College, Rajiv
Gandhi University of Health Sciences, Bengaluru, India.)

Figure 20.2 Hyperpigmented variant of pityriasis versicolor

showing brown macules coalescing into patches. (Courtesy
of Prof. Balachandra Ankad; Department of Dermatology, SN
Medical College, Rajiv Gandhi University of Health Sciences,
Bengaluru, India.)

Histopathology
A biopsy is not needed unless, in atypical cases, other skin
diseases should be excluded. Histologically, PV shows
hyperkeratosis, acanthosis,9,19 spongiosis, exocytosis,
reticular degeneration, hydropicdegeneration of basal layer,18
hyperpigmentation of basal layer,19 melanin incontinence,9 Figure 20.5 Multiple yeast forms within the stratum
epidermal thinning, and mononuclear cell infiltration, mainly corneum characterize pityriasis versicolor. (Courtesy of Prof.
of lymphocytes and histiocytes. Short hyphae and budding Bruce R. Smoller; University of Rochester, School of Medicine
yeast cells are seen in the stratum corneum9 (Figure 20.5). and Dentistry, USA.)
 Leprosy 135

Diagnosis mucosa of the upper respiratory tract and eyes, potentially

Diagnostic methods of PV include: resulting in irreversible disabilities and deformities if left
untreated. It also may involve joints, lymph nodes, bone
• Clinical examination: It forms the basis of diagnosis. 7,8,15
marrow, and internal organs.
Zileris sign or “evoked scale” sign is a marker for the
3
Leprosy is caused by an intracellular bacterium called
clinical diagnosis and is defined as producing fine Mycobacterium leprae (M. leprae), a weakly acid-fast bacillus
desquamation through stretching or scraping the skin. (AFB). It is contagious; however, the exact mechanism of
This sign confirms fragility of the stratum corneum in transmission is not known. It is believed to spread via
PV lesions.9 droplets from the nose or mouth or rarely by direct skin
• Wood’s lamp examination: Under Wood’s lamp, contact with lesions of infected individuals. 23–25 Among
yellowish or golden fluorescence may be seen.8 people exposed to M. leprae, 95% are not susceptible to
• Direct microscopy: In direct microscopic assessment infection, while among the 5% who become infected, only
of scaling lesions, treatment with 10%–20% KOH is 1% shows the disease. Hence, it appears that hosts’ genetic
performed.5 In this method, finding round spores and predisposition and impaired immune system play a critical
short curved hyphae with a spaghetti-and-meatballs role in disease development.26,27
appearance is typical for diagnosing PV. 5,7,14 Porto’s
method is finding collections of round or oval cells in Epidemiology
association with short hyphae of bizarre forms.3 Currently, it is distributed all over the world, particularly
• Culture: Malassezia can be cultured in slants of in Southeast Asia, Africa, and Latin America. Although
Sabouraud’s dextrose agar and Sabouraud’s dextrose its prevalence has significantly decreased secondary to
in mixture with sterile olive oil for isolating lipophilic introduction of the multiple drug therapy (MDT), more
species.5 Leeming–Notman agar or modified Dixonagar than 200,000 new patients have been reported annually
is another media for Malassezia culture.12 over the globe.28
• Molecular studies: Molecular methods such as the PCR-
based restriction fragment length polymorphism (RFLP) Classification
technique are used for identification and differentiation According to the Ridley-Jopling classification criteria,
of different species of Malassezia.5,20 histopathological changes, skin-slit smear assessment
(SSS), and bacteria index (BI), leprosy is divided into five
Differential diagnosis types: tuberculoid leprosy (TT), borderline tuberculoid
The differential diagnoses of PV include: seborrheic (BT), mid-borderline (BB), borderline lepromatous (BL),
dermatitis, erythrasma, secondary syphilis, mycosis and lepromatous leprosy (LL). Indeterminate leprosy (IL)
fungoides,14 pityriasis alba, leprosy, vitiligo,9,14 pityriasis rubra is considered the initial presentation of the disease.23,28,29
pilaris,18 post-kala-azar dermal leishmaniasis, idiopathic The World Health Organization (WHO) divides leprosy
guttate hypomelanosis, lichen sclerosus et atrophicus, lichen into paucibacillary (PB) and multibacillary (MB), based on
planus depigmentosus, nevus depigmentosus, sarcoidosis, the number of skin lesions, presence of nerve involvement,
confluent and reticulated papillomatosis, and pityriasis and identification of bacilli on slit-skin smear.23,30
rosea.14 Pure neuritic leprosy (PNL) is seen in 4%–8% of
leprosy cases; it is a type of leprosy with exclusively neural
Prognosis involvement without skin manifestations.31
PV is a benign condition with a high rate of relapse.5 It tends In the course of leprosy, and before, during, and after
to relapse in approximately 60% and 80% of patients during initiation of MDT, patients may show inflammatory episodes,
the first and second years of treatment, respectively.1,5,16,21 so-called lepra reactions. Lepra reactions are classified
In immunocompromised patients, the recurrence into three types: type 1 reaction (reversal reaction/RR/
frequency is higher and systemic therapy for PV may be downgrading), type 2 reaction (such as erythema nodosum
required.14 leprosum/ENL/upgrading), and Lucio phenomenon (LP).29,32

Treatment Clinical features

Although PV is a benign condition, cosmetic reasons and Based on M. leprae–specific cell-mediated immunity, leprosy
pruritus, particularly in more widespread extension, may has a wide spectrum of clinical manifestations, ranging from
require therapy including systemic azoles or topical agents more nerve involvement and its consequent anesthesia and
such as azoles, terbinafine, zinc pyrithione, selenium deformities to more skin lesions. Among the nerves, the
sulfide, and ciclopiroxolamine.16,21,22 ulnar, median, lateral popliteal, posterior tibial, and greater
auricular ones are commonly involved.33 The clinical features
LEPROSY of the most frequent types of leprosy include:
Introduction • IL: It is usually characterized by one or two
Leprosy, or Hansen disease, is a chronic granulomatous hypopigmented lesions with ill-defined borders
infection involving primarily peripheral nerves, skin, and and impaired temperature sensation. No peripheral
136 Infectious and parasitic causes of hypopigmentation

nerve thickening is seen. Erythema, infiltration, and • BL: It is characterized by numerous patches arranged in
impairment of pain and/or touch perception show its an almost symmetrical pattern. The number of smaller
progression to other clinical types.23 lesions is higher than that of larger lesions. Its clinical
• TT: It is characterized by a small number of round features are common with BB and LL. Normal skin
hypopigmented and erythematous macules and patches areas along with infiltrations are seen in BB (Figures
with well-defined populated borders, 28,29 atrophic 20.8 and 20.9). Without treatment, it can progress to
centers, and hair loss. Impairment of temperature, pain, subpolar lepromatous leprosy (LLp). Peripheral nerves
and touch sensation has been reported23 (Figure 20.6). are commonly involved.23
• BT: It is manifested as hypopigmented plaques of
different size and number. The number varies from 5 to
20. Asymmetrical distribution is characteristic. Bigger
lesions are more common as compared to smaller lesions.
Involvement of peripheral nerves is very common and
crucial in this type. Sensation over the patches is lost23
(Figure 20.7).

Figure 20.8 BL with well-to ill-defined patches and plaques

(note the greater number of larger patches and the infiltrated
Figure 20.6 TT showing well-defined plaque with peripheral
border extending peripherally). (Courtesy of Prof. Balachandra
activity and central clearing. (Courtesy of Prof. Balachandra
Ankad; Department of Dermatology, SN Medical College, Rajiv
Ankad; Department of Dermatology, SN Medical College, Rajiv
Gandhi University of Health Sciences, Bengaluru, India.)
Gandhi University of Health Sciences, Bengaluru, India.)

Figure 20.7 BT showing well- to ill-defined plaque on the Figure 20.9 A 45-year-old Ethiopian male with BL
left leg. Note the infiltrated border extending peripherally. downgrading from BB, presented with a hypopigmented
(Courtesy of Prof. Balachandra Ankad; Department of sharply demarcated lesion. (Courtesy of Prof. Leon Gilad;
Dermatology, SN Medical College, Rajiv Gandhi University of the Lepers Hospital, Department of Dermatology, Hadassah
Health Sciences, Bengaluru, India.) University Hospital, Hebrew University, Jerusalem, Israel.)
 Leprosy 137

• LL: It is characterized by symmetrically widespread

erythematous, hypopigmented and edematous macules
and infiltrated nodules, madarosis, xerosis, edema of
the extremities, cyanosis of the palmar and plantar
regions, and plantar trophic ulcers (Figure 20.10).
Lepromatous macules have poorly defined borders
and no loss of sensation. Local nerve enlargement is
not characteristic. In addition to macules, nodules,
plaques, or diffuse infiltration of skin are observed.
Such infiltration on the face results in “leonine facies.”
Nose septum perforation and total collapse of the nose
are the result of advanced LL. Papules are common on
the hard palate. Nerve involvement is characteristically
symmetrical and exhibits a stocking-glove distribution,
unrelated to the location of skin lesions.23 In addition
to skin manifestations, systemic involvement including
eyes, bones, testicles, and solid organ involvement have
been reported in LL.
• Type 1 reaction: It is seen in borderline leprosy.29 It is the
leading cause for hospitalization of leprosy patients and Figure 20.11 ENL in a case with LL showing erythematous,
is accompanied by lifelong neurological complications.30 tender nodules on the extremities, abdomen, and chest.
RR is characterized by skin and nerve inflammation, (Courtesy of Prof. Balachandra Ankad; Department of
which include exacerbation of preexisting skin lesions, Dermatology, SN Medical College, Rajiv Gandhi University of
appearance of new skin lesions, induration, and Health Sciences, Bengaluru, India.)
erythema. Lesions are tender. Neurological dysfunction
is reported in 50% of patients.34 include ulceration, pustule formation, bullous lesion,
• Type 2 reaction: It is seen more commonly in BL and livedo reticularis, and erythema multiforme- and Sweet
LL types. ENL is characteristically manifested by tender syndrome-like features.29
erythematous nodules along with constitutional and • LP: It is a rare reactional state seen exclusively in Lucio
systemic features including fever, malaise, and arthralgia leprosy. LP is characterized by vascular thrombosis and
(Figure 20.11). Rare and atypical manifestations of ENL skin ulceration and necrosis.35
Leprosy in children is an indicator of being in
prolonged contact with a person with untreated disease,
particularly in the family and with active infection in the
community. 25

Diagnosis
To achieve control and eradication of leprosy, its accurate
diagnosis and prompt therapy initiation would be
optimal.36 Hansen disease is diagnosed based on clinical
presentation, and the diagnosis is confirmed by skin or
nerve biopsy and acid fast staining. Serological tests lack
sensitivity and specificity and are not used to diagnose
leprosy.37 The diagnosis of leprosy remains based on the
presence of at least one of three cardinal signs:38
i. Definite loss of sensation in a pale (hypopigmented)
or reddish skin patch
ii. Thickened or enlarged peripheral nerve with loss of
sensation and/or weakness of the muscles supplied
by that nerve
iii. Presence of acid-fast bacilli in a slit-skin smear
• Physical examination: Hypopigmented macules
characteristic of leprosy can guide in the diagnosis of
Figure 20.10 LL showing numerous small patches (note leprosy. Other important signs and symptoms in physical
the symmetrical distribution). (Courtesy of Prof. Balachandra examination are related to neurological involvement,
Ankad; Department of Dermatology, SN Medical College, Rajiv which includes thickened peripheral nerve, dysesthesia,
Gandhi University of Health Sciences, Bengaluru, India.) and motor disorders.39
138 Infectious and parasitic causes of hypopigmentation

• Microbiological evaluation: Staining techniques like • BB: Admixture of scattered epithelioid cells,
Ziehl-Neelsen and Fite-Faraco are performed on lymphocytes, and foamy histiocytes; no well-formed
specimens derived through SSS, nasal swabs, and granulomas or necrosis; and easily identified AFB in
formalin-fixed paraffin embedded tissue.23 Wade Fite stain.
• Histopathology of cutaneous lesion23 • BL: Minimally thickened nerve, intense endoneurial
• IL: Nonspecific periadnexal and peri- and/or infiltrate of foamy histiocytes, a few lymphocytes,
intraneural inflammatory infiltration. no epithelioid histiocytes, no necrosis, no giant
• TT: Thickened nerve, enlarged funicles. Well-formed cells, and abundant AFB.
epithelioid cell granulomas, predominant component • LL: Diffuse and intense foam cell infiltrate, no
of epithelioid cells with vesicular slipper shaped lymphocytes, no epithelioid histiocytes, no necrosis,
nuclei, collar of lymphocytes, occasional giant cell, no giant cells, and numerous AFB (Figure 20.14).
foci of necrosis, no foamy histiocytes, and seldom • Molecular method: Polymerase chain reaction is used
AFB in Wade Fite stain (Figures 20.12 and 20.13). for the detection of AFB and is sensitive and specific,
• BT: Loose endoneurial granulomas, intermingled particularly for diagnosing neural involvement.31
lymphocytes, many Langhans-type giant cells, and • Nerve biopsy: Although it is the gold standard for
occasional AFB in Wade Fite stain. diagnosis of PNL, 39 because of probability of nerve
destruction and consequent disabilities, it has limited
use. Furthermore, its histopathologic interpretation
needs highly specific skills. 33 Fine-needle aspiration
cytology (FNAC) of the nerves is a relatively less
aggressive alternative to nerve biopsy whose results are
comparable with nerve biopsy.39
Other methods
• Imaging techniques: Ultrasonography, color Doppler, and
magnetic resonance imaging are used for detecting nerve
involvement in the course of leprosy or its reactions.33
• Nerve and muscle testing: Nerve conduction studies
have limited use in diagnosis of leprosy because
they fail to recognize leprosy as an exact cause of
neuropathy. 33
• Mitsuda skin test orlepromin skin test: It is intradermal
injection of heat-killed M. leprae and assessment of
the skin induration at the injection site after 21 days
Figure 20.12 Granuloma with surrounding lymphocytes
(A51). It is positive in 57%–100% of PNL cases. Because
and plasma cells present surrounding dermal nerves in TT.
of its poor diagnostic value, it is used along with other
(Courtesy of Prof. Bruce R. Smoller; University of Rochester,
studies.39
School of Medicine and Dentistry, USA.)

Figure 20.13 A well-formed granuloma is present in TT. Figure 20.14 A Fite stain demonstrates multiple organisms
(Courtesy of Prof. Bruce R. Smoller; University of Rochester, in LL. (Courtesy of Prof. Bruce R. Smoller; University of Rochester,
School of Medicine and Dentistry, USA.) School of Medicine and Dentistry, USA.)
 Treponematoses 139

Differential diagnosis by erythematous exanthema, with numerous small

Differential diagnosis of leprosy includes sarcoidosis, (1–3 mm), round papular elements, sometimes with
pityriasis versicolor, systemic lupus erythematosus, superficial and/or apical desquamation (acute papular
dermatomyositis granuloma annulare, and cutaneous onchodermatitis). Evolution is to chronic papular
tuberculosis.23 onchodermatitis and lichenified onchodermatitis, with
possible hypertrophic, verrucous, and/or eczema-like
Treatment and prognosis aspects, xerosis, and hyperpigmentation. Late skin lesions
Leprosy is a curable disease. Disability is prevented if include hypo-/atrophy, hypo-/depigmentation (“leopard
diagnosed and treated early. According to WHO guidelines, skin”), and onchocercomas (fibrous, mobile, asymptomatic
treatment includes multiple (two or three) drugs, and the nodules, located at bony prominences in areas of Simulidae
duration of treatment, dose, and number of antibiotics bites and containing adult nematodes).40,41,43
depend on the type of leprosy (PB or MB) and age of the Asymptomatic axillary, inguinal, or femoral
patient: adult or child. A three-drug regimen of rifampicin, lymphadenopathy may occur. The clinical picture-defined
dapsone, and clofazimine is recommended for a duration “hanging groins” include femoral lymphadenopathy,
of 6 months for PB leprosy and 12 months for MB leprosy.38 inguinal hernia, hydrocele, elephantiasis of external
Prompt diagnosis and initiating the MDT can genitals, and inguinal folds of inelastic, atrophic skin.43
prevent long-term disabilities.38 PNL can result in severe Peculiar cutaneous manifestations of onchocerciasis are
disabilities.39 mal morado, characterized by thickened, smooth, pale pink
skin and leprosy-like “leonine facies”; erisipela de la costa,
ONCHOCERCIASIS erysipeloid form involving face and neck; and sowda, with
Introduction lichenoid, hyperpigmented, unilateral leg lesions associated
with intense itch and inguinal lymphadenopathy.
Onchocerciasis, also known as “river blindness,” is a Eye involvement may cause punctuate/sclerosing
parasitic disease caused by the filarial nematode Onchocerca keratitis, iridocyclitis, uveitis, or active optic inflammation,
volvulus.40,41 Its burden and socioeconomic consequences and result in visual impairment, glaucoma, or blindness.45
are significant: estimated loss of 1 million disability-
adjusted life-years (healthy life-years lost due to disability Laboratory workup
and mortality), because of cutaneous manifestations, Blood exams show hypereosinophilia and elevated
severe visual impairment (500,000 cases), blindness erythrosedimentation rate, total IgE and IgG.40,41 During
(270,000 cases), parasite-induced immunosuppression, acute papular onchodermatitis, histopathology shows
epilepsy, and social stigmatization, all leading to a decrease microfilariae in the upper dermis, with infiltration of
of a host’s life expectancy, although onchocerciasis is not macrophages, eosinophils and neutrophils around dead
lethal per se.42 or degenerating ones, but little reaction against live
Onchocerca volvulus is an almost exclusively human ones. Ortho-parakeratotic hyperkeratosis, acanthosis
parasite (isolated cases reported in chimpanzees, gorillas, and dermal fibrosis are characteristic of chronic papular
cynomolgus monkeys). Blackflies of the genus Simulium, onchodermatitis. Microfilariae can also be detected by
living and breeding near fast-flowing, aerated water streams examining skin-snip biopsies incubated in saline solution
(e.g., rivers), are its vectors and obligate intermediate for 30 minutes.44,47
hosts.43,44
Treatment
Epidemiology Ivermectin (microfilaricidal), administered once or,
Onchocerciasis is endemic in tropical areas, mainly Sub- preferably, twice yearly for the lifespan of adult worms
Saharan countries, where more than 99% of patients live. (10–15 years), or as long as evidence of skin or eye infection
Estimated cases were 37 million in 2006.42 Thanks to exists, is the treatment of choice.40,48 Adjustment of
extensive long-term public health intervention, that figure treatment strategy is required for patients with high blood
is now halved, and four previously endemic countries are levels of Loa loa, to avoid possibly severe adverse events.48
disease free.40 Because of bactericidal effects on Wolbachia, doxycyclin is
indirectly lethal for adult Onchocerca volvulus, offering a
Pathogenesis new, promising therapeutic approach.49
Microfilariae invade mainly skin and eyes. Tissue damage
is most often due to inflammation triggered by molecules TREPONEMATOSES
from parasite death.45,46 Introduction
Treponematoses are chronic bacterial infections caused
Clinical features by the spirochetal organisms of the Treponema species.
Early signs of infection include fever, neuralgic pain The agents of human treponematoses include four closely
in joints, and temporary hives on trunk and face. related members of the genus Treponema: three subspecies
Onchocerciasis is initially characterized by itch, often of Treponema pallidum plus Treponema carateum.
intense and widespread. This is followed, in 3–36 months, T. pallidum subsp. pallidum causes venereal syphilis,
140 Infectious and parasitic causes of hypopigmentation

while T. pallidum subsp. pertenue, T. pallidum subsp. dermal infiltrate. In early bejel, granulomas consisting
endemicum, and T. carateum are the agents of the endemic of epithelioid cells and multinuclear giant cells may be
treponematoses yaws, bejel, and pinta, respectively. All present. In early pinta lesions, there is loss of melanin
human treponematoses share remarkable similarities in basal cells and liquefaction degeneration. Epidermal
in pathogenesis and clinical manifestations, consistent atrophy and the presence of many melanophages in the
with the high genetic and antigenic relatedness of their dermis are typical findings of late-stage pinta.54,55
etiological pathogens.50,51 Serologic tests are rarely available in those countries
where endemic treponematoses are abundant. The
Endemic treponematoses: Yaws, pinta, bejel serological tests used to diagnose endemic treponematoses
Epidemiology are the same as those used to diagnose syphilis:
Yaws is caused by Treponema pallidum subspecies pertenue. Nontreponemal agglutination tests, rapid plasma regain
It affects mainly children aged under 15 years who live in (RPR), or Venereal Disease Research Laboratory (VDRL)
poor communities in warm, humid, and tropical forested are positive in untreated cases; treponemal tests TPHA,
areas of Africa, Asia, Latin America, and the Pacific Treponema pallidum particle agglutination (TPPA), and
Islands.50–52 FTA-Abs are more specific, but remain positive for life.56,57
Transmission of endemic treponematoses is due to Rapid point-of-care (PoC) treponemal tests have become
skin-to-skin contact for all three diseases and mucous available in the form of immunochromatographic strips;
membrane contact in the case of bejel. these can be used with whole blood and do not require
refrigeration.58,59
Clinical manifestations
Treatment
The clinical manifestations of endemic treponematoses
occur in three distinct stages: primary lesions, For the treatment of yaws, the WHO recommends a single
dissemination, and late manifestations. In yaws, the oral dose of azithromycin (30 mg/kg, with a maximum of
primary lesions are either a localized papilloma or a 2 g). Benzathine penicillin as a single intramuscular dose
solitary ulcer 2–5 cm in diameter that may be mistaken for of 1.2 million units (MU) of BPG for people aged over
cutaneous leishmaniasis, tropical ulcer, or pyoderma. Yaws 10 years, and 0.6 MU for children less than 10 years of age,
skin ulcers are typically circular in shape and have central for those patients who “clinically fail on azythromycin” or
granulating tissue and elevated edges. The ulcers are often are allergic to azithromycin.60
painless and rarely produce a discharge with malodor.50–52 Syphilis
The pinta primary lesion is an itchy, scaly papule or plaque
that expands to greater than 10 cm but does not ulcerate. Introduction
In bejel, the primary lesion is seldom seen because of its Syphilis is a sexually transmitted disease caused by the
small size and location within the oral and oropharyngeal bacterium Treponema pallidum subsp. pallidum. Infection
mucosa. Primary lesions in yaws and pinta are most can be transmitted by sexual contact and to the unborn
commonly found on the exposed lower extremities, but child through the placenta at any gestational stage. In
also on the buttocks, arms, hands, and face.50–52 exceptional cases, syphilis can be transmitted at birth
Secondary skin lesions of yaws are polymorphous, through the child’s contact with the birth canal when there
affecting the skin with papulosquamous lesions resembling are maternal genital lesions (direct transmission).
other dermatoses such as psoriasis, mycosis, or crusted
Clinical manifestations
scabies. Secondary yaws lesions usually heal spontaneously
after 3 to 6 months, though infectious relapses may occur Acquired (by sexual contact) syphilis is divided into early
for up to 5 years. The differential diagnosis therefore and late syphilis. Early syphilis is further divided into
includes vitiligo, erythema dyschromicumperstans, and primary, secondary, and early latent syphilis. Late syphilis
leprosy.50,53 includes late latent and tertiary syphilis.61
Late changes of endemic treponematoses are osteo- Primary syphilis is usually manifested by an ulcer
periostitis (yaws, bejel) with diffuse cortical thick­ening in the anogenital region (or the mouth) with regional
­followed by bone deformation. lymphadenopathy. Secondary syphilis usually develops
9–12 weeks after primary disease and is characterized
Diagnostic tests by bacteriaemia and a broad spectrum of variable muco-
Treponemes may be identified in a wet preparation of cutaneous manifestations. Untreated, secondary syphilis
material obtained from primary lesions by dark-field can show a relapsing course for about 1 year before the
microscopy. Direct fluorescent antibody tests using latency phase emerges. Secondary syphilis is usually
anti–T. pallidum antibodies can distinguish pathogenic characterized by a non-itching skin rash that can be
treponemal infections from saprophyte treponemes. macular or papular. The rash may be generalized but has
The skin pathology of the silver impregnation technique a predilection for the palms and soles. Fever, generalized
is largely similar to that of venereal syphilis. The early lymphadenopathy, arthritis, hepatitis, splenomegaly,
lesions of yaws and bejel show epidermal hyperplasia and glomerulonephritis are possible manifestations of
with collections of neutrophils and a typical plasmocytic secondary syphilis.62
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J Vener Dis 1972;48:479–482. 63. Eyer-Silva WA, Martins CJ, Silva GARD et al.
57. Menke HE, Veldkamp J, Brunings EA et al. Secondary syphilis presenting as leukoderma
Comparison of cardiolipin and treponemal syphiliticum: Case report and review. Rev Inst Med
tests in the serodiagnosis of yaws. Br J Vener Dis Trop Sao Paulo 2017;59: e74.
1979;55:102–104. 64. Janier M, HegyiV, Dupin N et al. 2014 European
58. Jafari Y, Peeling RW, Shivkumar S et al. Are guideline on the management of syphilis. J Eur Acad
Treponema pallidum specific rapid and point-of- Dermatol Venereol 2014;28:1581–1e93.
care tests for syphilis accurate enough for screening 65. WHO. Guidelines for the Treatment of Treponema
in resource limited settings? Evidence from a meta- pallidum (Syphilis). Geneva: World Health
analysis. PLOS ONE 2013;8:e54695. Organization, 2016.
59. Yin YP, Chen XS, Wei W et al. A dual point-of-care 66. Stamm LV. Syphilis: Antibiotic treatment and
test shows good performance in simultaneously resistance. Epidemiol Infect 2015;143:1567–1574.
detecting non-treponemal and treponemal antibodies
Melanoma leukoderma
ALEXANDER J. STRATIGOS, POLYTIMI SIDIROPOULOU,
21
and DOROTHEA POLYDOROU

CONTENTS
Introduction 145 Prognosis 147
Pathogenesis 145 References 147
Clinical picture 145

INTRODUCTION melanocyte cross-reactive antigens are involved in

Skin depigmentation occurs in 2%–16% of melanoma modulating an enhanced cytotoxic activity against
patients either spontaneously or during/after immuno­ both tumor cells and normal melanocytes. 3,11 Although
therapy as a result of strong antimelanoma immunity autoantibodies are commonly found in melanoma
directed against shared melanocyte differentiation patients, growing evidence points toward an important
antigens.1,2,3 It is commonly known as melanoma- role for cellular immune reactions. Considering the
associated leukoderma (MAL), but also referred to presence of clonally expanded melanocyte-specific
as melanoma-associated hypopigmentation (MAH), T lymphocytes with identical Vp regions in a primary
melanoma-associated depigmentation (MAD), or melanoma and a depigmented halo surrounding the
melanoma-associated vitiligo (MAV).2,4 tumor, it has been speculated that MAL results from
MAL can develop in association with primary, recurrent, a cytotoxic T-cell cross-reaction targeting antigenic
or metastatic melanoma.1 Although it may precede determinants like MART-1 and gp100 expressed by both
melanoma detection, in most cases (79.5%), depigmentation healthy and malignant melanocytes.6
occurs after the diagnosis of melanoma. 3,5 Moreover, in Such spontaneous or therapy-induced antitumor
recent years, MAL is increasingly documented in advanced immunity is responsible for normal melanocyte
metastatic melanoma patients undergoing treatment with recognition and attack as well. This is clinically evident as
adoptive immune-based therapies with biological response depigmentation either within the melanoma (regression),
modifiers and/or vaccine strategies. around melanocytic nevi/melanoma (halo phenomenon),
Immune-based regimes reported to induce MAL include or in a distant site (vitiligo-like depigmentation).8 It has been
programmed cell death 1 (PD-1; e.g., pembrolizumab, suggested that melanoma regression, halo phenomenon,
nivolumab) or cytotoxic T-lymphocyte-associated antigen and vitiligo-like lesions are distinct in pathogenesis. Some
4 (CTLA-4; e.g., ipilimumab) antibodies (Figure 21.1a,b), authors believe that a locally effective immune response
BRAF/MEK inhibitors (e.g., vemurafenib, dabrafenib), against melanoma cells is responsible for the partial or
IL-2, IFN-α, tumor-infiltrating lymphocytes specific for complete regression of the tumor, while the halos and
tyrosinase-, gp100-, or TYRP1-derived antigens or peptide the vitiliginoid phenotype are rather the consequence of
vaccines based upon these antigens.1,3,6–8 the incidental immune destruction of normal epidermal
melanocytes.3,8
PATHOGENESIS
Although the pathogenesis of MAL still remains elusive, it CLINICAL PICTURE
is considered an immune-driven manifestation illustrating
Melanoma can be associated with local or diffuse
the immunogenic nature of melanoma.1 Melanoma
depigmenting changes. Several types of leukodermas have
has traditionally been described as an “immunogenic
been described in the setting of melanoma:3,5,6
tumor” that commonly overexpresses several melanocyte
differentiation antigens, including Melan-A/MART-1, • Spontaneous melanoma regression—Depigmentation
tyrosinase, TRP-1, TRP-2, and/or gp100, regardless of associated with spontaneous regression of the tumor
tumor stage. The immune response elicited against such (primary, recurrent, or metastatic).
antigens shared by normal and malignant melanocytes • Halo phenomenon—A localized depigmentation
links melanoma and its associated leukodermas.8 surrounding benign melanocytic nevi or the melanoma.
According to the most prevalent hypothesis, humoral • Vitiligo-like depigmentation in sites remote from the
and cell-mediated immune responses targeting primary tumor.

145
146 Melanoma leukoderma

Spontaneous melanoma regression the general population.8 Although the clinical appearance
Depigmentation due to melanoma regression is may be similar, MAL cannot be classified as a subtype of
uncommon in older adults.1 In this process, fibrous stroma vitiligo according to the Vitiligo Global Issues Consensus
progressively replaces the dermal portion of the tumor. Conference.2,5,11
From a clinical perspective, areas of tumor depigmentation The clinical differences and similarities between
with white, red, blue, or gray color may be the visible effect melanoma-associated and vitiligo vulgaris are not well
of spontaneous regression. However, complete resolution is defined and the literature is contradictory. Some authors
considered very rare, with approximately 40 cases reported consider them identical, while others claim that melanoma-
in the literature.7–9 associated vitiligo exhibits a more varied clinical spectrum
Melanoma of unknown origin may represent partially of manifestations.10 It is common that patients with MAL
or fully regressed primary tumors. 8 It has been well have a significantly higher age at onset of depigmentation
documented that metastatic melanoma has no detectable than vitiligo patients. The median age at onset of MAL is
primary site in 4%–10% of cases.1 Melanoma should 53–55 years, whereas vitiligo rarely develops in individuals
be considered in adults presenting with a depigmented over 50 years of age.1,2,5,8
macule or patch and a history consistent with regression Conflicting data are also reported regarding the
of a pigmented neoplasm. Skin depigmentation associated distribution pattern of depigmented lesions in MAL
with a palpable lymph node in the appropriate lymphatic versus vitiligo. In the majority of patients, MAL displays a
distribution may also be suggestive of a regressed primary symmetric bilateral distribution corresponding to classic
melanoma.1 Depigmentation at the site of a pigmented lesion vitiligo, developing in patients with typically no previous
in adults thus warrants a thorough history and physical history of vitiligo (Figure 21.1). However, atypical clinical
investigation aimed at suspicious melanocytic lesions. presentations of MAL have already been described with
mostly hypopigmented macules with irregularly-shaped
Halo phenomenon and not well-demarcated borders as well as confetti-like
The appearance of a rim (halo) of hypopigmentation or figuration contrary to vitiligo vulgaris.5,8,10
depigmentation around a pigmented lesion most commonly Additional findings that may be suggestive of MAL
occurs in children and young adults surrounding benign include the absence of a Koebner phenomenon, a
acquired melanocytic nevi (halo nevus or Sutton nevus). negative vitiligo family history, no gender predilection,
However, the halo phenomenon can rarely be seen around and depigmentation localized on photoexposed areas.1,5
melanoma. Careful examination of the central lesion is Furthermore, MAL lesions are generally refractory to
therefore required. The halo of melanoma is more irregular topical corticosteroids and UV phototherapy.4 While auto-
than that of the halo nevus, and the patients are usually antibodies against gp-100 and tyrosinase are commonly
older. The sudden appearance of multiple halos around found in both diseases, serum antibodies against melanoma
benign melanocytic nevi in older adults may also be a antigen recognized by T-cells 1 (MART1) are only present
sign of unknown melanoma. Moreover, halos can occur in MAL and undetectable in vitiligo. Thus, the presence
around sites of cutaneous metastatic deposits. Although of MART-1 antibodies may serve as a useful biomarker in
melanoma-associated halos are rare, individuals beyond order to distinguish MAL from vitiligo and indicate that
40 years with new-onset halo nevi should be thoroughly differences in immunity are involved.1,2,5
examined for melanoma (cutaneous and ocular).3,6,8 Interestingly, the clinical features of melanoma-associated
vitiligo have been supported to differ depending on the
Vitiligo-like depigmentation time onset of depigmentation, before or after the detection
Melanoma-associated vitiligo may represent an important of melanoma. Vitiligo occurring before melanoma tends to
differential diagnosis of vitiligo vulgaris.5 The occurrence involve younger patients and is mainly generalized with well-
of vitiligo-like lesions in melanoma patients is a well-known defined, round-shaped, milk-white lesions predominantly
even if puzzling and yet poorly understood phenomenon. located on the face, upper limbs, and feet, a picture similar
The risk of developing vitiligo has been estimated to be 7- to to that of the vulgaris form. In contrast, the clinical pattern
10-fold higher in subjects with melanoma compared with of vitiligo appearing after melanoma is distinct from that

Figure 21.1 (a, b) Vitiligo-like lesions in a 49-year-old woman undergoing anti-PD1 immunotherapy with nivolumab for melanoma.
 References 147

of vitiligo vulgaris, including pale-colored lesions with not 4. Teulings HE, Lommerts JE, Wolkerstorfer A et al.
well-demarcated, irregularly shaped borders mainly located Vitiligo-like depigmentations as the first sign of
on the face and upper trunk.10 melanoma: A retrospective case series from a tertiary
vitiligo centre. Br J Dermatol. 2017;176:503–506.
PROGNOSIS 5. Lommerts JE, Teulings HE, Ezzedine K et al.
Although the prognostic impact on the clinical course Melanoma-associated leukoderma and vitiligo
of melanoma remains a subject of debate, several studies cannot be differentiated based on blinded assessment
demonstrated that MAL portends a favorable clinical by experts in the field. J Am Acad Dermatol.
outcome in melanoma patients with significantly enhanced 2016;75:1198–1204.
5-year survival.3 Given the fact that the antigens recognized 6. Passeron T, Ortonne J. Vitiligo and Other Disorders of
by cytotoxic T cells in MAL are common to normal and Hypopigmentation. In: Callen J, editor. Dermatology
malignant melanocytes, MAL may represent a marker by Jean L. Bolognia, Julie V. Schaffer, and Lorenzo
of antimelanoma immunity. The development of skin Cerroni, 4th ed. China: Elsevier, 2018:1108–1109.
depigmentation over the course of immunotherapy is also 7. Ben-Betzalel G, Baruch EN, Boursi B et al. Possible
considered a sign predictive of prolonged efficacy and thus immune adverse events as predictors of durable
better prognosis.1,12 Clinical trials of immune-based therapies response to BRAF inhibitors in patients with BRAF
in advanced metastatic melanoma (stage III-IV) correlated V600-mutant metastatic melanoma. Eur J Cancer.
MAL with a durable response and survival benefits, 2018;101:229–235.
implicating an immune-modulating effect against metastatic 8. Naveh HP, Rao UN, Butterfield LH. Melanoma-
disease. It is interesting to note that this prognostic value associated leukoderma—Immunology in black and
seems to be independent of the time onset of MAL (before or white? Pigment Cell Melanoma Res. 2013;26:796–804.
after melanoma diagnosis). Moreover, no survival differences 9. Spring IR, de Wet J, Jordaan HF et al. Complete
were found in association with the therapeutic regime.10 spontaneous regression of a metastatic acral
melanoma with associated leukoderma. JAAD Case
REFERENCES Rep. 2017;3:524–528.
1. Saleem MD, Oussedik E, Schoch JJ et al. Acquired 10. Quaglino P, Marenco F, Osella-Abate S et al. Vitiligo is
disorders with depigmentation: A systematic an independent favourable prognostic factor in stage
approach to vitiliginoid conditions. J Am Acad III and IV metastatic melanoma patients: results from
Dermatol. 2018. pii: S0190-9622(18)32506-4. a single-institution hospital-based observational
doi:10.1016/j.jaad.2018.03.063. [Epub ahead of print]. cohort study. Ann Oncol. 2010;21:409–414.
2. Teulings HE, Willemsen KJ, Glykofridis et al. The 11. Ezzedine K, Lim HW, Suzuki T et al. Revised classi­
antibody response against MART-1 differs in patients fication/nomenclature of vitiligo and related issues: The
with melanoma-associated leucoderma and vitiligo. Vitiligo Global Issues Consensus Conference. Pigment
Pigment Cell Melanoma Res. 2014;27:1086–1096. Cell Melanoma Res. 2012;25:E1–13.
3. Vyas R, Selph J, Gerstenblith MR. Cutaneous 12. González R, Torres-López E. Immunological basis of
manifestations associated with melanoma. Semin melanoma-associated vitiligo-like depigmentation.
Oncol. 2016; 43: 384–389. Actas Dermosifiliogr. 2014;105:122–127.
Halo nevi
CHRISTINA STEFANAKI
22
CONTENTS
Halo nevi 149 References 151

HALO NEVI and blue nevi.5–7,12–14 Studies have described variability in

Definition the melanocytic atypia of halo nevi; however, although
halo nevi arise from a variety of histologic types of nevi,
Halo nevus (HN), also termed Sutton’s nevus or leukoderma
most are not dysplastic.2,15
acquisitum centrifugum, is a benign melanocytic nevus
Histopathologically, in the fully evolved stages, a
surrounded by an achromic rim that simulates a halo,
heavy, lichenoid lymphocytic infiltrate within the dermis
resulting in regression of the nevus.1
is noticed, with nevus cells arranged in nests or singly
Epidemiology among the inflammatory cells. The lichenoid infiltrate
can be so dense that nevus cells are difficult to distinguish
The estimated incidence of HN in the population is
from surrounding lymphocytes without special stains. The
around 1%, and there is no predilection for sex or race.1,2
whitish halo shows an absence of melanin and melanocytes
Children and young adults are predominately affected,
in the basal layer.11
with an average age of onset of 15 years.1,3,4 Stress and
puberty have been mentioned as major triggering factors
Dermoscopy—Reflectance confocal microscopy
for halo nevi, and a familial tendency has been reported.5–7
The occurrence of halo nevi has been associated with Wood’s lamp examination may help to enhance the halo,
sun exposure and sunburn, probably because of an particularly in fair-skinned individuals and to detect
increased accentuation of tanned skin contrasting with multiple lesions. On dermoscopy, the central nevus in
the depigmented halo.5 Drugs, such as tocilizumab, an halo nevi typically demonstrates the globular and/or
antibody directed against the interleukin (IL)-6 receptor, homogeneous pattern and the surrounding halo is white and
and anti-TNF-α therapies may also trigger the appearance structureless.16 Less often, the central nevus component may
of multiple halo nevi.8,9 Those patients who develop halo display a reticular pattern.11 In the case where the central
nevi have in general an increased number of melanocytic nevus has disappeared, then a reddish central pigmentation,
nevi, and the halo phenomenon usually presents in multiple eventually revealing visible vessels from the dermal vascular
lesions in 25%–50% of patients (Figure 22.1), usually on plexus, may be present. Reflectance confocal microscopy
nevi localized on the back.2,5–7,10 (RCM) of HN has been previously described in two studies,
and some atypical features, also seen in atypical melanocytic
Clinical features lesions and malignant melanoma, were observed in most
The appearance of the central melanocytic nevus in halo patients evaluated.11,17 These atypical features included
nevi varies and lesions range from flat to raised and dark pagetoid cells, non-edged papilla, junctional thickening,
brown to pink colored. The surface of the nevus may be nucleated cells in the dermal papillae, and plump bright
crusted or scaly. In typical halo nevi, the central nevus has cells, possibly due to local inflammation.11,17
all the features of a benign melanocytic lesion, measures
<5 mm, and has well-defined and smooth borders and Clinical course
homogenous color. The depigmented halo is occasionally After the development of a halo nevus, its subsequent course
preceded by erythema, lasting from weeks to months. The is variable and may regress partially or totally, leading to
white halo usually is symmetric, with a uniform width the presence of only the halo. It is described that at least
ranging from a few millimeters up to several centimeters. 50% of patients eventually have total disappearance of the
Uncommonly, the halo may be asymmetric, although central nevus.5,16 Before disappearance, the central nevus
surrounding a benign nevus.10 may become irregular and pink. Halo nevi typically persist
for a decade or longer and rarely may persist indefinitely. A
Histologic features subgroup may eventually return to normal-appearing skin,
Most commonly compound nevi are involved, although but even these lesions persist for an average of 7.8 years.11
junctional or dermal nevi may be affected as well.11 Both In one study, 51.5% of halo nevi followed up sequentially
congenital (Figure 22.2) and acquired nevi may present the with digital dermoscopy demonstrated a decrease in halo
halo phenomenon, less commonly compound Spitz nevi size, whereas 27.3% showed an enlargement.16 However, the

149
150 Halo nevi

(a) (b)

(c)

Figure 22.1 (a) Multiple halo nevi on the upper back of a young woman. (b) Multiple halo nevi on the lower back of the same
woman. (c) Multiple halo nevi on the chest of the same woman.

or seborrheic keratosis, among others, and mainly from

melanoma presenting with a halo.10 Although the halo
phenomenon is most common in benign melanocytic nevi,
there are reports of HN in individuals with a family and/or
personal history of melanoma and melanomas with halo.
However, halo melanomas are rare; they occur in
adults, demonstrate a more irregular halo, and on
dermoscopy exhibit the typical melanoma-specific
patterns, including a multicomponent pattern, an atypical
pigmented network, irregular dots and globules, irregular
streaks, blotches, blue-white veil, and atypical vascular
structures.16,18,19

Halo nevi and vitiligo—Pathogenesis

HN may be associated with atopic dermatitis or with
autoimmune disorders such as vitiligo and Hashimoto
thyroiditis.5 Whether halo nevi should be considered a
sign of vitiligo or a risk factor for developing vitiligo is still
Figure 22.2 Halo medium-sized congenital nevus on the under debate. Differences in the genetic background have
trunk of a girl. been demonstrated. HLA-DR3 has a negative association
and HLA-DR4 and DR53 a positive association with
dermoscopic pattern of the nevus remained unchanged as it vitiligo, whereas this could not be demonstrated in vitiligo
became smaller. Given that a lesion that displays extensive patients with halo nevi. 20 Vitiligo and halo nevi share
regression at baseline could eventually completely regress similar pathophysiological pathways, as both exhibit
during follow-up and subsequently would no longer be a strong cytotoxic T-cell reaction, which suggests an
detectable at the next visit, digital dermoscopic follow-up of immunological reaction against the same melanocyte-
HN is not recommended, as it does not provide additional specific targets.14 Whether vitiligo with or without halo nevi
diagnostic information compared with a good clinical constitute different subgroups with differences in degree,
dermoscopic correlation at baseline.16 mode, or type of surface auto(self)-antigen expression in
the initial stage of the disease remains to be elucidated. It
Differential diagnosis has been speculated that if only halo nevi are present, an
Halo nevi should be differentiated from nonmelanocytic abnormal auto-antigen expression, originating primarily
tumors demonstrating a halo such as dermatofibromas from melanocytic nevi, is triggering the immune response,
 References 151

while in vitiligo, the auto-antigen originates from normal an association, 26 while others have not. 5 Interestingly,
epidermal melanocytes.21 According to Van Geel et al.,21 discrete depigmentations at distance from halo nevi have
in cases where both vitiligo and halo nevi are present, been described in a limited subset of patients with multiple
the primary immune reaction can be directed to nevoid halo nevi.5
autoantigens, followed by an immune reaction against Regarding the presence of halo nevi and the prognosis
shared autoantigens, antigen cross-reactivity, or an epitope of vitiligo, it has been demonstrated that the presence of a
spreading phenomenon between nevoid melanocytes halo nevus does not significantly alter the risk of disease
and epidermal melanocytes, which might be faster or progression and rate of treatment.30
easier in patients with genetic susceptibility to vitiligo
or autoimmune diseases. On the other hand, a second Management
etiopathological pathway might exist in which halo nevi The management of the patient with halo nevi should
can induce a cytotoxic T-cell-mediated immune reaction be individualized. All patients should be questioned
against shared antigens between normal melanocytes about family or personal history of melanoma, vitiligo,
and nevoid melanocytes in patients without the genetic and autoimmune diseases. Each halo nevus should be
susceptibility to vitiligo, as seen in melanoma-associated inspected carefully for signs of atypia, and a full-body
leucoderma.21 examination is mandatory for vitiligo and in older
Some studies point to marked differences in the patients for the presence of melanoma. Only halo nevi
pathophysiology between halo nevi and vitiligo. with clinical signs of atypia, suggesting a melanoma,
Schallreuter et al. 22 observed high H 2O2 levels in need to be removed surgically. Young patients may be
vitiligo skin, which causes impairment of pterin-4a- reassured, whereas patients aged more than 40 with new
carbinol-amine dehydratase (PCD), whereas they found onset of halo nevi should be examined very carefully for
upregulated PCD activity in halo nevi. They suggest that melanoma.
low PCD activity leads to oxidation of pterins and causes
the characteristic bluish-white fluorescence of vitiligo skin, REFERENCES
which is not detectable in halo nevi.22 1. Aouthmany M, Weinstein M, Zirwas MJ, Brodell RT.
The natural history of halo nevi: A retrospective case
Halo nevi and vitiligo—Clinical series. J Am Acad Dermatol. 2012;67:582–586.
Several case reports have been published regarding the 2. Weyant G, Chung C, Helm K. Halo nevus: Review
development of vitiligo simultaneously or shortly after the of the literature and clinicopathologic findings. Int J
occurrence of a halo naevus.23–25 Dermatol. 2015;54:30–447.
The presence of halo nevi in vitiligo patients ranges in 3. Haliasos EC, Kerner M, Jaimes N et al. Dermoscopy
different studies between 1% and 47%.5,21 However, some for the pediatric dermatologist; Part III: Dermoscopy
cases of extensive vitiligo clearly spare melanocytic nevi.26 of melanocytic lesions. Pediatr Dermatol. 2012;
It has been demonstrated that the presence of halo nevi doi:10.1111/pde.12041.
in patients with vitiligo significantly reduces the risk of 4. Zalaudek I, Manzo M, Ferrara G, Argenziano G.
associated autoimmune diseases, and the age of onset A new classification of melanocytic nevi based on
of vitiligo was significantly lower when compared with dermoscopy. Expert Rev Dermatol. 2008;3:477–489.
vitiligo patients without halo nevi.21,27 On the other hand, 5. Van Geel N, Speeckaert R, Lambert J et al. Halo
patients with only halo nevi showed less frequently the naevi with associated vitiligo-like depigmentations:
presence of a Koebner phenomenon and family history of Pathogenetic hypothesis. J Eur Acad Dermatol
vitiligo.21 Venereol. 2012;26: 755–761.
Body surface area involvement by vitiligo has been 6. MacKie RM. Disorders of the cutaneous melanocyte:
found to be lower in patients with both vitiligo and HN, halo naevus. In: Burns T, Breathnach S, Cox N,
and the trunk tended to be more frequently involved.20,27 Griffith C, eds. Rook’s Textbook of Dermatology.
On the contrary, involvement of the hands and feet by Vol 2. 7th ed. Oxford, England: Blackwell Scientific
vitiligo was negatively associated with HN. 20,27 The Publications, 2004: 1–39.
question arises whether an increased number of HN 7. Herd RM, Hunter JA. Familial halo naevi. Clin Exp
increases the risk of vitiligo. Certain investigators have Dermatol. 1998;23:68–69.
found fewer HN in vitiligo patients, 21 while others 8. Kuet K, Goodfield M. Multiple halo naevi associated
demonstrated an association between multiple HN and with tocilizumab. Clin Exp Dermatol. 2014;39:717–719.
vitiligo. 28 9. Thivi Maruthappu T, Leandro M, Morris M.
Although halo nevi are in general more frequently Deterioration of vitiligo and new onset of halo naevi
reported in combination with generalized vitiligo, the observed in two patients receiving adalimumab.
concomitant presence of halo nevi with segmental vitiligo Dermatologic Therapy 2013;26:370–372.
has also been described in 1%–6.4% of patients. 29 A 10. Rabinovitz HS, Barnhill R. Benign melanocytic
controversy exists as to whether there is a link between neoplasms: halo nevus. In: Bolognia JL, Jorizzo JL,
the progression of segmental vitiligo to mixed vitiligo and Schaffer JV, eds. Dermatology. Vol 2. 3rd ed. Elsevier,
the initial presence of halo nevi; some authors have found 2012;1851–1880.
152 Halo nevi

11. Larre Borges A, Zalaudek I, Longo C et al. Melanocytic 22. Schallreuter KU, Kothari S, Elwary S et al. Molecular
nevi with special features: Clinical-dermoscopic and evidence that halo in Sutton’s naevus is not vitiligo.
reflectance confocal microscopic-findings. J Eur Acad Arch Dermatol Res. 2003;295:223–228.
Dermatol Venereol. 2014;28:833–845. 23. Kim HS, Goh BK. Vitiligo after halo formation
12. Kerr OA, Schlofield O. Halo congenital nevi. Pediatr around congenital melanocytic nevi. Pediatr
Dermatol. 2003;20:541–542. Dermatol. 2009;26: 755–756.
13. Harvell JD, Meehan SA, LeBoit PE. Spitz’s nevi with 24. Itin PH, Lautenschlager S. Acquired leukoderma in
halo reaction: A histopathologic study of 17 cases. J congenital pigmented nevus associated with vitiligo
Cutan Pathol. 1997;24:611–619. depigmentation. Pediatr Dermatol. 2002;19: 73–75.
14. Zeff RA, Freitag A, Grin CM, Grant-Kels JM. The 25. Stierman SC, Tierney E, Shwayder TA. Halo
immune response in halo nevi. J Am Acad Dermatol. congenital nevocellular nevi associated with
1997;37:620–624. extralesional vitiligo: Case series with review of the
15. Mooney MA, Barr RJ, Buxton MG. Halo nevus or literature. Pediatr Dermatol. 2009;26: 414–424.
halo phenomenon? A study of 142 cases. J Cutan 26. Ezzedine K, Diallo A, Leaute-Labreze C et al. Halo
Pathol. 1995;22: 342–348. naevi and leukotrichia are strong predictors of the
16. Kolm I, Di Stefani A, Hofmann-Wellenhof R et al. passage to mixed vitiligo in a subgroup of segmental
Dermoscopy patterns of halo nevi. Arch Dermatol. vitiligo. BrJ Dermatol. 2012;166:539–544.
2006;142:1627–1632. 27. Ezzedine K, Diallo A, Léauté-Labrèze C et al. Halo
17. Schwartz RJ, Vera K, Navarrete N, Lobos P. In vivo nevi association in nonsegmental vitiligo affects age
reflectance confocal microscopy of halo nevus. J at onset and depigmentation pattern. Arch Dermatol.
Cutan Med Surg. 2013;17:33–38. 2012;148:497–502.
18. Argenziano G, Soyer HP, Chimenti S et al. 28. Patrizi A, Bentivogli M, Raone B et al. Association of
Dermoscopy of pigmented skin lesions: Results of halo nevus/i and vitiligo in childhood: A retrospective
a consensus meeting via the Internet. J Am Acad observational study. J Eur Acad Dermatol Venereol.
Dermatol. 2003;48:679–693. 2013;27:e148–e152.
19. Zalaudek I, Argenziano G, Ferrara G et al. Clinically 29. van Geel NA, Mollet IG, De Schepper S et al. First
equivocal melanocytic skin lesions with features of histopathological and immunophenotypic analysis
regression: A dermoscopic-pathological study. Br J of early dynamic events in a patient with segmental
Dermatol. 2004;150:64–71. vitiligo associated with halo nevi. Pigment Cell
20. De Vijlder HC, Westerhof W, Schreuder GM et al. Melanoma Res. 2010;23:375–384.
Difference in pathogenesis between vitiligo vulgaris 30. Cohen BE, Mu EW, Orlow SJ. Comparison of childhood
and halo nevi associated with vitiligo is supported by vitiligo presenting with or without associated halo
an HLA study. Pigment Cell Res. 2004;17: 270–274. nevi. Pediatr Dermatol. 2016;33:44–48.
21. Van Geel N, Vandenhaute S, Speeckaert R et al.
Prognostic value and clinical significance of halo naevi
regarding vitiligo. Br J Dermatol. 2011;164:743–749.
Drug-induced hypopigmentation
KATERINA DAMEVSKA, SUZANA NIKOLOVSKA, RAZVIGOR DARLENSKI,
23
LJUBICA SUTURKOVA, and TORELLO LOTTI

CONTENTS
Introduction 153 Topical drugs 155
Systemic drugs 153 References 156

INTRODUCTION experienced hyperpigmentation.5 Both hair lightening and

Drug-induced hypopigmentation refers to the development hair darkening have been reported during TKI treatment.6
of skin and/or hair hypopigmentation or depigmentation In part, the different effects of TKIs on melanin production
associated with the use of a medication. This adverse could be explained by the inhibiting activity of these drugs
drug reaction is assumed to be relatively rare, and is most on other receptors, such as vasoactive endothelial growth
commonly associated with topical agents.1 However, the factor receptor (VEGFR) or platelet-derived growth factor
increasing use of target therapies will make the observation receptor (PDGFR).6
of these side effects more frequent.
Imatinib
Drug-induced hypopigmentations can be particularly
difficult to diagnose and differentiate from vitiligo. Thus, Imatinib is an oral TKI that inhibits Bcr-Abl, PDGFR,
if a patient presents with unexplained hypomelanosis, and c-Kit. Localized or diffuse, in the majority of cases,
drugs should be included in the differential diagnosis as reversible depigmentation has been observed in 15%–
a possible cause. 25% of patients. 5,7 The fact that the depigmentation is
frequent and dose-dependent suggests that it is due to
SYSTEMIC DRUGS a direct pharmacological effect of imatinib.7 Cases of
cutaneous, hair, nail, or gingival pigmentation,5–8 as well
Targeted antineoplastic agents
as repigmentation of vitiligo lesions, 9 have also been
Various cutaneous adverse events of targeted therapy have described.
been reported, nevertheless pigmentary changes associated
with these treatments have received less attention. 2 Dai Dasatinib
et al. identified 36 clinical trials involving 8052 patients Dasatinib is another TKI that targets the Bcr-Abl tyrosine
that reported on pigmentary adverse events associated with kinase, c-Kit, PDGFR, and Src family kinases. In reported
targeted therapies. 3 The overall incidence of pigmentary cases, hypopigmentation began 1 to 6 months following
changes was 17.7%, with the lowest incidence noted with treatment initiation, appears to be dose dependent, and has
pazopanib (0.7%) and the highest with sunitinib (75%). a predilection for the head and neck. Repigmentation began
In pediatric patients, pigmentary abnormalities were within 8 weeks of drug cessation.10 Cases of reversible hair
reported in 13% of patients receiving imatinib, dasatinib, depigmentation have been described using ≥100 mg daily
and cabozantinib.4 However, the pigmentary changes did of dasatinib.11
not represent a negative prognostic factor, nor imply the
necessity for treatment discontinuation.3 Pazopanib
Pazopanib is a second-generation TKI with multiple
Tyrosine kinase inhibitors targets including VEGFR, PDGFR, c-Kit, and FGFR.
According to their molecular mechanism of action, Goyal et al. reported a series of patients with breast cancer
tyrosine kinase inhibitors (TKIs) directly or indirectly treated with pazopanib in combination with radiation.
target the crucial modulators of pigmentation, namely Two patients (17%) experienced hair lightening, one of
c-KIT and its ligand stem cell factor (SCF). Thus, it is not whom also had skin hypopigmentations outside of the
surprising that interference with this pathway results in treatment field.12 Sideras et al. observed that at least half of
pigmentary anomalies. In most cases, the depigmentation patients treated with pazopanib developed both hair and
due to TKIs is reversible, suggesting that these drugs might skin hypopigmentation, with some patients experiencing
determine a temporary dysfunction of melanocytes rather hypopigmentation to a degree otherwise encountered only
than having a cytotoxic effect. It is not completely clear in albinism. The authors speculated that the potent dual
why TKIs may cause both hypo- or hyperpigmentation. inhibition of c-Kit and PDGFR by pazopanib may account
In one series, 3.6% of patients treated with imatinib for this phenomenon.13

153
154 Drug-induced hypopigmentation

Sunitinib
Sunitinib is an orally bioavailable molecule that inhibits
multiple receptor tyrosine kinases, including VEGFR-2,
PDGFR, and c-Kit receptor. Sunitinib is associated with
many cutaneous side effects, including acral erythema,
bullous dermatosis, edema, stomatitis, subungual splinter
hemorrhages, hand-foot syndrome, leukotrichia,14 and
depigmentation of the face.15

Sorafenib
Sorafenib is a multitarget TKI that inhibits VEGFR 1–3,
BRAF, and RET tyrosine kinase. To date, only one case of
reversible generalized depigmentation has been described
during treatment with sorafenib.16

Immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) may target cytotoxic
T-lymphocyte antigen 4, programmed cell death 1 (PD-1),
or its ligand (PD-L1). The activation of the immune system
may lead to a spectrum of immune-related adverse events
(irAEs), including vitiligo-like depigmentation. The
Figure 23.1 Pembrolizumab-induced depigmentation in a
cumulative incidence of depigmentation in melanoma
patient with metastatic melanoma. There was no personal or
patients receiving ICI ranges from 9.6% to 25%.17,18
family history of vitiligo.
According to Larsbal et al.,19 these depigmentations
are clinically and biologically distinct from vitiligo.
Some studies suggest that patients with metastatic initiation of treatment. The objective response rate was
melanoma (MM) have shown an association between higher in patients with depigmentation than in patients
depigmentation following ICI treatment, and beneficial without (44.4% vs 7.7%; P = 0.027). Depigmentation was
clinical outcomes.17–20 Hypopigmentation is not a common significantly associated with better overall survival. These
side effect in patients with other cancers who receive ICI.21 observations suggest that the occurrence of depigmentation
during nivolumab treatment may be associated with
Pembrolizumab favorable outcomes. Nivolumab has recently been
Pembrolizumab is a selective humanized monoclonal reported to induce hypopigmentation in a patient with a
IgG4 antibody that binds to the PD-1 receptor and blocks nonmelanoma malignancy.24
its interaction with PD-L1. Vitiligo-like depigmentation
Durvalumab
is a well-described side effect of pembrolizumab. Of 67
patients with MM who received pembrolizumab, 17 Durvalumab is an IgG1 monoclonal antibody that
(25%) developed hypopigmentation. The time to onset of binds to PD-1 and CD80, allowing T cells to recognize
hypopigmentation ranged from 52 to 453 days. Complete or tumor cells. In the combined safety database (n = 1414),
partial response to treatment was associated with a higher ­immune-mediated rash occurred in 220 patients (15.6%),
occurrence of hypopigmentation (71% vs 28%; P =  0.002). and 4 patients (0.3%) developed hypopigmentation.25
The authors concluded that these visible irAEs could be
Antimalarial drugs
associated with the clinical benefit to pembrolizumab.18 In
contrast to ordinary vitiligo, patients did not report any Chloroquine is classically associated with bluish-black or
personal or family history of vitiligo, thyroiditis, or other gray pigmentation of the skin and mucosa, attributed to the
autoimmune disorders.19 The most common involved skin deposition of the drug in the affected tissues. Case reports
sites in post anti-PD1 depigmentation are sun-exposed suggest that chloroquine can also cause depigmentation26
areas (Figure 23.1). and bleaching of hair pigment. 27 Depigmented patches
Recently, Wolner et al.22 described a patient with MM are most prominent on sun-exposed areas, starting a few
treated with pembrolizumab who subsequently developed months after initiation of chloroquine therapy and readily
lightening of the skin, poliosis, and fading of solar reversible after cessation of the drug.
lentigines, seborrhoeic keratoses, and melanocytic nevi.
Hematopoietic stem cell transplantation
Nivolumab A population-based study found newly acquired vitiligo-
Nakamura et al. 23 reviewed stage III or IV melanoma like depigmentation in 1% of hematopoietic stem cell
patients treated with anti-PD-1 antibody nivolumab. Of 35 transplantation (HSCT) recipients.28 In another study, 15
patients, 9 (25.7%) developed vitiligo-like depigmentation. (5.3%) participants with vitiligo were identified among
The time to onset ranged from 2 to 9 months after the 282 patients with chronic GvHD. Pigmentary changes
 Topical drugs 155

Figure 23.3 Hypopigmentation due to topical steroid

abuse in the treatment of flexural eczema.

acetonide causes hypopigmentation more frequently than

other steroids. 38 As a macromolecule with suspended
crystals, triamcinolone can spread along lymphatic channels
and proximal veins, causing ill-defined, linear, stellate, or
angulated hypopigmented macules. Differentiation from
segmental vitiligo is based on a history of intralesional
Figure 23.2 Leucoderma in chronic GvHD 24 months after injection and the pattern and ill-defined border of the
allogeneic hematopoietic stem cell transplantation. There was lesion. Corticosteroid-induced hypopigmentation can be
no personal or family history of vitiligo. seen after single or multiple injections and, in the majority
of cases, resolves after a few months. Probably the main
developed in a median of 41 months after transplantation.29 mechanism of action is reversible inhibition of the function
Allogeneic HSCT-associated leucoderma has been reported of melanocytes.37
as localized disease, generalized involvement (Figure
23.2), and total leukoderma. T-cell recognition of foreign Topical imiquimod
melanocyte antigens may elicit a persistent immune A few case reports have documented vitiligo-like
response against host melanocytes.30 depigmentation and poliosis associated with imiquimod
Miscellaneous treatment. This side effect has been reported in imiquimod
treatment of genital warts (Figure 23.4), verruca vulgaris,
Rare cases of drug-induced hypopigmentation have been
reported from anticonvulsants, ganciclovir, arsenic-based
antineoplastic drugs, interferon-a, proton pump inhibitors,
levodopa, psoralens, and psoralen-UVA (PUVA)
photochemotherapy.1,31–33

TOPICAL DRUGS
Topical glucocorticosteroids
Hypopigmentation after use of topical corticosteroids
(TCS) may occur, but is more noticeable in dark-skinned
individuals. 34 According to an FDA report, depigmen­
tation or discoloration is the second most frequent
adverse event in the pediatric population, observed in 30
of 202 patients. 35 Depigmentation occurs regularly with
prolonged treatment and is dependent on the chemical
nature of the drug, the vehicle, and the site of its application
(Figure 23.3). These lesions are generally reversible upon
discontinuation of steroid therapy. It has been postulated
that TCS probably interferes with the synthesis of melanin
by smaller melanocytes.
Several case reports have documented local hypo­
pigmentation after intralesional, periocular, or Figure 23.4 Imiquimod-induced hypopigmentation
intraarticular injection of steroids. 36–38 Triamcinolone following treatment of perianal warts in a child.
156 Drug-induced hypopigmentation

molluscum contagiosum, basal cell carcinoma, lentigo Several cases of depigmentation have been reported
maligna, and extramammary Paget disease. 39–41 Depig­ at injection sites of paraffin, 53 interferon beta-1a, 54 and
mentation is rarely associated with imiquimod use for the botulinum toxin A.55
treatment of actinic keratoses, which may be due to the
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44. Nasca MR, Micali G, Pulvirenti N et al. Transient An unusual side effect. J Cutan Aesthet Surg. January
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Phototherapy as a useful therapeutic option in the 51. Zackheim HS, Epstein EH Jr, McNutt NS et al.
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leukoderma after the application of a transdermal Vitiliginous lesions induced by amyl nitrite exposure.
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2012;66(6):e237–e238. 53. Kim SW, Han TY, Lee JH et al. A case of vitiligo
47. Center for Drug Evaluation and Research. FDA Drug associated with paraffin injection. Annals of
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htm. 55. Roehm PC, Perry JD, Girkin CA, Miller NR.
48. Prakash N, Chand P. Chemical leukoderma: A rare Prevalence of periocular depigmentation after
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hypopigmentation following lignocaine injection:
Hypopigmentation from chemical
and physical agents
24
KATERINA DAMEVSKA, IGOR PEEV, RANTHILAKA R. RANAWAKA, and
VIKTOR SIMEONOVSKI

CONTENTS
Introduction 159 Hypopigmentation from physical agents 161
Chemical leukoderma 159 References 162

INTRODUCTION Table 24.1 Chemicals reported to induce

Hypopigmentation from chemical and physical agents hypopigmentation
represents a post-inflammatory hypopigmentation, a
Hydroquinone (HQ)
reactive hypomelanosis that develops following external
Monobenzyl ether of HQ
insults to the skin. It is most prominent among dark-
Monomethyl ether of HQ
skinned individuals, as the contrast between affected
Monoethyl ether of HQ
and nonaffected skin is more noticeable.1 In fair-skinned
p-Tertiary amylphenol
individuals, these lesions may require Wood’s lamp
p-Phenyl phenol
illumination to become obvious.
p-Octylphenol
Physical and chemical agents can alter skin pigmentation
p-Nonylphenol
in various ways. Whether the end result is a gain or loss of
Buthylhydroxytoluene (BHT)
melanocyte activity depends on the nature of the inciting
Buthylhydroxyanisole (BHA)
agent, while host susceptibility is equally important. The
p-Cresol (4-methylphenol)
term “individual chromatic tendency” was initially coined
Para-tertiary butylphenol formaldehyde resin (PTBP)
by Ruiz-Maldonado to describe this inherited chromatic
p-Methylcatechol
tendency.1
p-Isopropylcatechol
Occasionally, both hyperpigmentation and hypo­
Pyrocatechol (1,2-benzenediol)
pigmentation will occur in the same individual.
Diisopropyl fluorophosphates
Among physical causes, heat, cold, and ionizing and
β-mercaptoethylamine hydrochloride (cysteamine)
nonionizing radiation are known to alter skin pigmentation.
N-(2-mercaptoethyl)-demethylamine hydrochloride
Skin damage with post-inflammatory leukoderma can be
Sulfanolic acid
caused by a great variety of chemicals.2
Cystamine dihydrochloride
3-Mercaptopropylamine hydrochloride
CHEMICAL LEUKODERMA
Source: Adapted from Bonamonte D et al. Dermatitis.
Chemical leukoderma, also known as occupational or
2016;27(3):90–9.
contact leukoderma, is an acquired hypopigmentary
disorder after a single or multiple exposures to melano-
cytotoxic or depigmenting chemicals.3 consumer products. Many substituted phenols were used
The first case of chemical leukoderma was reported in as antioxidants or rust inhibitors in the manufacture
1939 in tannery workers who had experienced total loss of of plastics, resins, lubricants, petroleum products,
pigmentation from their hands and forearms. Additional photographic chemicals, insecticides, printing inks,
studies confirmed that agerite alba, a monobenzyl ether disinfectants, synthetic rubber, paints, deodorants, and
of hydroquinone (HQ), added in rubber gauntlet gloves germicides.2,3,5 Some of the most common chemicals that
was indeed the culprit.2 Since then, numerous chemicals cause chemical leukoderma are formaldehyde, azo dyes,
causing chemical leukoderma have been reported and para-phenylenediamine (PPD).
(Table 24.1). Phenols and aromatic or aliphatic catechol-
derivatives as well as sulfhydryl compounds are common Skin-lightening agents
culprits.4 Hypopigmentation is a recognized effect of skin-lightening
Chemical leukoderma is mostly an industrial hazard. products. The most important indications for the use of
However, it can also occur from exposure to common lightening agents in the White population are melasma,

159
160 Hypopigmentation from chemical and physical agents

dyschromia of photoageing, and post-inflammatory creams in Mexico and found that mercury content varied
hyperpigmentation (PIH). The practice of skin bleaching between 878 and 36,000 ppm, despite the fact that the FDA
for a cosmetic purpose is becoming more common in non- has determined that the limit for mercury in creams should
White populations throughout the world. The prevalence be less than 1 ppm.10
of voluntary depigmentation among different population
groups ranges from 25% to 67%. Included are the active Plant extracts
principles of HQ, glucocorticoids, mercury iodide, plant Plant extracts and newer TYR inhibitors such as kojic
extracts, and caustic agents.6 acid derivatives are popular ingredients in skin lightening
products. The majority of active compounds isolated from
Hydroquinone plants inhibit melanogenesis without melanocytotoxicity;11
Hydroquinone is the most commonly used bleaching agent thus, hypopigmentation is rarely observed after use of kojic
and the gold standard for treatment of hyperpigmentation. dipalmitate, liquorice extract, Mitracarpus scaber extract,
Chronic adverse effects include exogenous ochronosis, and lemon toner.11–13
cataract, colloid milia, nail pigmentation, impaired wound Oral submucous fibrosis (OSF) is a chronic disorder,
healing, and fish odor. There are infrequent reports of predominantly encountered in South Asian and Southeast
confetti-like, 1–3 mm hypopigmented macules.7 Asian countries. It has been established that OSF is
etiologically linked to the consumption of the Areca nut in
Mequinol flavored formulations or as an ingredient in the betel quid.
Monomethyl ether of HQ, also known as p-hydroxyanisole Depigmentation of the lips may be the earliest feature to
or mequinol, produces side effects like burning, contact develop in the natural history of OSF (Figure 24.2).14
dermatitis, and ochronosis. Recently, a case of irregular
leukoderma following mequinol was described.8 Clinical features
The hypopigmentation may develop not only at the site of
Rhododendrol chemical contact (Figures 24.3 and 24.4), but also remotely
Rhododendrol, 4-(4-hydroxyphenyl)-2-butanol, a natu­ (Figure 24.5). The mechanism responsible for this distant
rally occurring phenolic compound in plants such as spread is unclear. Depigmented areas may continue to appear
Acer nikoense and Betula platyphylla, was developed as even after discontinuation of contact with the suspected
a tyrosinase (TYR) inhibitor for lightening cosmetics. chemicals. Repigmentation may or may not occur despite
Recently, an outbreak of patients with leukoderma discontinuation of the offending agents. The presence of
occurred in Japan with the use of cosmetics containing confetti or pea-sized macules (Figure 24.5) is characteristic
rhododendrol. Patients developed leukoderma mostly at of chemical leukoderma, albeit not diagnostic.4
the contact site, but some at nonexposed areas, too. The
intensity of rhododendrol exposure did not correlate to the Diagnosis
severity of depigmentation. In most cases, repigmentation Relevant diagnostic elements are the history of exposure
is observed after treatment discontinuation.9 to a depigmenting agent and distribution corresponding
to sites of chemical exposure. Despite its limitations, patch
Cosmetic preparations containing mercury
testing is important in patients with suspected chemical
Preparations containing mercury are still available in leukoderma. However, no guidelines exist for standardized
many developing countries, and their contents are poorly
controlled (Figure 24.1). Peregrino et al. analyzed whitening

Figure 24.1 Irregular hypopigmented areas following

exposure to mercury-containing lightening product for Figure 24.2 Depigmentation of the lips as the manifestation
melasma. of oral submucous fibrosis.
 Hypopigmentation from physical agents 161

performance of the patch testing in chemical leukoderma,

and the diagnostic value of this procedure depends on
the choice of vehicle (petrolatum, dimethyl sulfoxide,
and propylene glycol are recommended), substance
concentration (elevated, between 2% and 10%, if possible),
and results interpretation (not only after 48–96 hours, but
after 1 or more months as well).4 The open application test is
not useful in chemical leukoderma. Chemical leukoderma
should be differentiated from post-inf lammatory
leukoderma and Koebner phenomenon in vitiligo.4,5

Treatment
Depigmentation often resolves spontaneously after
discontinuation of the offending agent. Treatment
options for persistent hypopigmentation include topical
Figure 24.3 Chemical leukoderma. Depigmentation at the steroids, tacrolimus, oral steroid pulse, phototherapy, and
site of contact with black underwear. techniques of surgical repigmentation.4

HYPOPIGMENTATION FROM PHYSICAL AGENTS

Destruction or inhibition of melanocytes can result
from exposure to a numerous physical agents, including
mechanical and thermal injuries, ionizing and nonionizing
radiation, and various types of burns. Some physical agents
can induce a biological stress response in melanocytes that
are not directly exposed, a phenomenon known as cellular
bystander effect.15
Hypopigmentation from physical agents manifests as
macules distributed on the site of skin injury. The macules
may have an indistinct outline, in contrast to the discrete
border seen in vitiligo.16
Repigmentation depends on the depth and width of the
injury. In deep injuries in which all adnexal elements have
been destroyed, the only available source for melanocytes
will be the wound edges. These wounds will take longer to
heal and will heal with a hypopigmented center in contrast
to the surrounding unwounded skin.17
Figure 24.4 Chemical leukoderma from rubber sandals. The hypopigmentation is usually transient and resolves
over time. There are various methods to treat permanently
hypopigmented skin, such as split skin grafting, lasers,
cultured skin cell transplantation, medical needling, and
noncultured skin cell suspension.3,17

Mechanical injuries
Hypopigmentation or hypopigmented scars can occur after
various mechanical injuries, including surgical (Figure
24.6) and accidental injury, pressure sores, frictional
forces, acne excoriée, and factitious disorder (Figure
24.7).16,17 Skin signs of torture as well as child abuse can
also result in residual hypopigmentation; lack of symmetry
and linear lesions in irregular or criss-cross arrangements
are supportive of external infliction.18

Cold injuries
Melanocytes are delicate and only require a temperature
of −5°C for destruction, resulting in hypopigmentation in
Figure 24.5 Chemical leukoderma due to hair dye applied darker-skinned individuals.19–21 Frostbite or congelation
on moustache. A few depigmented satellite macules can also is tissue injury resulting from exposure to temperatures
be observed. below 0°C. Cells are damaged by ice formation in their
162 Hypopigmentation from chemical and physical agents

Figure 24.8 Hypopigmentation following topical

application of crushed garlic for headache.

process often takes over a year to be completed. Permanent

Figure 24.6 Depigmentation after microdermabrasion. depigmentation occasionally develops after deep partial-
thickness and full-thickness burn injuries.22
Laser and intense pulsed light (IPL) used for medical
and cosmetic purposes can cause pigmentary side effects
such as PIH, mottling, and “confetti-like” or “guttate”
hypomelanosis.23

REFERENCES
1. Ruiz-Maldonado R, Orozco-Covarrubias ML.
Post­
inflammatory hypopigmentation and hyper­
pigmentation. Semin Cutan Med Surg. 1997;16:36–43.
2. Dubey SK, Misra K, Tiwari A, Bajaj AK. Chemically
induced pigmentary changes of human skin,
interaction of some azo dyes with human DNA.
J Pharmacol Toxicol. 2006;1:234–247.
3. Ortonne JP, Bahadoran P, Fitzpatrick TB et al.
Hypomelanoses and hypermelanoses. In: Freedberg
IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA,
Katz SI, eds. Fitzpatrick’s Dermatology in General
Medicine. New York: McGraw-Hill, 2003:836–881.
4. Bonamonte D, Vestita M, Romita P et al. Chemical
leukoderma. Dermatitis. 2016;27(3):90–99.
5. Ghosh SK, Bandyopadhyay D. Chemical leukoderma
induced by colored strings. J Am Acad Dermatol.
2009;61(5):909–910.
Figure 24.7 Hypopigmentation in dermatitis artefacta. 6. Benn EKT, Alexis A, Mohamed N et al. Skin bleaching
Self-induced skin lesions caused by scratching, picking, and and dermatologic health of African and Afro-
pouring chemicals on the skin. Caribbean populations in the US: New directions
for methodologically rigorous, multidisciplinary,
structures and denaturation of lipid–protein complexes as and culturally sensitive research. Dermatology and
well as by vascular supply disruption.20 Therapy. 2016;6(4):453–459.
7. Nordlund JJ, Grimes PE, Ortonne JP. The safety
Burns of hydroquinone. J Eur Acad Dermatol Venereol.
In burn injuries, skin and appendageal structures 2006;20:781–787.
are damaged by mechanical friction, heat, electrical 8. Mohamed M, Toumi A, Soua Y et al. Confetti
discharge, chemicals, and radiation. Pigment changes leukoderma following application of mequinol: A
persist for months (Figure 24.8). The repigmentation case report. J Clin Dermatol Ther. 2018;4:028.
 References 163

9. Yoshikawa M, Sumikawa Y, Hida T et al. Clinical and 16. Vachiramon V, Thadanipon K. Postinflammatory
epidemiological analysis in 149 cases of rhododendrol- hy popigmentation. Clin Exp Dermatol.
induced leukoderma. J Dermatol. 2017;44(5):582–587. 2011;36(7):708–714.
10. Peregrino CP, Moreno MV, Miranda SV et al. 17. Chadwick S, Heath R, Shah M. Abnormal pigmenta­
Mercury levels in locally manufactured Mexican tion within cutaneous scars: A complication of wound
skin-lightening creams. Int J Environ Res Public healing. Indian J Plast Surg. 2012;45(2):403–411.
Health. 2011;8(6):2516–2523. 18. Danielsen L, Rasmussen OV. Dermatological findings
11. Zhu W, Gao J. The use of botanical extracts as topical after alleged torture. Torture. 2006;16(2):108–127.
skin-lightening agents for the improvement of skin 19. Eryilmaz T, Tuncer S, Uygur S, Ayhan S. Finger
pigmentation disorders. J Investig Dermatol Symp tip defect after cryotherapy. Dermatol Surg
Proc. 2008;13(1):20–24. 2009;35:550–551.
12. Madhogaria S, Ahmed I. Leucoderma after use of a 20. Sachs C, Lehnhardt M, Daigeler A, Goertz O. The
skin-lightening cream containing kojic dipalmitate, triaging and treatment of cold-induced injuries.
liquorice root extract and Mitracarpus scaber extract. Dtsch Arztebl Int. 2015;112(44):741–747.
Clin Exp Dermatol. 2010;35(4):e103–e105. 21. Damevska K, Duma S, Pollozhani N. Median
13. Gye J, Nam CH, Kim JS et al. Chemical leucoderma canaliform dystrophy of Heller after cryotherapy.
induced by homemade lemon toner. Australas J Pediatr Dermatol. 2017;34(6):726–727.
Dermatol. 2014;55(1):90–92. 22. Greenhalgh DG. A primer on pigmentation. J Burn
14. Sitheeque M, Ariyawardana A, Jayasinghe R, Care Res. 2015;36(2):247–257.
Tilakaratne W. Depigmentation of oral mucosa as 23. Cil Y. Second-degree skin burn after intense pulsed
the earliest possible manifestation of oral submucous light therapy with EMLA cream for hair removal. Int
fibrosis in Sri Lankan preschool children. J Investig J Dermatol. 2009;48(2):206–207.
Clin Dent. November 2010;1(2):156–159.
15. Redmond RW, Rajadurai A, Udayakumar D et al.
Melanocytes are selectively vulnerable to UVA-
mediated bystander oxidative signaling. J Invest
Dermatol. 2013;134(4):1083–1090.
Guttate hypomelanosis and progressive
hypomelanosis of the trunk (progressive
25
macular hypomelanosis)
ALEXANDER KATOULIS and EFTHYMIA SOURA

CONTENTS
Guttate hypomelanosis 165 References 173
Progressive hypomelanosis of the trunk
(progressive macular hypomelanosis) 170

GUTTATE HYPOMELANOSIS with hyperkeratosis and a scalloped border.5 It is unclear

Introduction whether these variants share the same etiopathogenesis.
Idiopathic guttate hypomelanosis (IGH) is a very common Epidemiology
skin disorder that mainly affects the older population. IGH
The exact prevalence of IGH is largely unknown, but it is
was first described by Costa in 1951 as “symmetric
believed that the disorder tends to be underdiagnosed in
progressive leukopathy of the extremities.” Soon after,
many populations. In previous studies, it has been shown
Cummings and Cottel described the same condition
that the probability of acquiring IGH tends to increase with
in a group of patients, naming the disorder “idiopathic
age and may range from 80% to 97% in patients who are older
guttate hypomelanosis,” a term that is still used today.1 The
than 40 years.2,4 More specifically, Shin et al. reported that
pathogenesis of this condition has not been clearly elucidated,
in a study that included 646 patients with IGH, the disorder
but aging, sun exposure, and genetic predisposition have
was present in 47% of patients aged 31–40 years, in 80% of
been described as possible etiopathologic factors. In general,
patients aged 41–50 years, and in 97% of patients aged 81–90
IGH is characterized by a benign course, although it may be
years.4 However, it must be mentioned that in rare cases, IGH
a cause for concern for patients who frequently seek medical
may be present in younger patients as well.6 The condition
care for cosmetic reasons.2,3
can appear in any skin phototype but tends to be more visible
in patients of darker skin phototypes (Figure 25.3). The
Clinical presentation incidence of IGH seems to be similar in males and females.4
IGH presents as small (0.5–6 mm), asymptomatic, sharply
circumscribed, round, porcelain-white macules.2 Although Pathogenesis
IGH lesions do not tend to increase in size or coalesce to form The exact etiopathogenesis of IGH remains unclear. Until
plaques, lesions up to 2.5 cm in diameter have been reported now, various hypotheses have been stated regarding
in the literature.2,4 However, in a study performed by Shin the eliciting factors and pathogenesis of IGH, including
et al., 16% of patients reported a progressive increase in lesion chronic UV exposure, local melanogenesis abnormalities,
size.4 It cannot be stated whether this was a true or subjective cell senescence, possible genetic factors, trauma, and
observation of patients as a result of cosmetic concerns. autoimmunity.2 Overall, it is believed that the pathogenesis
IGH is usually located on sun-exposed areas of the skin of IGH is multifactorial, with more than one factor being
and more commonly on the dorsal areas of arms and legs implicated in the appearance of the disorder at different
(distal sites more common than proximal sites) and very ages (older versus younger) and at different localizations
rarely on the face or trunk.2,4 In some patients, lesions may (sun exposed versus non-sun exposed).
be present on non-sun-exposed areas as well.4 Hairs on the The most prevalent of hypotheses is linked to chronic
affected areas retain their pigment, and adnexal structures UV radiation exposure. This theory can be supported by
are normal. Three types of morphological distributions the fact that IGH lesions tend to appear mainly on sun-
have been described for this disorder: hypopigmented exposed areas, and by small case series reporting the
macules on chronically sun-damaged skin (Figures 25.1 appearance of IGH lesions in patients receiving psoralen
and 25.2); single porcelain-white, well-circumscribed, ultraviolet A (PUVA) radiation therapy or narrowband-
small whitish macules (can be sclerotic) observed in both ultraviolet B (nb-UVB) radiation for the treatment of
sun-exposed and non-sun-exposed areas; and small, mycosis fungoides.7,8 In addition, the skin of patients
well-circumscribed hypopigmented macules presenting with IGH lesions commonly exhibits histopathologic

165
166 Guttate hypomelanosis and progressive hypomelanosis of the trunk (progressive macular hypomelanosis)

Figure 25.1 Presence of hypopigmented macules on Figure 25.4 Idiopathic guttate hypomelanosis on the skin
chronically sun-damaged skin on the anterior surface of a of a patient with solar elastosis. Adjacent to the IGH lesions,
female patient’s tibia. several actinic keratoses and lentigos can be seen.

and ultrastructural signs of solar elastosis4,9(Figure 25.4).

However, it should be mentioned that IGH is not limited to
sun-exposed areas, while heavily sun exposed areas (such
as the face) are only rarely affected by the disorder.6
It is uncertain whether genetic factors play a role in the
pathogenesis of IGH, although a correlation with specific
HLAs (human leukocytic antigens) has been established.10,11
One the other hand, continuous microtrauma may play an
important role in the appearance of IGH.4 Defective local
melaninogenesis has also been included in the possible
causes of IGH.12–15

Diagnostic modalities
Histopathology
The main histopathological findings commonly associated
Figure 25.2 Idiopathic guttate hypomelanosis on the with IGH lesions are basket-weave hyperkeratosis
dorsal area of a male patient’s wrist. (stratum corneum), acanthosis, and a decreased number
of melanocytes.4 Decreased melanin pigmentation is
observed in the epidermis, and melanocytes may exhibit a
decreased number of melanosomes, swelled mitochondria,
and attenuated dendrites.4,6 In some instances, the
epidermis can be atrophic and the rete ridges flattened.4,6,10
No dermal changes associated with IGH are usually
seen; however, solar elastosis (and other histopathologic
features of sun exposure) may be present.9 A thicker Grenz
zone and increased glycosaminoglycan presence may be
demonstrated if Hale staining is used.16

Electron microscopy
Very few data are available regarding the ultrastructural
characteristics of IGH. Kim et al. and Ortonne et al.
reported characteristics such as melanocyte degeneration,
decreased numbers of melanosomes, attenuation or absence
of melanocyte dendrites, dilatation of the endoplasmic
reticulum, and swelling of the mitochondria. 6,15 In
addition, Wilson et al. and Ploysangam et al. have
Figure 25.3 Idiopathic guttate hypomelanosis can be observed a decreased content of melanosomes in the
more evident in patients with darker skin color. keratinocytes neighboring melanocytes.14,17 Other authors
 Guttate hypomelanosis 167

did not observe a decreased number or melanosomes Treatment

in the melanocytes, but rather a decreased number of Until this point, no specific regimen has been considered
melanosomes in keratinocytes, suggesting an error in the gold standard for the treatment of IGH. However,
melanosome uptake from keratinocytes as opposed to various modalities have been investigated, including
decreased melanosome production.9 topical retinoids and calcineurin inhibitors, tattooing
with 5-fluorouracil (5-FU), lasers, dermabrasion, chemical
Dermoscopy peels, skin grafting, and cryotherapy.
The dermoscopic findings in IGH are usually nonspecific. The efficacy of topical tretinoin in the treatment of IGH
Recently, Ankad et al. reported the dermoscopic features has been investigated in a small clinical trial. Pagnogni et al.
of IGH lesions in 31 patients. Patterns that were described administered tretinoin cream to four female patients with
by the authors as “amoeboid,” “feathery,” “petaloid,” and photoaged skin and IGH. The patients received tretinoin
“nebuloid,” as well as combinations of these patterns, cream on one arm and placebo cream on the other.16 After
were the most frequently observed.18 Interestingly, the 4 months of treatment, repigmentation of IGH lesions was
authors observed that the “feathery” pattern was more observed, a result that was found statistically significant
common in older lesions, while the “nebuloid” pattern when the results from both arms were compared.16 The
was more common in newer lesions and in older patients18 authors suggested that increased melanin pigmentation
(Figure 25.5). after topical tretinoin use could be a result of melanin
transfer improvement to keratinocytes or stimulation of
Differential diagnosis melanin synthesis.16
Topical calcineurin inhibitors have also been investigated
The differential diagnosis of IGH includes all conditions in the treatment of IGH. In a study by Asawanonda
that are characterized by macular hypopigmentation. These et al., four patients with IGH received treatment with
include vitiligo (early stages), pityriasis versicolor, pityriasis 1% pimecrolimus cream for 8 weeks. The results were
alba, hypopigmented flat warts, and post-inflammation acceptable, as three out of four patients reported some
hypomelanosis.2,4,7 In addition, in the rare instances where improvement in their lesions (25%–75%).20 Similar results
IGH presents with characteristics of skin sclerosis, tuberous were reported in a double-blinded placebo-controlled
sclerosis, lichen sclerosus and atrophicus, and guttate study by Rerknimitr et al., which involved 26 patients with
morphea might also be considered.2,4,7 Progressive macular IGH.21 More specifically, patients received 0.1% topical
hypomelanosis may also resemble IGH; however, the two tacrolimus ointment two times per day for 6 months on one
disorders can be distinguished through various clinical side of the body and placebo cream on the other. Patients
features (summarized in Table 25.1). Differentiating IGH reported a better outcome and higher repigmentation on
from early-stage vitiligo may also pose a problem and is a the tacrolimus-treated side compared to the placebo treated
source of concern for most patients.19 In general, vitiligo side after 6 months of treatment.21 In addition, physician’s
presents at younger ages compared to IGH, exhibits a improvement grading score showed that 11% of the patients
different pattern of distribution, and is characterized by demonstrated improvement of their skin lesions on the
larger and irregularly circumscribed lesions.2,4 treated side after 6 months of treatment. Adverse events
included mild burning sensation in about 20% of patients.21
Topical calcineurin inhibitors may be considered an option
for the treatment of IGH; however, when used, long-term
therapeutic regimens are probably required.
In recent years, topical injections with 5-FU have
been used as a possible treatment for IGH. Arbache et al.
recently published the preliminary results of a small
study that included eight patients with IGH.22 A specific
microneedling device was used (tattooing) to inject lesions
with either 5-FU or placebo. According to the authors,
73.5% of lesions receiving 5-FU exhibited repigmentation
compared to only 33.8% of lesions receiving placebo. 22
Wambier et al. used a similar technique to inject 5-FU
50 mg/mL solution to IGH lesions.23 Results were noticeable
within the first month and were persistent. Possible adverse
events included irritation and transient post-inflammatory
hyperpigmentation.23
Chemical peels have been also been used in the treatment
Figure 25.5 Dermoscopic image of a patient with IGH. of IGH, with acceptable results. In a study by Ravikiran et al.,
No specific dermoscopic features can be identified besides a 88% phenol solution was topically applied in 20 patients
“nebuloid/cloudy”-type appearance. with a total of 149 IGH lesions.24 The authors reported that
Table 25.1 Differential diagnosis of progressive macular hypopigmentation
Disorder Clinical presentation Histologic findings Dermoscopic findings Laboratory tests
Progressive macular Hypopigmented, ill-defined, nummular, Unremarkable, decreased melanin Ill-defined whitish • Red follicular fluorescence on
hypopigmentation macules (trunk, abdomen), no scales or in epidermis, perifollicular area without scaling lesional skin (Wood’s light)
pruritus Gram+ staining • Negative KOH preparations
• Presence of follicular P. acnes
Pityriasis alba Oval macules commonly located on Hypopigmentation of epidermis, N/A • Negative KOH preparations
the face, neck, and arms covered by thin eczematous changes in the • Positive history of atopic dermatitis
scales epidermis and dermis
Idiopathic guttate Hypopigmented, well-circumscribed Decreased melanocyte and “Cloudy sky-like” or “cloudy” patterns Unremarkable, clinical diagnosis
hypomelanosis circular/oval macules on sun-damaged melanin content, epidermal atrophy
skin in middle-aged and older patients
Post-inflammatory Positive history of previous skin disorder, Decreased melanin in basal layer, Dermoscopic findings associated N/A, clinical diagnosis based on patient
hypopigmentation restricted to sites of initial lesions pigment-containing with initial lesions history
melanophages in upper dermis,
characteristics of previous disorder
Guttate vitiligo Hypopigmented/depigmented, well- Complete loss of melanocytes Well-circumscribed, N/A, clinical diagnosis based on patient
circumscribed macules with variable dense/glowing, history
distribution (can be symmetric), no whitish areas, perifollicular
scales hyperpigmentation
Achromic tinea Hypopigmented irregular asymmetric Hypopigmentation of epidermis, Well-circumscribed whitish area • Positive KOH preparation
(pityriasis) circular/oval, well-circumscribed yeast and hyphae present in stratum with thin scales present in the • Blue-green fluorescence of scales
versicolor macules, commonly on trunk, thin corneum, dermal inflammation skin furrows under Wood’s lamp
scales • Pityrosporum ovale in culture

(Continued)
168 Guttate hypomelanosis and progressive hypomelanosis of the trunk (progressive macular hypomelanosis)
Table 25.1 (Continued) Differential diagnosis of progressive macular hypopigmentation
Disorder Clinical presentation Histologic findings Dermoscopic findings Laboratory tests
Mycosis fungoides Hypopigmented oval macules Decreased epidermal melanin, no Polygonal structures consisting of • Histopathology
(hypopigmented) located on trunk and extremities, epidermal atrophy, epidermotropism lobule of white storiform streaks • Immunohistochemistry findings
can be symmetric, often pruritic of lymphocytes, minimal dermal with septa of pigmented dots, fine (clonal T-cell proliferation)
involvement, presence of Paultrier red dots or hairpin vessels present
microabscesses
Tuberculoid and Well-circumscribed hypopigmented Loss of epidermal pigment, White areas, decreased density of • Lepromin test
borderline macules, induration may be present, granulomatous inflammation hairs, presence of yellow globules, • Clinical history
tuberculoid leprosy asymmetric branching vessels • Should be suspected only in
endemic areas
Pinta Hypo- or hyperpigmented lesions of Decreased epidermal melanin N/A • Positive syphilis serology
variable content, dermal lymphoplasmacytic • Dark-field microscopy (Tr. carateum)
distribution infiltrate, treponemes may be present • Should be suspected only in
in early lesions (silver stain) endemic areas
Dermal Hypopigmented macules with variable Hypopigmentation of basal cell layer, Erythema, various configurations of • Positive history of visceral
leishmaniasis distribution dermal infiltration by lymphocytes vascular structures, white starburst- leishmaniasis
(post-kala-azar) and macrophages, parasites may be like patterns, central ulcers, “yellow • Should be suspected only in
present tears,” hyperkeratosis endemic areas
Guttate hypomelanosis
169
170 Guttate hypomelanosis and progressive hypomelanosis of the trunk (progressive macular hypomelanosis)

64% of the lesions exhibited acceptable repigmentation.24 demonstrated that 91.67% of lesions in the treatment group
Adverse events included persistent crusting (17.2% of exhibited some improvement compared to 18.34% in the
lesions), post-inflammatory hyperpigmentation (11.5%), control group.30 Similarly, the relative lightness index of
ulceration (7.9%), secondary infection (8.6%), and scarring IGH reached statistical significance at week 12, after three
(5.6%).24 Therapeutic wounding with 88% phenol solution sessions of laser treatment (p  =  0.026). 30 The authors
was also investigated in a more recent study by Gupta et al., suggest that the use of erbium laser may improve the
with acceptable results.25 absorption of tacrolimus in the skin, further potentiating
Various lasers have been used in the treatment of its efficacy.30 Adverse events included transient erythema
IGH. These include fractional carbon dioxide (CO2FL), and edema.30
ytterbium/erbium fiber, and excimer lasers. In a recent Cryotherapy and dermabrasion are two more modalities
pilot study by Gordon et al., six patients received treatment that have been investigated for the treatment of IGH. In a
with an excimer laser (wavelength of 308 nm) twice recent study by Laosakul et al., tip cryotherapy was applied
weekly for 12 weeks.26 Improvement was observed in all for 5 seconds in a single treatment session.31 A total of 29
patients, while at the end of the study, 50% of patients patients were included in the study and lesions on both sides
reported full repigmentation of lesions.26 No adverse events of the body were randomized to either receive treatment or
were reported besides mild transient erythema after the be used as controls.31 The authors of this study reported
application of the laser treatment.26 that 94.9% of treated lesions exhibited improvement after 4
Fractional carbon dioxide lasers have also shown weeks, while at week 16, 82.3% of the treated sites exhibited
acceptable efficacy in the treatment of IGH. In a pilot more than 75% improvement compared to just 2.0% of
study by Shin et al., 40 patients received treatment with sites in the control group (p < 0.001).31 Adverse events
CO2FL once, and repigmentation was assessed 2 months included mild burning sensation, post-inflammatory
following treatment.27 According to the authors, at least hyperpigmentation, erythema, and blister formation.31
50% improvement of lesions was observed in 90% (36) The efficacy of classic cryotherapy was investigated
of patients.27 In addition, patient satisfaction was high, in previous clinical trials, with acceptable results. 5,17 In
as 82.5% (33) of patients reported being very satisfied or general, no more than 3–5 seconds of liquid nitrogen
satisfied with just this one session of CO2FL treatment, while application was required. However, it is strongly
the results remained stable at 1 year follow-up.27 Adverse recommended that a well-trained health care professional
events included pain, burning sensation, and appearance perform the treatment, as there is always the possibility of
of erythema during the procedure. Post-inflammatory scarring if lesions are overtreated.2,5
hyperpigmentation was also observed in four patients. Dermabrasion may also be considered an option in
In a similar study by Goldust et al., 240 patients received specific cases. A disadvantage of this method is that it
treatment with a 10,600-nm CO2FL.28 A single treatment is applied in larger areas (whereas IGH is composed of
session was performed and the patients were assessed 2 small lesions) and requires expert supervision when
months later. According to the authors, 47.9% (115) and performed. In a study by Hexsel et al., 20 patients with
41.6% (100) of patients had achieved >75% and 51%–75% IGH lesions smaller than 5 cm were treated with a standard
clinical improvement, respectively.28 No recurrences were dermabrader, with acceptable results.32 According to the
observed at 1 year follow-up. Patient satisfaction was high authors of this study, 80% of patients exhibited satisfactory
in this study as well, with 39.6% (95) and 42.5% (102) of repigmentation after treatment.32 However, crust formation
patients reporting being “very satisfied” and “satisfied” and persistent erythema (6 months) were reported as
with the results, respectively.28 treatment-associated adverse effects.32
Fractional 1550-nm ytterbium/erbium fiber laser was
used by Rerknimitr et al. in a study that included 30 PROGRESSIVE HYPOMELANOSIS OF THE TRUNK
patients with a total of 120 IGH lesions.29 Patients received (PROGRESSIVE MACULAR HYPOMELANOSIS)
four treatments at 4-week intervals. Assessment was Introduction
performed with colorimetry, digital photography, and
digital dermoscopy at weeks 0, 4, 8, 12, and 16.29 According Progressive hypomelanosis of the trunk (progressive
to the authors, 83.34% of the lesions that received treatment macular hypomelanosis; PMH) is a skin condition that
exhibited some type of improvement compared to only is poorly understood and often misdiagnosed. It was first
18.34% of the control group lesions. 29 Adverse events described by Guillet et al. 33 in French people of mixed
included transient mild erythema and edema.29 No post- racial ancestry (Caucasian and African). The condition
inflammatory pigmentation was observed, possibly making was later described by other investigators as well, and they
this laser a more suitable option for patients with darker assigned several terminologies to it, including “cutis trunci
skin phototypes. In a more recent study by Chitvanich variata,” “Creole dyschromia,” and “idiopathic multiple
et al., 30 patients received treatment with fractional 1550- large macule hypomelanosis.”34–36
nm ytterbium/erbium fiber laser every 4 weeks combined
with twice daily topical application of 0.1% tacrolimus Clinical presentation
ointment on lesions on one side and placebo on lesions of This dermatologic entity is characterized by the appearance
the other side of their body.30 Photographic evaluations of asymptomatic, poorly defined nummular, symmetric,
 Progressive hypomelanosis of the trunk (progressive macular hypomelanosis) 171

role of hormones remains obscure, it could be supported

by the high female-to-male ratio observed in this disorder.

Diagnostic modalities
Histopathology
Very subtle histopathologic differences are observed
between lesional and nonlesional skin in patients with
PMH. Overall, the dermis appears normal, while a decrease
in melanin content in the epidermis, compared with that
in normal adjacent skin, may be present.35,36 There are no
signs of spongiosis or other histopathological features of
inflammation present,38 although Gram+ material may be
observed in areas adjacent to the pilosebaceous units of the
skin. This material is probably associated with the presence
of P. acnes.35,36
Figure 25.6 Typical clinical picture of PMH on the trunk of a
male patient. Presence of nonscaly symmetric, hypopigmented Electron microscopy
macules. It is believed by many authors that the hypopigmentation
observed in patients with PMH should be attributed to
hypopigmented macules that coalesce into patches and are alterations in the melanogenesis pathway rather than
usually nonscaly.34–36 In general, the lesions are distributed changes in the melanosome transfer or degradation
in the trunk (back, lumbar, and abdominal areas), but processes. This belief is based on electron microscope
can also extend to the neck and proximal extremities34 findings that indicate a decreased production of
(Figure 25.6). The hands of the patients are never affected melanosomes and the transfer of less melanized
by the condition, while lesions on the face are considered melanosomes and aggregated melanosomes in the lesional
extremely uncommon.35,36 skin of PMH patients with Fitzpatrick skin types V and
VI.35,36,44 More specifically, Kumarasinghe et al. observed
Epidemiology a statistically significant (p = 0.047) higher ratio of stage
The exact prevalence of PMH is currently unknown and IV and late stage III (dark) melanosomes in normal versus
may be difficult to determine, as it could vary widely from lesional skin in eight Chinese patients with PMH.45 Similar
country to country based on the type of population.33–37 findings were also reported in previous studies. 33,44 No
PMH usually appears during adolescence or early other significant ultrastructural differences between
adulthood, with reported patient ages ranging from 13 to lesional and nonlesional skin of patients with PMH have
45 years.34–36 In general, it is considered more common in been reported.
female patients, with the Netherlands Institute for Pigment
Disorders reporting a 7:1 female-to-male ratio.34–36 Dermoscopy
Similar to histopathology, the dermoscopic picture of PMH
Pathogenesis is unremarkable, with lesions presenting as an ill-defined
A theory has suggested that the lesions of PMH tend to whitish area without scaling46 (Figure 25.7). A distinction
appear in areas of the body with a high concentration of can be made from other hypopigmented macular
sebaceous glands.34–36 More specifically, the microbial flora diseases of the skin based on very subtle differences. For
of sebaceous glands may play an important role in disease instance, achromic pityriasis versicolor presents as a well-
pathogenesis.38 A specific strain of P. acnes, different from demarcated whitish area with fine scaling in the skin
that isolated in acne patients, has been identified in several furrows, guttate vitiligo as a dense and well-demarcated
patients with PMH.39–41 To further support the theory of white area with perifollicular hyperpigmentation, and
the implication of P. acnes in the pathogenesis of PMH, idiopathic guttate hypomelanosis as a “cloudy sky-like” or
various case series have shown that antimicrobial treatment “cloudy” pattern46,47 (Figure 25.5).
may improve pigmentation of the affected areas in some
patients.42,43 Another theory has suggested that PMH is a Wood’s lamp
type of post-inflammatory hypopigmentation that persists The use of a Wood’s lamp may assist greatly in the
after a fungal infection has resolved, but very few data diagnosis of PMH. The hypopigmented macules are more
support this hypothesis.35 Other authors have suggested clearly visible under a Wood’s lamp, and a typical coral-
that PMH could be a type of genodermatosis. This theory red follicular/ perifollicular fluorescence, observed only in
was considered because the condition is commonly seen in lesional skin and not in adjacent nonlesional skin, can be
members of the same family; however, there are very few seen when lesions are inspected under a powerful Wood’s
scientific data to support it.37 Finally, hormonal reasons may lamp in a pitch-black room.38 This type of fluorescence is
also play a role in the pathogenesis of PMH. Although the most probably caused by an agent produced by the P. acnes
172 Guttate hypomelanosis and progressive hypomelanosis of the trunk (progressive macular hypomelanosis)

authors have attempted the use of topical antimicrobial

agents in the treatment of this disorder. More specifically,
Relyveld et al. investigated the effectiveness of combination
therapy with benzoyl peroxide 5% hydrogel, clindamycin 1%
lotion, and UVA irradiation compared to the combination
of fluticasone 0.05% cream and UVA irradiation in
patients with PMH.42 A total of 45 patients were enrolled
in the study, and each regimen was administered in a
preselected side of every patient’s face (left and right).
Patients received the treatments for 14 weeks, followed by a
12-week follow-up period to evaluate repigmentation rates.
The antimicrobial combination regimen showed strong
superiority to the anti-inflammatory combination regimen
(photometric measurements p = 0.007, patient assessment
p < 0.0001, and dermatologist assessment p < 0.0001).42 In
addition, repigmentation rates were reported to be slower
on the side of the face that had received the antimicrobial
combination regimen treatment.42 Similar results were
reported by Santos et al. in a double-blinded, placebo-
controlled study that included 23 patients with PMH. 53
In this study, 10 patients received treatment with placebo
and 13 a combination of topical benzoyl peroxide 5%
Figure 25.7 Dermoscopic image of PMH. There are no and clindamycin 1%, for a total duration of 12 months.53
specific dermoscopic characteristics, and lesions present as A statistically significant improvement was observed for
asymmetrical, ill-defined whitish macules. the patients receiving the antimicrobial regimen after
this period. There were no follow-up results reported. 53
Although both of these studies have many limitations (e.g.,
strain that is associated with the appearance of PMH48 and subjective methods of result evaluation and low patient
has been shown to be almost universally present in patients numbers), they both report encouraging results for the
with the disorder.48,49 use of antimicrobial agents, suggesting that this could be
considered a treatment of choice for patients with PMH.
Differential diagnosis Phototherapy has also been evaluated in the treatment
PMH should mainly be distinguished from other acquired of PMH. Previous studies have reported acceptable efficacy
disorders characterized by macular hypopigmentation for the use of PUVA or narrowband UVB in patients
localized in the area of the trunk. These disorders can with the disorder. In a study by Duarte et al., 85 patients
be caused by nonmicrobial skin inflammation (i.e., received treatment with either PUVA or nb-UVB, with the
pityriasis alba, post-inflammatory hypopigmentation, majority of patients reporting at least 50% repigmentation
idiopathic guttate hypopigmentation), by infection- after 16 phototherapy sessions.54 Although 65% of patients
associated skin inflammation, by fungi (i.e., pityriasis were reported as “cured or much improved,” 72% relapsed
versicolor) or bacteria/other infectious agents (i.e., soon after treatment cessation.54 There were no statistically
tuberculoid or borderline tuberculoid leprosy, pinta, significant differences between the efficacy of PUVA and
etc.), or by proliferative neoplastic disorders (e.g., mycosis nb-UVB reported in this study. 54 Similar results were
fungoides). Progressive macular hypopigmentation can be reported in a small, uncontrolled study by Kim et al.
differentiated from several of these conditions due to the that included 17 patients with PMH.55 More specifically,
lack of pruritus and desquamation. In addition, in cases of nb-UVB therapy was successfully used in 56.2% of patients,
post-inflammatory hypopigmentation, a positive history who demonstrated more than 90% repigmentation. 55
for an inflammatory dermatosis precedes the appearance Interestingly, the beneficial results of the treatment seemed
of lesions. A summary of conditions that are included in to have an acceptable duration, as 68.7% of the responders
the differential diagnosis of PMH and their differences can did not show signs of relapse after 13.2 ± 8.2 (mean, SD)
be seen in Table 25.1.34–36,50–52 months of follow-up.55 In general, case reports and a short
case series corroborate these results, although the duration
Treatment of response is still debated.56,57
There is no specific treatment algorithm for PMH. In the Finally, oral isotretinoin has also been used in the
past, various topical and systemic corticosteroids and treatment of PMH, with mixed results. In a previous case
antifungal agents have been used in the treatment of report, 10 mg of oral isotretinoin were administered in a
PMH, with limited effectiveness.35,36 Due to the recent data patient with PMH and rosacea, with complete response
that indicate that the presence of P. acnes plays a major of PMH lesions reported after 1 month of treatment. 58
pathogenetic role in the appearance of the disease, various The authors reported that no relapse was observed after
 References 173

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Index
A Cold injuries, 161–162; see also H
Acid-fast bacillus (AFB), 135 Hypopigmentation Hair depigmentation, 109; see also
Afamelanotide, 86 Confetti-like hypopigmentation, 91; see also Waardenburg syndrome
Albinism, 93; see also Oculocutaneous albinism Tuberous sclerosis complex Hair hypopigmentation, 109
red, 94 Conradi-Hünermann-Happle syndrome, 123; Halo nevus (HN), 44–45, 149
Albinoid disorders, 93 see also Mosaic hypopigmentation clinical course, 149–150
Alezzandrini syndrome, 113 Contact leukoderma, see Leukoderma, chemical dermoscopy, 149
clinical presentation, 114–115 Corticotropin-releasing hormone (CRH), 36 differential diagnosis, 150
differential diagnosis, 115 Cosmetic preparations containing mercury, epidemiology, 149
epidemiology, 113 160; see also Skin-lightening agents features, 149
pathophysiology, 113–114 Cross syndrome, 113 histologic features, 149
treatment, 115 clinical presentation, 114–115 management, 151
Alopecia areata (AA), 103 differential diagnosis, 115 medium-sized congenital, 150
Angiofibromas, 91; see also Tuberous sclerosis epidemiology, 113 multiple, 150
complex pathophysiology, 113–114 pathogenesis, 150–151
Antibody-dependent cellular cytotoxicity treatment, 115 and vitiligo, 151
(ADCC), 36 Cytotoxic T-lymphocyte-associated antigen 4 Halo phenomenon, 146; see also Melanoma
Antimalarial drugs, 154; see also Systemic (CTLA-4), 145 leukoderma
drugs agonists, 87 Hansen disease, see Leprosy
Atopic dermatitis (AD), 128 Hematopoietic stem cell transplantation
D (HSCT), 99, 115, 154–155; see also
B Dasatinib, 153; see also Tyrosine kinase Systemic drugs
Birt-Hogg-Dubé syndrome (BHD syndrome), 91 inhibitors Hemophagocytic lymphohistiocytosis
Blaschko lines, 118, 119; see also Mosaic Dermatitis/eczema, 129–130; see also Post- (HLH), 113
hypopigmentation inflammatory hypopigmentation Hepatocyte growth factor (HGF), 7
hypomelanosis following, 118–120 Discoid lupus erythematosus (DLE), 128 Hermansky-Pudlak syndrome (HPS), 17, 97,
Bleeding diathesis, 97 Drug-induced hypopigmentation, 153 113; see also Hypopigmentation
Borderline lepromatous (BL), 135; see also systemic drugs, 153–155 clinical features, 97, 114–115
Leprosy topical drugs, 155–156 diagnosis, 97–98
Borderline tuberculoid (BT), 135; see also Durvalumab, 154; see also Immune checkpoint differential diagnosis, 115
Leprosy inhibitors disorder types, 114
Burns, 162; see also Hypopigmentation epidemiology, 113
E management, 98
C Endemic treponematoses, 140; see also pathophysiology, 113–114
Café au lait macules (CALMs), 101, 103 Treponematoses prevalence and prognosis, 97
Calcineurin inhibitors, 49, 53–54; see also Endothelin-1 (ET-1), 7 treatment, 115
Vitiligo treatments Endothelin receptor (EDNR), 108; see also Hermansky-Pudlak syndrome type 1–7
CALMs, see Café au lait macules Waardenburg syndrome (HPS1–7), 15
Catalase/dismutase superoxide (C/DSO), 52 Endothelin receptor type B (EDNRB), 7 Heterochromia, partial, 109; see also
Cell–cell crosstalk, 7; see also Melanocyte Endothelins (EDNs), 108; see also Waardenburg Waardenburg syndrome
melanocyte-endothelial cell interactions, 9 syndrome High-resolution computed tomography of the
melanocyte-fibroblast interactions, 8–9 ENL, see Erythema nodosum leprosum chest (HRCT), 97
melanocyte-keratinocyte interactions, 7–8 Epidermal nevus, 120, 122; see also Mosaic Histamine, 55; see also Topical agents
stimulating and inhibiting bioactive hypopigmentation Human pigmentation; see also Melanocyte
mediators, 8 Erythema nodosum leprosum (ENL), 135; adaptation of, 1–2
Cellular transplantation, 73–76; see also see also Leprosy in dark and light skin, 4
Vitiligo surgical treatment Extracellular matrix (ECM), 9; see also Hydroquinone (HQ), 159, 160; see also Skin-
Chediak-Higashi syndrome (CHS), 15, 17, 98, Melanocyte lightening agents
113; see also Hypopigmentation Hypomelanosis, 118–120, 128; see also Mosaic
clinical presentation, 114–115 F hypopigmentation
diagnosis, 98–99 Fibrous cephalic plaques, 91; see also Tuberous in checkerboard pattern, 120, 122
differential diagnosis, 115 sclerosis complex linear, 118, 122
epidemiology, 113 Fine-needle aspiration cytology (FNAC), 138 Hypopigmentation, 13, 127, see
management, 99 Focal dermal hypoplasia, see Goltz syndrome Leukoderma, chemical; Mosaic
pathophysiology, 113–114 hypopigmentation; Post-
prevalence and prognosis, 98 G inflammatory hypopigmentation;
treatment, 115 Genetic mosaicism, 124; see also Mosaic Tuberous sclerosis complex;
Childhood vitiligo (CV), 43; see also hypopigmentation Waardenburg syndrome
Post-childhood vitiligo Goltz syndrome, 123–124; see also Mosaic acquired disorders of, 17
clinical presentation, 43–44 hypopigmentation burns, 162
comorbidities, 44 Granulocyte-macrophage colony-stimulating from chemical and physical agents, 159
differential diagnosis, 45 factor (GM-CSF), 7 classification of, 14
epidemiology, 43 Griscelli syndrome (GS), 17, 99, 113; see also cold injuries, 161–162
halo nevi, 44–45 Hypopigmentation congenital, 14–15
leukotrichia, 43 clinical presentation, 114–115 considerations, 14
nonsegmental, 44 differential diagnosis, 115 depigmentation of lips, 160
phototherapy, 46 epidemiology, 113 in dermatitis artefacta, 162
psychological burden of vitiligo, 45 pathophysiology, 113–114 diagnostic approach to, 13–14
segmental, 44 subtypes, 114 differential diagnosis, 16, 18
surgical treatment, 46–47 treatment, 115 disorders involving, 13, 129
308-nm excimer laser, 46 Griscelli syndrome type 1–3 (GS1–3), 15 distribution of, 14
topical treatment, 45–46 Guttate hypomelanosis, see Idiopathic guttate drug-induced, see Drug-induced
treatment, 45–47 hypomelanosis hypopigmentation

177
178 Index

Hypopigmentation (Continued) Leucoderma in chronic GvHD, 155 Mequinol, 160; see also Skin-lightening agents
epidermal nevus, 122 Leukoderma, chemical, 159 Metastatic melanoma (MM), 154
due to gene defects, 15, 17 clinical features, 160 Methionine sulfoxide reductase (MSR), 86
infectious and parasitic causes of, 133 cosmetics with mercury, 160 5-methoxypsoralen (5-MOP), 24
leprosy, 135–139 depigmentation at site of contact, 161 8-methoxypsoralen (8-MOP), 24
macules, 90–91 diagnosis, 160–161 Methylprednisolone (MPD), 60
mechanical injuries, 161 due to hair dye, 161 Microphthalmia-associated transcription
melanocyte and genes controlling hydroquinone, 160 factor (MITF), 3, 7, 107–108; see also
pathway, 15 mequinol, 160 Waardenburg syndrome
due to mercury-based lightening plant extracts, 160 Million units (MU), 140
product, 160 rhododendrol, 160 Minimal erythema dose (MED), 80
after microdermabrasion, 162 from rubber sandals, 161 Mini-punch grafting, 73; see also Vitiligo
noncongenital, 17 skin-lightening agents, 159 surgical treatment
onchocerciasis, 139 treatment, 161 vs. noncultured epidermal cell
from physical agents, 161 Leukoderma in DLE lesions, 130; see also Post- suspension, 75
pityriasis versicolor, 133–135 inflammatory hypopigmentation Mixed vitiligo (MV), 39
of skin, 109 Leukotrichia, 43 Monoamine oxidase (MAO), 36
due to topical application of garlic, 162 Lichen sclerosus (LS), 128, 130–131; Monochromatic excimer light (MEL), 81, 85; see
due to topical steroid abuse, 155 see also Post-inflammatory also Phototherapy
treponematoses, 139–141 hypopigmentation Mosaic, 117
tuberous sclerosis complex, 17 Linear hypomelanosis, 118, 122; see also Mosaic Mosaic hypopigmentation, 117, see
Hypopigmented MF (HMF), 131; see also Post- hypopigmentation Hypopigmentation
inflammatory hypopigmentation LS-associated leukoderma, 130; see also Post- Blaschko lines, 118, 119, 120
inflammatory hypopigmentation clinical manifestations, 118–124
I Lucio phenomenon (LP), 135; see also Leprosy comparison of principal diseases of, 121
Idiopathic guttate hypomelanosis (IGH), Lupus erythematosus, 130; see also Post- Conradi-Hünermann-Happle
165; see also Progressive macular inflammatory hypopigmentation syndrome, 123
hypomelanosis Lymphangioleiomyomatosis (LAM), 89 cutaneous mosaicism pattern, 118
clinical presentation, 165 Lysosome-related organelles (LROs), 114 diagnosis, 124
dermoscopy, 167 epidermal nevus, 120, 122
diagnostic modalities, 166 M follow-up and treatment, 124
differential diagnosis, 167 Margolis syndrome, see Ziprkowski-Margolis genetic mosaicism, 124
electron microscopy, 166–167 syndrome genomic and epigenetic mosaicism, 117
epidemiology, 165 Marinesco-Sjögren syndrome (MSS), 115 Goltz syndrome, 123–124
histopathology, 166 Mechanical injuries, 161; see also hypomelanosis, 118–120, 122
pathogenesis, 165–166 Hypopigmentation incontinentia pigmenti, 122–123
treatment, 167, 170 Melagenina, 55; see also Topical agents mosaicism, 117–118, 120
Imatinib, 153; see also Tyrosine kinase Melanin nevus achromicus, 122
inhibitors biosynthetic pathway, 5 Pallister-Killian syndrome, 123
Imiquimod-induced hypopigmentation, 155 synthesis, 3–4 phylloid hypomelanosis, 123
Immune checkpoint inhibitors (ICIs), 154; see Melanocortin 1 receptor (MC1R), 7, 36 postzygotic mutation, 117
also Systemic drugs Melanocyte, 1, 9 segmental expression of nonlethal
Immune regulatory cells, 76 cell–cell crosstalk, 7–9 disorders, 118
Immune-related adverse events (irAEs), 154 DOPA staining, 2 Mosaicism, 117; see also Mosaic
Incontinentia pigmenti (IP), 17, 122–123; see double immunofluorescence staining, 6 hypopigmentation
also Hypopigmentation; Mosaic epidermal-melanin unit, 3 cutaneous, 118
hypopigmentation extracellular microenvironment, 9 genetic, 124
Indeterminate leprosy (IL), 135; see also homeostasis, 9 genomic and epigenetic, 117
Leprosy keratinocytes, 4–6 mechanisms of, 117–118
Inflammatory dermatoses, 127 markers, 3 patterns of, 120
Intense pulsed light (IPL), 162 and melanin synthesis, 2, 3–4, 5 Multibacillary (MB), 135
Interferon gamma (IFN-γ), 8, 36 melanosome, 2 Multiple drug therapy (MDT), 135
melanosome maturation within, 5 Multiple endocrine neoplasia type 1
J melanosome transport, 1–6 (MEN1), 91
Janus kinases (JAKs), 36, 55, 87 microscopic analysis, 2 Mycophenolate mofetil, 55; see also Topical
Juvenile localized scleroderma (JLS), 131 MITF expression analysis, 7 agents
pigmentation adaptation, 1–2 Mycosis fungoides (MF), 128, 131–132;
K Melanogenesis, 128; see also Post-inflammatory see also Post-inflammatory
Keratinocyte growth factor (KGF), 8 hypopigmentation hypopigmentation
Keratinocytes, 7 Melanoma antigen recognized by T cells 1
Koenen tumors, 91; see also Tuberous sclerosis (MART1), 3, 146 N
complex Melanoma-associated depigmentation Narrowband ultraviolet B (NB-UVB), 46, 52,
(MAD), 145 79, 81, 85
L Melanoma-associated hypopigmentation Nerve growth factor (NGF), 7
l-3,4-dihydroxyphenylalanine (l-DOPA), 4 (MAH), 145 Neurochemical mediators, 36
Lasers, 79; see also Phototherapy Melanoma-associated leukoderma (MAL), 145 Neurofibromatosis 1 (NF1), 101
Lepromatous leprosy (LL), 135; see also Leprosy Melanoma-associated vitiligo (MAV), 145 Nevus achromicus, 122; see also Mosaic
Leprosy, 135; see also Hypopigmentation Melanoma leukoderma, 145 hypopigmentation
borderline lepromatous, 135, 136 halo phenomenon, 146 Nivolumab, 154; see also Immune checkpoint
borderline tuberculoid, 135, 136 melanoma regression, 146 inhibitors
classification, 136 pathogenesis, 145 Noncultured epidermal cell suspension
diagnosis, 137 prognosis, 147 (NCES), 74; see also Vitiligo surgical
differential diagnosis, 139 vitiligo-like depigmentation, 146 treatment
epidemiology, 136 vitiligo-like lesions, 146 mini-punch graft vs., 75
erythema nodosum leprosum, 135, 137 Melanophilin (MLPH), 99 modifications of transplantation, 75
Fite stain, 138 Melanosome, 2 preparation method, 74
granuloma, 138 maturation, 5 Noncultured, extracted follicular outer root
lepromatous leprosy, 135, 137 transfer to keratinocytes, 4–6 sheath suspension (NC-EHF-
treatment and prognosis, 139 Membrane-associated transport protein ORS-CS), 87
tuberculoid leprosy, 135, 136 (MATP), 93 Nonsegmental vitiligo (NSV), 17, 29, 43;
well-formed granuloma, 138 MEN1, see Multiple endocrine neoplasia type 1 see also Hypopigmentation
 Index 179

O hyperpigmented variant of, 134 Psoralen plus ultraviolet A (PUVA), 24,

Occupational leukoderma, see Leukoderma, with hypopigmented patches with fine 46, 52, 69, 80, 115, 155; see also
chemical scaling, 134 Phototherapy
Oculocerebral hypopigmentation syndrome with pink scaly patches, 134 Pterin-4a-carbinol-amine dehydratase
(OCHS), 114, see Cross syndrome prognosis, 135 (PCD), 151
Oculocutaneous albinism (OCA), 17, 93; see RDPV, 133 Pure neuritic leprosy (PNL), 135; see also
also Hypopigmentation treatment, 135 Leprosy
clinical manifestations, 93–94 yeast within stratum corneum, 134 PUVA, see Psoralen plus ultraviolet A
diagnosis, 94–95 Plant extracts, 160; see also Skin-lightening
epidemiology, 93 agents R
etiology, 93 Platelet-derived growth factor receptor Rapid plasma regain (RPR), 140
histology, 94 (PDGFR), 153 Reactive oxygen species (ROS), 1, 86
pathogenesis, 93 Platelet transmission electron microscopy Recurrent and disseminated pityriasis
prevalence and genetics of, 94 (PTEM), 98 versicolor (RDPV), 133; see also
prognosis, 95 Point-of-care (PoC), 140 Pityriasis versicolor
red albinism, 94 Polypodium leucotomos (PL), 64, 86 Red albinism, 94; see also Oculocutaneous
treatment, 95 Post-childhood vitiligo (PCV), 43; see also albinism
Onchocerciasis, 139; see also Childhood vitiligo Reflectance confocal microscopy (RCM), 149
Hypopigmentation clinical presentation, 43–44 Restriction fragment length polymorphism
Oral corticosteroids, 60, 81 comorbidities, 44 (RFLP), 135
Oral submucous fibrosis (OSF), 160 differential diagnosis, 45 RFLP, see Restriction fragment length
epidemiology, 43 polymorphism
P halo nevi, 44–45 Rhododendrol, 160; see also Skin-lightening
Pallister-Killian syndrome (PKS), 123; see also phototherapy, 46 agents
Mosaic hypopigmentation psychological burden of vitiligo, 45 River blindness, see Onchocerciasis
Partial heterochromia, 109; see also surgical treatment, 46–47
Waardenburg syndrome 308-nm excimer laser, 46 S
Paucibacillary (PB), 135 topical treatment, 45–46 Sarcoidosis, 131; see also Post-inflammatory
PAX3, 107; see also Waardenburg syndrome treatment, 45–47 hypopigmentation
Pazopanib, 153; see also Tyrosine kinase Post-inflammatory hyperpigmentation (PIH), SCC, see Squamous cell carcinoma
inhibitors 160, 167, 170 Scleroderma, 131; see also Post-inflammatory
Pembrolizumab, 154; see also Immune Post-inflammatory hypopigmentation (PIH), hypopigmentation
checkpoint inhibitors 127, 132 Secreted frizzled-related protein 2 (sFRP2), 9
Peroxisome proliferator-activated receptor-γ clinical features, 128 Segmental heterochromia, 109; see also
(PPAR-γ), 7 course and prognosis, 129 Waardenburg syndrome
Phenylalanine hydroxylase (PAH), 35 dermatitis/eczema, 129–130 Segmental hypomelanosis, 120
Pheomelanin, 4 diagnosis, 128 Segmental vitiligo (SV), 17, 29, 32, 39, 43; see
Phosphate buffer saline (PBS), 74 disorders with hypopigmentation, 129 also Hypopigmentation
Phosphatidylinositol (PI), 7 etiology, 127 classification on face, 41
Photo(chemo) therapy, 24; see also Vitiligo with fine scaling due to psoriasis, 127 clinical features, 40
Phototherapy, 46, 79, 80 following resolution of AD eruption, differential diagnosis, 41
and carcinogenicity, 80 129–130 epidemiology, 39–40
combination treatments with, 81 histological features, 128 features different from nonsegmental
hospital and home, 79–80 hypopigmented MF, 131 vitiligo, 40
mechanism of action of, 79 leukoderma in DLE lesions, 130 mixed vitiligo, 41
monochromatic excimer light, 81 lichen sclerosus, 130–131 monosegmental vitiligo, 40
oral corticosteroids and, 81 LS-associated leukoderma, 130 pathogenesis, 39
side effects and contraindications, 80 lupus erythematosus, 130 treatment, 41–42
targeted phototherapy devices, 80–81 management, 128–129 sFRP2, see Secreted frizzled-related protein 2
topical cancineurin inhibitors and, 81 melanogenesis, 128 Shagreen patches, 91; see also Tuberous sclerosis
topical steroids and, 81 mycosis fungoides, 131–132 complex
using NB-UVB B, 80 pathogenesis, 127–128 Signal transduction and transcription
vitamin D analogues and, 81 pityriasis alba, 129 (STAT), 87
Phylloid hypomelanosis, 123; see also Mosaic sarcoidosis, 131 Skin depigmentation, 109; see also
hypopigmentation scleroderma, 131 Waardenburg syndrome
Piebaldism, 15, 101; see also skin disorders causing, 127, 132 Skin harvesting method, 72; see also Vitiligo
Hypopigmentation Postzygotic mutation, 117 surgical treatment
amelanotic macules, 102 Programmed cell death protein 1 (PD-1), Skin-lightening agents, 159
Café au lait macule, 101, 103 145, 154 cosmetic preparations containing
clinical presentation, 101 PD-1 ligand, 87 mercury, 160
differential diagnosis, 103 Progressive hypomelanosis of trunk, see hydroquinone, 160
different phenotypes, 102 Progressive macular hypomelanosis mequinol, 160
epidemiology, 101 Progressive macular hypomelanosis (PMH), plant extracts, 160
etiopathogenesis, 101 170; see also Idiopathic guttate rhododendrol, 160
histopathology, 103 hypomelanosis Skin-slit smear assessment
leukodermatous patches, 103 clinical presentation, 170–171 (SSS assessment), 135
sparring of dorsal midline, 102 dermoscopy, 171, 172 SNAI2, 108; see also Waardenburg syndrome
treatment, 103–104 diagnostic modalities, 171 Sorafenib, 154; see also Tyrosine kinase
white forelock and triangularly shaped differential diagnosis, 168–169, 172 inhibitors
leukoderma, 102 electron microscopy, 171 SOX10, 108; see also Waardenburg syndrome
Pityriasis alba (PA), 129; see also Post- epidemiology, 171 SPRED1, 101
inflammatory hypopigmentation histopathology, 171 Squamous cell carcinoma (SCC), 131
Pityriasis versicolor (PV), 133; see also pathogenesis, 171 Squaric acid dibutylester (SADBE), 156
Hypopigmentation prognosis, 173 Stem cell factor (SCF), 7, 35, 153
clinical features, 133 treatment, 172–173 Suction blister epidermal grafting, 73; see also
diagnostic methods of, 135 wood’s lamp, 171–172 Vitiligo surgical treatment
differential diagnoses of, 135 Pro-opiomelanocortin (POMC), 7, 36 Sunitinib, 154; see also Tyrosine kinase
epidemiology, 133 Prostaglandins (PGs), 55, 59; see also Topical inhibitors
etiopathogenesis, 133 agents Synophrys, 109–110; see also Waardenburg
follicular variant of, 134 Pseudocatalase, 52, 55, 58; see also Topical syndrome
histopathology, 134 agents Syphilis, 140–141; see also Treponematoses
180 Index

Systemic drugs of vitiligo, 60, 153; see also treatment of cutaneous lesions, 92 treatment of, 22–24
Drug-induced hypopigmentation ungual fibromas, 91 trigger factors, 29
antimalarial drugs, 154 Tumor necrosis factor (TNF), 36, 128 variants of, 29
antioxidants, 64 TNF-α, 8 white macules of, 29
biologics and small molecules, 64 Tyrosinase gene (TYR), 93 Vitiligo pathophysiology, 35, 37
corticosteroids, 60, 62 Tyrosinase-related protein 1 (TYRP-1), 3 autoimmunity, 36
hematopoietic stem cell transplantation, gene, 93 genetic predisposition, 35
154–155 Tyrosinase-related protein 2 (TYRP-2), 4 neuroendocrine phenomena, 36
immune checkpoint inhibitors, 154 Tyrosine hydroxylase (TH), 35 oxidative stress, 35–36
immunosuppressive treatments, 60, 63 Tyrosine kinase 2 (TYK2), 87 Vitiligo surgical treatment, 69, 76
targeted antineoplastic agents, 153 Tyrosine kinase inhibitors (TKIs), 153; see also area preparation, 69
tyrosine kinase inhibitors, 153–154 Systemic drugs cellular transplantation, 73–76
Systemic sclerosis (SS), 131 dasatinib, 153 mini-punch grafting, 73
imatinib, 153 NCES preparation method, 74
T pazopanib, 153 noncultured epidermal cell suspension
Targeted antineoplastic agents, 153; see also sorafenib, 154 transplantation, 75
Systemic drugs sunitinib, 154 patient selection, 69
Targeted phototherapy devices, 80–81; see also skin harvesting method, 72
Phototherapy U suction blister epidermal grafting, 73
12-Tetradecanoylphorbol 13 acetate (TPA), 74 Ultraviolet (UV), 1, 24, 52, 128 techniques, 70–71
T helper 2 (Th2), 133 Ultraviolet A (UVA), 24, 79 tissue grafts, 69, 72–73
308-nm excimer laser, 46 Ultraviolet B (UVB), 1 types of vitiligo surgery, 69
Thymic stromal lymphopoietin (TSLP), 35 Ultraviolet radiation (UVR), 1, 85 Vitiligo treatments, 85, 87; see also Calcineurin
Tietz syndrome, 17; see also Hypopigmentation Ungual fibromas, 91; see also Tuberous sclerosis inhibitors; Lasers; Phototherapy;
Tissue grafts, 69, 72–73; see also Vitiligo complex Vitiligo lesions
surgical treatment U.S. Food and Drug Administration (FDA), 85
Topical agents, 52 W
histamine, 55 V Waardenburg syndrome (WS), 17, 103; see also
melagenina, 55 Vasoactive endothelial growth factor receptor Hypopigmentation
mycophenolate mofetil, 55 (VEGFR), 153 clinical findings, 108–109
prostaglandins, 55, 59 VDRL, see Venereal Disease Research cutaneous features, 109
pseudocatalase, 52, 55, 58 Laboratory depigmentation, 109
Topical calcineurin inhibitors (TCIs), 45, 49 Venereal Disease Research Laboratory diagnosis, 110
and phototherapy, 81 (VDRL), 140 diagnostic criteria of, 110
Topical drugs, 155; see also Drug-induced Vici syndrome, 113 EDN3 and EDNRB, 108
hypopigmentation clinical presentation, 114–115 genetic background, 107
corticosteroids, 45, 49, 50–51, 155 differential diagnosis, 115 microphthalmia-associated transcription
hypopigmentation due to abuse of, 155 epidemiology, 113 factor, 107–108
imiquimod, 155–156 pathophysiology, 113–114 partial/segmental heterochromia, 109
immunotherapy, 156 treatment, 115 PAX3, 107
steroids and phototherapy, 81 Vitamin D analogues, 52, 56–57 SNAI2, 108
transdermal patch, 156 and phototherapy, 81 SOX10, 108
for vitiligo therapy, 49–52, 61 Vitiligo, 17; see also Hypopigmentation subtypes and mode of inheritance, 108
Transdermal patch, 156; see also Topical drugs autoimmune diseases associated with, 29 synophrys, 109–110
T-regs, see T-regulatory cells classification, 28, 30 treatment, 110
T-regulatory cells (T-regs), 76 clinical features, 28 variation in clinical features, 109
Treponema pallidum particle agglutination dyschromy, 22 World Health Organization (WHO), 135
(TPPA), 140 epidemiology, 27–28
Treponematoses, 139; see also etiopathophysiological theories for, 27 X
Hypopigmentation etymology, 21 Xenon chloride device (XeCl device), 81
endemic, 140 genes implicated in vitiligo pathogenesis, 28 X-linked albinism-deafness syndrome (ADFN),
syphilis, 140–141 genetic alterations with comorbidities, 28 114, see Ziprkowski-Margolis
Tuberculoid leprosy (TT), 135; see also Leprosy halo nevi and, 151 syndrome
Tuberous sclerosis complex (TSC), 17, 89; see with inflammatory raised border, 129 X-linked ocular albinism (XLOA), 115; see also
also Hypopigmentation lesions, 86 Oculocutaneous albinism
angiofibromas, 91 nonsegmental vitiligo, 30, 31 XLOA, see X-linked ocular albinism
ash leaf spot, 90 pathogenesis, 85
clinical features, 89–90 perceptios, 21–22 Z
confetti-like hypopigmentation, 91 photo(chemo) therapy, 24 Ziprkowski-Margolis syndrome, 113
cutaneous manifestations of, 90 prognosis, 24 clinical presentation, 114–115
diagnosis, 89 in religious books, 21 differential diagnosis, 115
fibrous cephalic plaques, 91 segmental, 32 epidemiology, 113
hypopigmented macules, 90–91 social stigma, 22 pathophysiology, 113–114
large hypopigmented macules with serrated topical calcineurin inhibitors, 24 treatment, 115
margins, 90 topical corticosteroid, 24
shagreen patches, 91 treatment list, 23