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Neonatal Dermatology Second Edition Lawrence F.
Eichenfield Md Digital Instant Download
Author(s): Lawrence F. Eichenfield MD, Ilona J. Frieden MD, Nancy B.
Esterly MD
ISBN(s): 9781416034322, 1416034323
Edition: Second Edition
File Details: PDF, 31.70 MB
Year: 2008
Language: english
NEONATAL DERMATOLOGY
Second Edition

Lawrence F. Eichenfield, MD
Professor of Pediatrics and Medicine (Dermatology), University of
California, San Diego School of Medicine
Chief, Division of Pediatric and Adolescent Dermatology, Rady Children's
Hospital, San Diego, San Diego, California, USA

Ilona J. Frieden, MD
Professor of Dermatology and Pediatrics
Chief, Division of Pediatric Dermatology, University of California, San
Francisco School of Medicine, San Francisco, California, USA

Nancy B. Esterly, MD
Professor Emerita of Dermatology and Pediatrics, Medical College of
Wisconsin, Milwaukee, Wisconsin, USA

Dedication
To
Lori, Matthew, Julia and to my parents, Frances and Stuart Eichenfield
LFE
To Mark, Mike, and Sarai and to the rest of the ‘Four Friedens': Bonnie,
Karl, and Sarajo
IJF
To my four-legged friends
NBE

SAUNDERS ELSEVIER

Mosby is an affiliate of Elsevier Inc.

First edition 2001

? 2008, Elsevier Inc. All rights reserved.

No part of this publication may be reproduced, stored in a retrieval

system, or transmitted in any form or by any means, electronic,
mechanical, photocopying, recording or otherwise, without the prior
permission of the Publishers. Permissions may be sought directly from
Elsevier's Health Sciences Rights Department, 1600 John F. Kennedy
Boulevard, Suite 1800, Philadelphia, PA 19103-2899, USA: phone: (+1) 215
239 3804; fax: (+1) 215 239 3805; or, e-mail:
[email protected]. You may also complete your request on-
line via the Elsevier homepage (www.elsevier.com), by selecting ‘Support
and contact’ and then ‘Copyright and Permission’.
 Foreword
In the 33 years since Larry Solomon and Nancy Esterly first wrote a monograph devoted to describing skin
diseases of the newborn, the field of neonatology has changed from a descriptive one (without a physiological
or biochemical basis to recommend treatment), to one in which the molecular pathogenesis for many disor-
ders is now known. Although many of these disorders are quite rare, clinicians are now able to identify them
with great precision, tailor therapies, and offer families genetic counseling and prognostic information that,
until recently, were unknowns. The skin offers extraordinary opportunities for gene transfer, not only to
treat rare metabolic disorders, but also to deliver immunomodulatory agents (e.g., IL-12) and/or growth
factors to aid healing. With its unique capacity to heal without scar formation, the skin of the young fetus
can teach us much about wound repair.
Over the last 30 years, the increased survival rate of extremely low birth weight (ELBW) infants has posed
the greatest challenge in the neonatal ICU. Neonatologists have long recognized that the skin of the prema-
ture newborn infant is unusual, but until recently did not appreciate the magnitude of the physiological,
biochemical and structural differences, nor conceived of potential interventions to lessen morbidities. For
example, the vernix caseosa has been shown to contain a significant number of antimicrobial substances,
including the defensins, lactoferrin, lysozyme, bactericidal/permeability-increasing protein, calprotectin,
secretory leukocyte protease inhibitor and a cathelicidin [LL-37]. Beta defensins and LL-37 protect epithelial
surfaces. On dry epithelia, they function as ‘preservatives.’ On mucosal surfaces, they can be secreted into
the biofilm that covers the epithelial surface, creating a milieu that is antibacterial. The presence of vernix
in fetal life may help prevent infections from microorganisms colonizing the amniotic fluid. Vernix caseosa
may also enhance wound healing and has been suggested as a possible treatment for burn patients. The loss
of the vernix caseosa with washing and handling not only increases the magnitude of insensible water losses,
but also alters the types of skin bacteria, and may increase susceptibility to nosocomial infection. Hospital-
acquired infections are a major problem worldwide; they increase mortality, prolong hospitalization and are
associated with adverse neurodevelopmental outcomes. Breaches in skin integrity (through the use of central
lines and venous/capillary sampling) are likely a major contributor to this increased risk of infection in hos-
pitalized newborn infants. The application of topical emollients (e.g., sunflower seed oil) can improve skin
integrity (thereby decreasing insensible water losses) and may also be a useful strategy to decrease the risk
of nosocomial infections in selected high-risk populations.
The first edition of Neonatal Dermatology was a remarkable achievement and brought the subspecialty
of neonatal dermatology into the modern era. The second edition comprehensively addresses the questions
of practicing neonatologists and pediatricians as well as pediatric subspecialists. For example, the addition
of algorithms to aid in differential diagnosis and new chapters on topics such as Diaper Dermatitis will cer-
tainly be of great interest to practitioners, while the additional basic science information and new chapters
on Erythrodermas, Immunodeficiency, and Metabolic Disorders will be welcomed by pediatric-subspecialists
(geneticists, neurologists, hematologists, oncologists and dermatologists). The extensive number of detailed
photographs has been increased by thirty percent. Furthermore, the up-to-date references and the clarity of
prose that characterized the last edition have been retained. This textbook represents an extraordinary
accomplishment for Drs Eichenfield, Frieden and Esterly, and they should be congratulated.

By Richard A. Polin MD
Professor of Pediatrics
Columbia-Babies & Childrens Hospital
New York
USA

vii

FM-X3432.indd vii 11/26/2007 10:41:49 AM

 Preface
Seven years have passed since the publication of the first edition of this textbook. For Nan, this book reflects
a lifelong interest in the newborn skin and the joys and challenges of teaching. For Larry and Ilona it was a
tremendous opportunity to work with our co-editor Nancy Esterly. We thank her for her inspiration in
helping us create this book, and for holding the bar for academic rigor high in pediatric dermatology, a field
which she helped to create as the ‘mother of pediatric dermatology’ and editor par excellence.
While no book is perfect, we have been gratified by the success of the first edition, both in its brisk sales
and, more importantly, in its use as an authoritative reference. In our own busy clinical practices we have
turned to the textbook again and again as we try to diagnose or think about management of infants and
newborns with skin diseases. For us, the first edition truly passed the ‘use test,’ as attested to by the frayed
copies in our offices and clinics.
For this second edition, we faced an important question: how could we make it better, and even more
useful? The first and most obvious way was to add more high-quality photographs of both common and
uncommon conditions. We have increased our photo number by 212. We have also added several new
chapters. ‘Diaper Area Eruptions’ highlights, with both illustrations and text, the multitude of conditions
which can present in this anatomic area. A chapter on ‘Epidermolysis Bullosa’ emphasizes the diagnosis and
management of this group of genetic diseases, which pose tremendous management challenges in affected
newborns. All chapters in the book have been updated and several chapters, including ‘Vascular Birthmarks’
and ‘Selected Genetic Disorders,’ have been extensively revised, since these are subjects where knowledge is
rapidly changing.
Although the text title is Neonatal Dermatology, this scope of the book’s content goes beyond the neonatal
period well into infancy. As a direct result of our commitment to this, we have devoted an entire chapter to
‘Eczematous Disorders’, with a particular emphasis on atopic dermatitis, which can begin in the neonatal
period but becomes increasingly common and significant soon afterwards.
As in the first edition, we were blessed to have had help from many generous colleagues from all over the
world, who contributed their time and expertise to make this second edition even better than the first. We
thank them for their great efforts in helping this book live up to its potential as a day-to-day resource for
evaluating infants and newborns. We also thank the tremendously supportive colleagues, medical staff and
administrative support teams in our workplaces, and our patients who continue to inspire us.

LFE
IJF
NBE

ix

FM-X3432.indd ix 11/26/2007 10:41:49 AM

 List of Contributors
Richard J. Antaya MD Yuin-Chew Chan MD Sheila Fallon Friedlander MD
Associate Professor of Dermatology Consultant Dermatologist and Chief Director, Fellowship Training Program
and Pediatrics Paediatric Dermatology Unit Pediatric & Adolescent Dermatology
Director, Pediatric Dermatology National Skin Centre Rady Children’s Hospital, San Diego
Yale University School of Medicine Singapore Professor of Pediatrics & Medicine
New Haven, CT (Dermatology)
USA David H. Chu MD PhD University of California, San Diego School
Howard Hughes Medical Institute of Medicine
Eulalia Baselga MD The Rockefeller University; San Diego, CA
Pediatric Dermatologist The Ronald O. Perelman Department of USA
Hospital de la Santa Creu i. Saint Pau Dermatology
Barcelona, Spain New York University School of Medicine Sheila S. Galbraith MD
Consultant Pediatric Dermatologist New York, NY Assistant Professor of Dermatology
Department of Dermatology USA Department of Dermatology
Institut Universitari Dexeus Medical College of Wisconsin
Barcelona, Spain Bernard A. Cohen MD Milwaukee, WI
Laurie A. Bernard MD Professor of Pediatrics and Dermatology USA
Assistant Clinical Professor of Pediatrics, Division of Pediatric Dermatology
UCSD School of Medicine Johns Hopkins University School of Medicine Maria C. Garzon MD
Pediatric Hospitalist, Rady Children’s Baltimore, MD Associate Professor of Clinical Dermatology
Hospital San Diego USA and Clinical Pediatrics, Columbia
Department of Pediatrics University, NY
San Diego, CA Bari B. Cunningham MD Director, Pediatric Dermatology,
USA Director, Dermatologic Surgery Morgan Stanley Children’s Hospital of
Pediatric & Adolescent Dermatology NY Presbyterian
John S. Bradley MD Rady Children’s Hospital, San Diego New York, NY
Director, Division of Infectious Disease Associate Professor of Pediatrics & Medicine USA
Rady Children’s Hospital, San Diego (Dermatology), University of California, San
San Diego, CA Diego School of Medicine Neil F. Gibbs MD
USA San Diego, CA Assistant Clinical Professor of Pediatrics and
USA Medicine (Dermatology)
Alanna F. Bree MD University of California, San Diego School of
Assistant Professor of Dermatology and Medicine;
James G.H. Dinulos MD
Pediatrics Assistant Clinical Professor
Associate Professor of Medicine and
Department of Dermatology and Pediatrics Department of Dermatology
Pediatrics (Dermatology)
Baylor College of Medicine Uniformed Services University of the Health
Section of Dermatology
Texas Children’s Hospital Sciences School of Medicine
Dartmouth-Hitchcock Medical Center
Houston, TX Bethesda, MD;
Lebanon, NH
USA San Diego, CA
USA
Anna L. Bruckner MD USA
Assistant Professor of Dermatology and Beth A. Drolet MD
Amy E. Gilliam MD
Pediatrics Professor of Dermatology and Pediatrics
Assistant Clinical Professor of Dermatology
Stanford University School of Medicine Medical College of Wisconsin
and Pediatrics
Director, Pediatric Dermatology Medical Director of Dermatology and
Department of Dermatology and Pediatrics
Lucile Packard Children’s Hospital Birthmarks and Vascular Anormales
University of California, San Francisco
Stanford, CA Children’s Hospital of Wisconsin
San Francisco, CA
USA Milwaukee, WI
USA
USA
Craig N. Burkhart MD
Pediatric Dermatology Fellow Adelaide A. Hebert MD
Odile Enjolras MD Professor of Dermatology and Pediatrics
Department of Pediatric Dermatology Director, Consultation des Angiomes
Children’s Memorial Hospital Department of Dermatology
Hôpital d’enfants Armand Trousseau University of Texas Medical School
Chicago, IL Paris
USA Houston, TX
France USA
K. Robin Carder MD
Clinical Assistant Professor of Dermatology
University of Texas, Southwestern Medical
Center at Dallas
Pediatric Dermatology of Dallas xi
Dallas, TX
USA

FM-X3432.indd xi 11/26/2007 10:41:49 AM

 List of Contributors

Paul J. Honig MD Cynthia A. Loomis MD PhD Amy S. Paller MD

Attending Physician, Pediatric Dermatology Assistant Professor of Pathology and Professor and Chair, Department of
Professor Emeritus, Pediatrics and Dermatology Dermatology
Dermatology NYU School of Medicine Professor, Department of Pediatrics
Children’s Hospital of Philadelphia New York, NY Northwestern University
University of Pennsylvania School of USA Chicago, IL
Medicine USA
Philadelphia, PA Anne W. Lucky MD
USA Acting Director Julie S. Prendiville MB MRCPI FRCPC
Division of Pediatric Dermatology Clinical Professor
Renee J. Howard MD The Cincinnati Children’s Hospital Department of Pediatrics
Assistant Clinical Professor of Dermatology Volunteer Professor of Dermatology and University of British Columbia
University of California, San Francisco Pediatrics Head, Division of Pediatric Dermatology
San Francisco, CA The University of Cincinnati College of British Columbia’s Children’s Hospital
USA Medicine Vancouver, BC
Cincinnati, Ohio Canada
Alan D. Irvine MD FRCPI MRCP Dermatology Research Associates, Inc.
Associate Professor Department of Clinical Cincinnati, OH Neil S. Prose MD
Medicine Trinity College Dublin; USA Professor of Dermatology and Pediatrics
Consultant Paediatric Dermatologist Duke University Medical Center
Our Lady’s Hospital for Sick Children Hanspaul S. Makkar MD FRCP(C) Durham, NC
Crumlin Assistant Professor of Dermatology, USA
Dublin Pediatrics and Surgery
Ireland University of Connecticut School of Medicine Maureen Rogers MBBS FACD
Farmington, CT Emeritus Consultant Dermatologist
Ho Jin Kim MD USA Department of Dermatology
Dermatologist and Pediatric Dermatologist The Children’s Hospital at Westmead
McLean, VA Anthony J. Mancini, MD Sydney
USA Associate Professor of Pediatrics & Australia
Dermatology
Liborka Kos, MD Northwestern University Feinberg School of Dawn Siegel MD
Assistant Clinical Professor of Dermatology Medicine Assistant Professor of Dermatology and
Department of Dermatology Head, Division of Pediatric Dermatology Pediatrics
Medical College of Wisconsin Children’s Memorial Hospital Oregon Health and Sciences University
Milwaukee, WI Chicago, IL Portland, OR
USA USA USA
Tamara Koss MD Denise W. Metry MD Elaine C. Siegfried MD
Instructor in Clinical Dermatology Associate Professor Dermatology and Professor of Pediatrics and Dermatology
Department of Dermatology Pediatrics Department of Pediatrics
Columbia University Texas Children’s Hospital Saint Louis University Medical School
New York, NY Baylor College of Medicine St. Louis, MO
USA Houston, TX USA
USA
Bernice R. Krafchik MBChB FRCPC Robert A. Silverman MD
Professor Emeritus Brandie J. Metz MD Clinical Associate Professor of Pediatrics
Departments of Pediatrics and Medicine Assistant Professor of Dermatology and Georgetown University, Washington, DC;
University of Toronto Pediatrics INOVA Fairfax Hospital for Children
Toronto, ON Departments of Dermatology and Pediatrics University of Virginia, Charlottesville
Canada University of California, Irvine Fairfax, VA
Irvine, CA USA
Alfons L. Krol MD FRCPC USA
Professor of Dermatology and Pediatrics Yong-Kwang Tay MD
Department of Dermatology Dean S. Morrell MD Head and Senior Consultant Dermatologist
Oregon Health and Science University Associate Professor Department of Dermatology
Director, Pediatric Dermatology, Doernbecher Director of Pediatric and Adolescent Changi General Hospital
Children’s Hospital Dermatology Singapore
Portland, OR UNC Department of Dermatology
USA Chapel Hill, NC Antonio Torrelo MD
USA Pediatric Dermatologist
Leslie P. Lawley MD Director, Department of Dermatology
Assistant Professor of Pediatrics and Nicole C. Pace MD Hospital Infantil del Niño Jesús
Dermatology Instructor of Medicine and Pediatrics Madrid
Emory University School of Medicine (Dermatology) Spain
Atlanta, GA Section of Dermatology
USA Dartmouth-Hitchcock Medical Center Annette M. Wagner MD
Lebanon, NH Assistant Professor of Pediatrics and
Moise L. Levy MD USA Dermatology
Professor, Departments of Pediatrics and Northwestern University Medical School
Dermatology Specialist in Pediatric Dermatologic Surgery
Baylor College of Medicine and Lasers
Dermatology, Chief of Service Children’s Memorial Hospital
xii Texas Children’s Hospital Chicago, IL
Houston, TX USA
USA

FM-X3432.indd xii 11/26/2007 10:41:49 AM

 List of Contributors

Mary L. Williams MD Li-Chuen Wong MD Albert C. Yan MD

Adjunct Professor of Dermatology and Consultant Dermatologist Section Chief, Pediatric Dermatology
Pediatrics Department of Dermatology Assistant Professor, Pediatrics and
Department of Dermatology The Children’s Hospital at Westmead Dermatology
University of California, San Francisco Sydney Children’s Hospital of Philadelphia
San Francisco, CA Australia University of Pennsylvania School of
USA Medicine
Philadelphia, PA
USA

xiii

FM-X3432.indd xiii 11/26/2007 10:41:49 AM

 1
Fetal Skin Development
Cynthia A. Loomis, Tamara Koss, David Chu

Skin is a complex tissue made up of many different cell types, functional evolution of these skin components so that they
derived from both embryonic mesoderm and ectoderm. Skin provide adequate thermoregulatory capacity, surface tensile
cells originating from embryonic mesoderm include fibro- strength, and barrier function for postnatal survival in the
blasts, vascular cells, and adipocytes, as well as the bone harsh, arid environment outside the uterus.
marrow-derived Langerhans’ cells, which reside in the epider-
mis. Skin cells originating from embryonic ectoderm include
epidermal keratinocytes and the neural crest-derived melano-
EPIDERMIS
cytes. Development, growth, and regional patterning of the
skin are regulated by sequential and tightly regulated inductive
Overview
interactions between these various cell types within the skin, The epidermis is a self-renewing stratified epithelium that
as well as between skin and adjacent nonskin tissues. Genetic covers the entire surface of an individual. The predominant
or teratogenic disruptions in these regulatory interactions cell within this epithelium is the keratinocyte. In its mature
result in serious congenital anomalies that can directly affect form, the epidermis consists of four histologically distinct
the care of the infant. Moreover, premature birth before full keratinocyte layers, described from deep to superficial: the
maturation of the skin can lead to impaired thermoregulation basal layer, the spinous layers, the granular layer, and the
and defective barrier function in the neonate. stratum corneum. The proliferative basal keratinocytes are
A timeline highlighting several important morphologic anchored to the basement membrane, an extracellular mesh-
events that occur during skin morphogenesis is illustrated in work separating the epidermis from the underlying dermis. As
Figure 1-1. In this figure, and throughout the text, two distinct the daughter cells produced by this layer differentiate, they
dating systems are indicated. We use the term estimated down-regulate the synthesis of matrix adhesion proteins,
gestational age (EGA), as it is used in basic embryology texts detach from the basement membrane, and move outward into
and by researchers, to refer to the age of the fetus.1 In this the spinous layers. In this zone, the keratinocytes expend
system, fertilization occurs on day 1. However, the dating much of their energy in the production of keratin intermediate
system used by obstetricians and most other clinicians as a filaments. These rigid rods insert into the numerous desmo-
reliable and convenient method for staging the pregnancy somal adhesion junctions and through these interconnections
defines day 1 as the first day of the last menstrual period (LMP) provide tensile strength and mechanical integrity for the epi-
and is synonymous with menstrual age.2 In this dating system, dermis.4 On further differentiation, keratinocytes accumulate
fertilization occurs on approximately day 14. Thus a woman large protein and lipid granules, structures that define the
who is 14 weeks pregnant (LMP) is carrying a 12-week-old most superficial viable layer, the granular layer. As the cells
fetus (EGA). undergo terminal differentiation, moving from the granular
From a functional point of view, fetal skin development can layer into the stratum corneum, several biochemical events
be divided into three temporally overlapping stages – organo- occur simultaneously, including (1) cell enucleation, (2) the
genesis, histogenesis, and maturation3 – that correspond aggregation of keratin filaments by the protein filaggrin, (3)
roughly to the embryonic period (0–60-plus days), the early transglutaminase-mediated protein cross-linking to form an
fetal period (60 days to 5 months), and the late fetal period insoluble cornified envelope, and (4) lamellar granule extru-
(5–9 months) of development. The first stage, organogenesis, sion of lipid sheets to form the water-impermeable mortar
involves the specification of ectoderm lateral to the neural surrounding the cornified envelopes.
plate to become epidermis and the allocation of subsets of Keratinocytes are not the only cells present within the epi-
mesenchymal and neural crest cells to become dermis. During dermis, however. Melanocytes are pigment-producing cells
this stage, embryonic ectoderm and mesoderm become physi- interspersed among the basal keratinocytes.5 Transport of
cally apposed, and they initiate the signaling cross-talk neces- their pigment-containing melanosomes to nearby keratino-
sary for basement membrane and subsequent skin appendage cytes provides protection from the mutagenic effects of ultra-
(hair, nail, and sweat gland) formation. The second stage, violet irradiation. Langerhans’ cells are antigen-presenting
histogenesis, is characterized by dramatic morphologic changes cells located primarily within the suprabasal epidermal layers,
in the presumptive skin, including epidermal stratification, and they act as immunologic sentinels responding to the inva-
epidermal appendage involution and differentiation, mesen- sion of skin pathogens. Merkel cells are specialized neuro-
chymal subdivision of the dermis and hypodermis, and vas- endocrine cells that are important in mechanoreception. Both
cular neogenesis. The third stage, maturation, entails the Langerhans’ cells and melanocytes migrate into the epidermis 1

Ch001-X3432.indd 1 11/26/2007 10:42:41 AM

 FETAL SKIN DEVELOPMENT

Clinical timing Fetal age Epidermal Dermal-subcutis Appendageal

of pregnancy development development development

wks LMP wks EGA

6 4
Periderm
Basal layer Tooth primordia
Organogenesis Periderm Nail primordia
CVS
10 8 Histogenesis Intermediate layer Dermal-subcut Volar eccrine gland primordia
Basal layer boundary distinct Hair follicle/sebaceous
gland primordia
14 12 Melanocytes
Langerhan s cells
Merkel cells
Amino- Papillary and reticular
centesis dermal boundry
18 16
distinct
Second trimester

Skin Follicular keratinization

biopsy
22 20 Dermal ridges
Trunk eccrine
gland primordia

Periderm sloughs
26 24 Stratum corneum
Interfolliculer
Maturation

Granular layer
Spinous layers keratinization
Basal layer
30 28

34 32

38 36

42 40 Birth

3 weeks
postnatal age

FIG. 1-1 Critical events in the development of skin and its specialized structures, indicating their times of initiation as defined by fetal age (EGA)
and duration of pregnancy (LMP). Unless otherwise stated, times refer to the skin of the back.

during embryonic development, whereas Merkel cells appear membrane.8–10 The periderm layer is a transient embryonic
to be derived from a pluripotent keratinocyte. layer that does not participate in the production of definitive
epidermal progenitors, and the presumptive epidermis at these
early stages is not considered a true stratified epithelium.
Embryonic Development The basal cells of the embryonic epidermis display morpho-
During the third week after fertilization the human embryo logic and biochemical features similar – but not identical – to
undergoes gastrulation, a complex process of involution and basal cells of later developmental stages. Embryonic basal cells
cell redistribution that generates the three primary embryonic are slightly more columnar than later fetal basal cells and lack
germ layers: endoderm, mesoderm, and ectoderm.1 Shortly the morphologically distinct matrix adhesion structures called
after gastrulation, the ectoderm is further subdivided into neu- hemidesmosomes.11,12 Matrix adhesion of the early embryonic
roectoderm, a medial strip parallel to the long axis of the epidermis is probably mediated largely by the actin-associated
developing embryo, and presumptive epidermis on either side α6β4 integrin, as suggested by expression and genetic studies
of this strip. The early presumptive epidermis is a loosely in mice and humans.12–15
associated single cell layer.6,7 By 6 weeks’ EGA (8 weeks LMP), Intercellular attachment between individual basal cells at
the earliest point in time that human embryos are generally this stage appears to be mediated by classic cadherin adhesion
available for study, the surface ectoderm covering most regions molecules, such as E- and P-cadherin, as well as by a few des-
of the body already consists of basal cells and more superficial mosomal junctions. E- and P-cadherin have both been detected
2 periderm cells (Fig. 1-2), which are not attached to basement on basal cell membranes as early as 6 weeks’ EGA, whereas

Ch001-X3432.indd 2 11/26/2007 10:42:41 AM

 Epidermis

C D

FIG. 1-2 Epidermal morphogenesis. A At 36 days the epidermis consists only of a basal layer and a superficial periderm layer. B By 72 days
a well-formed intermediate layer is present between the basal and periderm layers. By the end of the second trimester, there are several
intermediate cell layers and the stratified epidermis begins to keratinize. C In neonatal skin, a distinct granular layer and stratum corneum
are present. Hair follicles first begin to bud down in the dermis between 75 and 80 days. D An early bulbous hair peg-stage follicle from a
mid-second trimester fetus. (Photomicrographs courtesy Dr Karen Holbrook.)

E-cadherin alone is expressed on the early periderm.16 Cyto- hemopoietic production has shifted to the bone marrow. This
plasmic filaments in the basal cells include both actin micro- marks the classic division between embryonic and fetal devel-
filaments and the less abundant keratin intermediate filaments, opment, and it corresponds to the timing of definitive epider-
which even at these early stages are composed of K5 and K14 mal stratification and the formation of the third ‘intermediate’
keratins, proteins generally restricted to definitive stratified layer between the two pre-existing cell layers (Fig. 1-2).
epithelia.17–19 Mouse studies indicate that p63, a protein closely related to
Periderm cells of the embryonic epidermis are larger and the tumor suppressor gene p53, plays a critical role in directing
flatter than the underlying basal cells. As such, periderm cells the simple-to-stratified epithelial transition.27 Cells in the
have been termed a pavement epithelium.8,20 Apical surfaces intermediate layer of the early fetal epidermis express the
in contact with the amniotic fluid are studded with microvilli. K1/10 skin differentiation-type keratin markers, as well as
Their lateral surfaces in contact with adjacent peridermal cells the desmosomal protein desmoglein 3, which is also known
are sealed with tight junctions, possibly precluding passive – as the pemphigus vulgaris antigen.28,29 Moreover, intermediate
but not active – diffusion of fluids across this outer layer of filaments and desmosomal junctions are more abundant in
the embryo.10 Periderm cells, like the embryonic basal cells, this layer than in the basal or periderm layers. In contrast to
express the stratified epithelial keratins K5 and K14, but also the spinous cells of the mature nonwounded epidermis, cells
express simple epithelial keratins K8, K18, and K19.21–24 within the intermediate layer remain highly proliferative.30,31
Towards the end of the second trimester these superficial cells Over the next several weeks more layers are gradually added
are eventually sloughed and become a component of the vernix to this intermediate zone of the developing epidermis, such
caseosa covering the newborn.25 At this stage of fetal develop- that by 22–24 weeks’ EGA the epidermis contains four to five
ment, the maturing epidermis begins to form its own barrier layers in addition to the degenerating periderm.
to the external environment.26 After the onset of stratification, the basal layer also displays
characteristic morphologic and biochemical changes. Basal
cells become more cuboidal and begin to synthesize other
Early Fetal Development keratin peptides, including K6, K8, K19, and the K6/K16
By the end of 8 weeks’ gestation (10 weeks LMP), the basic hyperproliferative pair.25,26 This latter keratin pair is not nor-
components of most organ systems have been laid down and mally expressed in mature interfollicular epidermis but is up- 3

Ch001-X3432.indd 3 11/26/2007 10:42:41 AM

 FETAL SKIN DEVELOPMENT

regulated in response to wounding and hyperproliferative

conditions.32 During early fetal development, the basal cell
Clinical Relevance
layer also begins to express the hemidesmosomal proteins Gross defects in early epidermal specification and organogen-
BPA1 and BPA2, and to secrete collagen types V and VII, the esis are rarely observed in the neonate, probably because they
latter being the major component of the anchoring fibrils of are incompatible with fetal survival. Using mice as an animal
the dermis.28,33–35 DNA-labeling studies indicate that by 80–90 model system, researchers demonstrated that obliteration of
days’ EGA a distinct subset of slow-cycling cells exists within p63 gene function precludes the formation of most multilay-
the basal cell population, suggesting that an epidermal stem ered epithelia in the body, leading to perinatal lethality due to
cell population has already been set aside at these early loss of skin barrier function (Table 1-1). Humans who have
stages.30 been found to carry mutations in this gene still retain some
functionality and therefore display less severe alterations in
their epidermis and appendages (see below).
Late Fetal Development Unlike defects in early epidermal organogenesis, congenital
Maturation of the epidermis during late fetal development is defects in epidermal maturation are not uncommon as they
characterized by the generation of granular and stratum corneal do not usually impinge on in utero survival. Lamellar ichthyo-
layers, the formation of a water-impermeable barrier, and the sis is usually inherited in an autosomal recessive manner and
sloughing of the periderm. Keratinization, which is the type of in 30% of patients is caused by mutations in the gene encoding
terminal differentiation mediated by granular layer and stratum epidermal transglutaminase,41–44 the enzyme that cross-links
corneum formation, is initiated first in the skin appendages submembranous proteins to form the insoluble cornified enve-
between 11 and 15 weeks’ EGA, and only begins to involve lope of the stratum corneum. In its absence, large dark polygo-
the interfollicular epidermis from about 22–24 weeks’ EGA.25 nal scales form over the entire body, and at birth the infant
Initiation of keratinization is characterized morphologically by may be transiently wrapped in a waxy, collodion-like mem-
the marked increase in cytoplasmic density of the superficial brane.45 A similar clinical presentation can be seen in patients
keratinocytes and the precursor of the keratin-aggregating homozygous for mutations in the ABCA12 gene, which encodes
protein filaggrin. The early granular layer continues to mature an ATP-binding cassette thought to be important for lipid
with the formation of more granules. More superficial layers trafficking across keratinocyte membranes. Infants with the
arise that undergo incomplete terminal differentiation, result- more severe ‘harlequin ichthyosis’ are born encased in armor-
ing in the formation of transglutaminase-mediated cross- like plates of thickened, adherent stratum corneum,46–49 and
linked envelopes that still encase remnant organelles. At this extreme variant also appears to be due to mutations in
slightly later stages the terminal differentiation is more com- the ABCA12 gene. Additional disorders associated with
plete, resulting in the complete absence of organelles in kera- impaired epidermal maturation and the relevant genes are
tinized cells of the stratum corneum. During the third trimester listed in Table 1-2.
the cornified cell layers increase in number, aiding in the for- In contrast to the permanent manifestations of genetic
mation of a barrier. Although the third-trimester stratum defects, the inadequate epidermal keratinization and matura-
corneum is structurally similar to that of the adult, functional tion of the premature epidermis are transient. Immaturity of
studies indicate that it is much less effective at prevent- the stratum corneum, especially in infants born before 28
ing water loss and is less permeable to exogenous weeks’ EGA (30 weeks LMP), places these neonates at increased
compounds.36–40 risk for dehydration, excessive penetration of topical drugs or

TABLE 1-1 Specification/patterning/morphogenesis

EPIDERMIS DERMIS
Protein/GENE Disorder Protein/GENE Disorder
p63 AEC Lmx1b Nail-Patella syn
Appendages LaminA, Restrictive Dermopathy
SMPSTE24
Protein/GENE Disorder LaminA Lipodystrophy, partial, 2
Lmx1b Nail Patella syn PPARG Lipodystrophy, partial 3
EDA X-linked hypohidrotic ED AcetylcholineR Multiple pterygium syn’s
(fetal subunit)
EDAR Autosomal hypohidrotic PTPN11, KRAS, Noonan syn
ED, Ty3 NF1
Connexin 30 Autosomal hydrotic ED, GNAS1 Progressive osseus
Ty2 heteroplasia
p63 Hay-Wells, AEC, EEC syn’s GNAS1 Albright hereditary
osteodystrophy
Msx1 Wtkop syn
Dlx3 Tichodento-osseous syn

4 ED, ectodermal dysplasia; syn, syndrome

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Ch001-X3432.indd 5

TABLE 1-2 Differentiation

EPIDERMIS DERMIS Appendages
Protein/GENE Disorder Protein/GENE Disorder Protein/GENE Disorder
Structural proteins Structural proteins Structural proteins
K1, K10 BCIE Collagen VII Dystrophic EB Plakoglobin Naxos Dz
K1, K9 Vorner, Unna-Thost, Col1a1 or 1a2 Osteogenesis Plakophilin Skin fargility syndrome
Greither keratinopathies imperfecta, I, II, IV
K5, K14 EB simplex Col5A1, Col5A2 Ehlers-Danlos, I Desmoplakin skin fragility–woolly hair syndrome
ATP2A2 (Ca-ATPase) Darier White Dz Col5A1, Col5A2, Ehlers-Danlos, II Claudin 1 Ichthyosis-Sclerosing cholangitis
Col1A2 (alopecia) syn
ATP2C1 (Ca-ATPase) Hailey-Hailey Dz Col3A1, tenascin-XB Ehlers-Danlos, III K6a, K16 Pachyonychia congenita, Type I
Connexin 26 GJB2 KID syn Col3A1 Ehlers-Danlos, IV K6b, K17 Pachyonychia congenita, Type II
Claudin 1 Ichthyosis-Sclerosing FBN1 (fibrillin) Marfan syn K6b, K18 Steatocystoma multiplex
cholangitis syn
Loricrin NBCIE, Vohwinkel syn’s FBLN5, FBLN4 Cutis laxa, AR Type I KRTHB1, B3, B6 Monilethrix
Plectin EB with MD ELN (Elastin) Cutis laxa RMRP mitochondrial RNA cartilage-hair hypoplasia
BPAG2 GABEB
a6B4 integrin Junctional EB with PA
Laminin5 Junctional EB
Processing proteins Processing or regulatory proteins Regulatory proteins
LEKTI Netherton syn Iysyl hydroxylase Ehlers-Danlos, VI Hairless Papular atrichia
Transglutaminase 1 Lamellar ichthyosis 1; ADAMTS2 Ehlers-Danlos, VII WHN T-cell immunodeficiency
NCIE alopecia, nail dystrophy
ATP-binding casette Lamellar ichthyosis 2 Cu-transporting Ehlers-Danlos, IX
A12 ATPase, apha pep (Cutix laxa, X-linked)
NAD(P)H steroid CHILD syn sterol isomerase Chondrodysplassia
dehydrogenase-like emopamil-binding punctata, X2
protein, NSDHL protein (EBP)
Fatty aldehyde Sjogren-Larsson HRAS Costello syn
dehydrogenase
Steroidsulfatase/ X-linked ichthyosis MRP6 PXE
arylsufatase C
Transglutaminase 5 Acral peeling skin GNAS1 Osseous Heteroplasia,
syndrome progressive
spremidine/spermine Keratosis follicularis Col1A1fused to DFSP
N(1)-acetyltransferase spinulosa decalvans PDGFB
Phytanoyl CoA Refsum

Epidermis
hydroxylase
11/26/2007 10:42:42 AM

Irf6 (transcription Polpoteal pterygium syn;

factor) Wan der Woude syn
5
 FETAL SKIN DEVELOPMENT

other chemicals, and infection from organisms newly coloniz- or dendritic, and are found at particularly high densities in
ing the skin36–40,50 (see Chapters 4 and 5). In general, even volar skin. They are frequently associated with epidermal
full-term newborns display a somewhat reduced barrier func- appendageal structures and are occasionally detected within
tion, and continued maturation occurs over the first few weeks the dermis. Their distinguishing morphologic and immuno-
of life, such that by 3 weeks of age, the newborn’s stratum histochemical features are cytoplasmic dense-core granules,
corneum is structurally and functionally equivalent to that of keratin 18, and neuropeptide expression, which can be detected
the adult; maturation is accelerated in the premature infant, as early as 8–12 weeks’ EGA in palmoplantar epidermis and
although the duration may be longer in extremely premature at slightly later times in interfollicular skin.17,64 Recent keratin
infants.38,51 expression data, as well as transplant studies, suggest that
Merkel cells are derived from pluripotent keratinocytes, rather
than neural progenitors such as neural crest, but the results
are not conclusive.64–67
Specialized Cells Within the Epidermis
Two major immigrant cells – melanocytes and Langerhans’
cells – populate the epidermis during early embryonic develop-
Clinical Relevance
ment. Melanocytes are derived from a subset of neuroectoderm Many clinical defects are known to affect normal pigmentation
cells, the neural crest, which forms along the dorsal neural within an individual (Table 1-3). Defects in melanoblast migra-
tube and gives rise to a variety of cell types, including many tion, proliferation, and/or survival occur in several clinical syn-
tissues of the face and peripheral autonomic neurons.52 Neural dromes, and many of the genetic mutations responsible for
crest cells destined to become melanocytes migrate away from these defects have been identified. Failure of an adequate
the neural tube within the mesenchyme subjacent to the pre- number of melanoblasts to completely supply distal points on
sumptive epidermis. They migrate as semicoherent clones their embryonic migration path occurs in the different types of
laterally and then ventrally around the trunk to the thoraco- Waardenburg syndrome, as well as in piebaldism, resulting in
abdominal midline, anteriorly over the scalp and face, and depigmented patches on the central forehead, central abdomen,
distally along the extremities. Postnatally, the embryonic and extremities. These defects are associated with mutations
paths taken by these partially coherent clones can be readily in several different genes, including genes encoding transcrip-
visualized in patients with banded pigmentary dyscrasias tion factors, such as Pax3 and MITF, as well as membrane
following Blaschko’s lines, such as the disorders classified as receptors and their ligands, such as endothelin 3, endothelin-
hypomelanosis of Ito, and linear and whorled hypermelanosis receptor B, and c-kit.68–78 In albinism, on the other hand, mela-
(see Chapters 21 and 22).53,54 nocyte development is normal, but production of pigment or
The melanocytes can be first detected within the epidermis melanin is inadequate. The most severe form of oculocutane-
of the human embryo at approximately 50 days’ EGA, based ous albinism results from null mutations in the gene encoding
on their dendritic morphology and their specific immunoreac- tyrosinase, the rate-limiting enzyme in the production of
tivity.55 Even at these early developmental time points the melanin. Less severe forms of albinism are caused by mutations
density of melanocytes is quite high (1000 cells/mm2).56 The in tyrosinase alleles, which lead to partial loss of function, as
density increases further around the time of epidermal strati- well as by mutations in other genes encoding proteins impor-
fication (80–90 days’ EGA) and initiation of appendageal tant in melanin assembly in melanosomes or transport.5
development. Between 3 and 4 months EGA, depending on
body site and the race of the fetus, melanin (visible pigment)
production becomes detectable, and by 5 months melanocytes
DERMIS AND SUBCUTIS
begin transferring melanosomes to the keratinocytes, a process
that will continue after birth.57–59 Although all melanocytes are
Overview
in place at birth and melanogenesis is well under way, the skin The mature dermis is characterized by complex interwoven
of the newborn infant is not fully pigmented and will continue collagen and elastic fibers enmeshed in a proteoglycan matrix.
to darken over the first several months. This is most apparent Fibroblasts, mast cells, and macrophages are scattered through-
in individuals with darker skin tones. out this mesh, and nerve fibers and vascular networks course
Langerhans’ cells, the other major immigrant population, through it, dividing it into distinct domains. In contrast, the
are detectable within the epidermis by 40 days’ EGA.60 Similar embryonic dermis is quite cellular and amorphous, lacking
to melanocytes, the early embryonic Langerhans’ cells do not organized extracellular fibers. Embryonic mesenchymal cells
yet possess the specialized organelles characteristic of mature capable of differentiating into a wide variety of cell types are
cells, but can be distinguished from other epidermal cells by embedded in a highly hydrated gel, rich in hyaluronic acid.
their dendritic morphology, immunopositive reaction for the Moreover, only a few nerve fibers have reached this peripheral
HLA-DR surface antigen, and high levels of ATPase activity. location, and vessels have not evolved into their mature pat-
After the transition from embryo to fetus they begin to express terns. During the course of fetal development, this so-called
the CD1 antigen on their surface and to produce characteristic cellular dermis, which is conducive to cell migration and tissue
granules of mature Langerhans’ cells.60,61 Although the extent remodeling, is transformed into the fibrillar dermis of the
of dendritic processes from individual Langerhans’ cells in- adult, which provides increased strength, resilience, and struc-
creases during the second trimester, the total number of cells tural support.79
remains low and only increases to typical adult numbers in
the third trimester.62,63
Another distinct subset of cells within the basal cell layer
Embryonic Dermal Development
are Merkel cells, which are highly innervated neuroendocrine The specification and allocation of dermal mesenchymal cells
6 cells involved in mechanoreception. Merkel cells can be round are rather complex and not well understood. The cell of origin

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 Dermis and Subcutis

TABLE 1-3 Development and tumor overlaps

Dermis Epidermis/Appendages
Protein/GENE Disorder Protein/GENE Disorder
PTEN Proteus S PTEN Cowden syn
Fumarate hydratase Hereditary Mult MSH2, MLH1 Muir-Torre syndrome
leiomyoma (mismatch repr) (sebaceous tumors)
B-catenin/APC desmoid tumors B-catenin (Wnt?) pilomatricomas
GNAS McCune Albright APC Adenomatous polyposis of the
syndrome colon
PKA reg subunit-1-alpha Carney; Name, LAMB Ptch/Shh Gorlin syn (palmar pits/BCCs)
TSC1, 2, 3, 4 Tuberous sclerosis
Merlin/Neurofibromin 2/NF2 Neurofibromatosis I STK11 (ser-thr kinase) Peutz-Jeghers syndrome
NF2 (merlin) Neurofibromatosis II FLCN (folliculin) Birt-Hogg-Dube syndrome
glomulin Glomuvenous
Malformations
Col1A1fused to PDGFB DFSP

for the presumptive dermis depends on its anatomic location. associated microfibrils of the adult, can be detected at earlier
The dermis of the face is derived from neural crest cells; that stages.3 By the end of gestation the dermis is thick and well
of the dorsal trunk is derived from the dermatomyotome organized, but is still much thinner than in the adult and has
portion of the differentiated somite; and the dermis of the a higher water content, reminiscent of the fetal dermis. Matu-
limbs is derived from the lateral plate (somatic) mesoderm.79–81 ration of the dermis is marked by increasing tensile strength
Regional patterning of the skin and differences in the type and and the transition from a nonscarring to a scarring response
quality of the epidermal appendages produced in the older after wounding. Thus fetal skin biopsies tend to heal with little
fetus might in part reflect these early differences in dermal cell evidence of the surgical event. This has obvious clinical impli-
precursors. In addition, signaling from adjacent tissues plays cations, and the molecular controls critical for nonscarring
a critical role.82,83 fetal wound healing are an area of active research by many
By 6–8 weeks’ EGA the presumptive dermal cells already groups.88–90
underlie the epidermis. However, there is as yet no sharp
demarcation between cells giving rise to skin dermis and those
giving rise to musculoskeletal elements. Electron microscopic
Clinical Relevance
(EM) studies of the presumptive dermis at these stages dem- Congenital defects in the specification and development of the
onstrate fine filaments, but rarely fibers.84 Although most dermis are probably incompatible with survival to term,
protein components of collagen fibers and some microfibrillar although there are a few exceptions (see Tables 1-1 and 1-2).
components of elastin fibers (fibrillin) are synthesized by the Infants with restrictive dermopathy disorder, which is charac-
embryonic dermal cells, the proteins are not yet assembled terized by a thin, flat dermis, lack of elastic tissue fibers, and
into large, rigid fibers.3,35 Moreover, the ratio of collagen III to shortened appendageal structures, do survive to birth but then
collagen I is 3:1, the reverse of what it is in the adult.35,85,86 die in the neonatal period, partly because of insufficient elabo-
ration of the dermis.91–93 This disorder is caused by mutations
in either the LaminA gene or the gene encoding the LaminA
Fetal Dermal Development processing enzyme. Another syndrome characterized by inad-
After embryonic–fetal transition at 60 days, the presumptive equate dermal development is Goltz syndrome (focal dermal
dermis is distinguishable from the underlying skeletal conden- hypoplasia).45,94 This is an X-linked dominant condition in
sations. Moreover, within the dermis there is a progressive which males who inherit the mutation on their single X chro-
change in matrix organization and cell morphology, such that mosome die in utero. In contrast, females are functional
by 12–15 weeks the fine interwoven mesh of the papillary mosaics as a result of random X-inactivation early in embryo-
dermis adjacent to the epidermis can be distinguished from genesis, and those with Goltz syndrome display areas of dermal
the deeper, more fibrillar reticular dermis.3,35 Large collagen hypoplasia where the mutant X is active. These bands of
fibers accumulate in the reticular dermis during the second dermal hypoplasia follow Blaschko’s lines and alternate with
and third trimesters. Definitive elastin fibers first become bands of normal dermal development where the normal X is
detectable by EM studies around 22–24 weeks’ EGA,87 although active.54,95 Another disorder that displays patchy dermal hypo-
both the microfibrillar protein fibrillin and the microfibril- plasia and in many cases probably reflects mosaicism for an
lar structures, which are morphologically similar to elastin- autosomal dominant mutation is Proteus syndrome, although 7

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 FETAL SKIN DEVELOPMENT

some affected individuals appear to carry mutations in the

PTEN gene.96 TABLE 1-4 Skin development

Vascular regulators
Specialized Components of the Dermis CMG2 Fibromatosis, Juvenile Hyaline
The structure and organization of the cutaneous nerves and TIE2 Inherited venous malformations
vessels begin early in gestation but do not develop into those
Endoglin, activin receptor- HHT/Osler-Weber Rendu
of the adult until a few months after birth. And although the like kinase 1
pattern of the vasculature varies among regions of the body,
vessels of the endoderm–mesoderm interface form through the VEGF-3 Hereditary lymphedema, Type I
in situ differentiation of endothelial cells (vasculogenesis).97,98 Foxc2 Hereditary lymphedema, Type II
Originally, they form horizontal plexuses within the subpapil- (Lymphedema w/distichiasis)
lary and deep reticular dermis, which are interconnected by Foxc2 Lymphedema and yellow nail
groups of vertical vessels. This vascular framework has been Syndrome
elegantly reconstructed by the use of computer graphics to SOX18 Hypotrichosis-Lymphedema-
illustrate the complexity that already exists by 45–50 days’ Telangiectasia Syndrome
EGA.99 Such structure does not remain constant even through-
VG5Q translocation Some cases of Klippel-
out fetal life, but varies depending on the body region and Trenaunay syndrome
gestational age, as well as on the presence of hair follicles and
glands that may require an increased blood supply. Further-
more, vascular emergence and development correlate directly of families with heritable vascular anomalies have begun to
with the particular tissue, determined specifically by the influ- provide insights into the pathways critical for normal fetal
ences of pressure and function. vascular development and subsequent postnatal remodeling.
Regional variation also depends on gestational age. Blood Specifically, increased activity of the TIE2 receptor tyrosine
vessels have been identified in fetal skin as early as 9 weeks’ kinase, one of the vascular endothelial cell-specific receptor
EGA. At this stage, they help delineate the dermal–hypoder- tyrosine kinases that have been characterized, has been
mal junction. By 3 months, the distinct horizontal and vertical described in some families with inherited venous malforma-
networks have formed. And by the fifth month vasculogenesis tions.100,101 In addition, aberrant activities of TGF-β binding
has largely ceased and the formation of the complex vascular proteins, endoglin and activin receptor-like kinase 1, have
plexus is initiated by angiogenesis, the budding and migration been reported in patients with hereditary hemorrhagic telan-
of endothelium from pre-existing vessels. With increasing ges- giectasia (Osler–Weber–Rendu syndrome), resulting in remod-
tational age the superficial architecture becomes more orga- eling of the apparent abnormal capillary bed.102,103 The
nized, culminating at birth in an extensive capillary network importance of early fetal innervation to normal skin morpho-
responsible for the skin redness often observed in the newborn. genesis is the recent demonstration that lack of the fetus-
Within the first few postnatal months the complexity decreases specific component of the acetylcholine receptor produces
as skin surface area increases, lanugo hairs are lost, and seba- the extensive dermal webbing seen in multiple pterygium
ceous gland activity decreases. It is during this time that the syndrome.
rate of skin growth is greatest. By approximately 3 months of
age, the vascular patterns most closely resemble those of the
(mature) adult.
Development of the Hypodermis
Development of the cutaneous innervation closely parallels A distinct region that is the hypodermis can be delineated by
that of the vascular system in terms of its pattern, rate of 50–60 days’ EGA.3 It is separated from the overlying cellular
maturation, and organization. Nerves of the skin consist of dermis by a plane of thin-walled vessels. Toward the end of
somatic sensory and sympathetic autonomic fibers, which are the first trimester the sparse matrix of the hypodermis can be
predominantly small and unmyelinated. The development of distinguished morphologically from the slightly denser, more
these nerve fibers consists of myelination with a concomitant fibrous matrix of the dermis.79,104 In the second trimester,
decrease in the number of axons, and is far from complete at mesenchymally derived preadipocytes begin to differentiate
birth. It may in fact continue until puberty. and accumulate lipids,105 and by the third trimester the more
mature adipocytes are aggregated into large lobules of fat
divided by fibrous septa. Although the molecular pathways
Clinical Relevance that direct mesenchyme cells to commit to the adipocyte
Not only do the number and caliber of the blood vessels change pathway are not well understood, many regulators involved in
over time, so too does the direction of blood flow. Considering the subsequent preadipocyte differentiation have been identi-
the dynamic nature of this circulatory system, it is not surpris- fied.106,107 An example is the gene that encodes leptin, whose
ing that, of the congenital malformations seen in newborns, abnormal regulation has been implicated in the pathogenesis
vascular defects are the most common (Table 1-4). The of obesity.108–110
Klippel–Trenaunay and Sturge–Weber syndromes are exam-
ples of these. In the former, unilateral cutaneous vascular
malformations, usually involving an extremity, are seen in
COMBINED DERMOEPIDERMAL STRUCTURES
association with venous varicosities and hypertrophy of the
associated soft tissue and/or bone. In the latter, cutaneous
Dermoepidermal Junction
capillary malformations are also often unilateral and may The dermoepidermal junction (DEJ) is the region where the
8 involve the lips, tongue, and nasal and buccal mucosae. Studies epidermis and dermis abut. In the broadest definition, it

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 Combined Dermoepidermal Structures

includes the specialized extracellular matrix on which the outer surface of the basal cell α6β4, the hemidesmosome
basal keratinocytes sit, known as the basement membrane, as integrin binds laminin-5, the major constituent of anchoring
well as the basal-most portion of the basal cells and the super- filaments.113 Laminin-5 in turn binds collagen VII, the major
ficial-most portion of the dermis. Importantly, both dermal component of anchoring fibrils, thus indirectly connecting the
and epidermal compartments contribute to the molecular syn- hemidesmosome to the anchoring fibrils.114 On the inner side
thesis, assembly, and integration of this region. of the basal cell membrane, the cytoplasmic tail of β4 interacts
A simple basement membrane, separating the dermis and with the submembranous plaque protein plectin, which then
epidermis, can be discerned as early as 8 weeks’ EGA. The binds with keratin intermediate filament proteins.115 In addi-
basic protein constituents common to all basement mem- tion, the cytoplasmic tail of BPA2 binds the hemidesmosomal
branes can already be detected immunohistochemically at this plaque protein BPA1, which in turn appears to bind the keratin
stage.12,34,111 These include collagen IV, laminin, and heparin intermediate filaments.116
sulfate and proteoglycans.
Specialized components of the DEJ do not appear until after
the embryonic–fetal transition, around the time of initial epi-
Clinical Applications
dermal stratification.12,34,111 With a few exceptions, all base- Several congenital disorders characterized by severe blistering
ment membrane antigens are in place by the end of the first of the skin occur as a result of mutations in genes encoding
trimester.3 As discussed, the α6 and β4 integrin subunits are DEJ components117 (see Chapter 10). The severity of the dis-
expressed quite early by embryonic basal cells.12 However, they order, the exact plane of tissue separation, and the involve-
do not become localized to the basal surface until after 9.5 ment of nonskin tissues depend in part on which proteins are
weeks, which is coincident with the time when bullous pem- affected by the genetic mutations (see Table 1-2). Because
phigoid antigens are first detected immunohistochemically these blistering disorders are associated with a high postnatal
and hemidesmosomes are recognized ultrastructurally.11,12,34,112 morbidity and mortality they are frequent candidates for pre-
Similarly, anchoring filaments and anchoring fibrils, the base- natal testing, and when the responsible genetic mutation is
ment membrane components that mediate basal cell attach- one that has been identified, this can be accomplished by
ment to extracellular matrix, are recognizable by 9 weeks’ chorionic villus sampling (CVS) or amniocentesis (see section
EGA.3,11 Collagen VII, the anchoring fibril protein, is detected on Prenatal Diagnosis of Severe Congenital Skin Disorders).
slightly earlier, at 8 weeks.11
Recent experimental data have delineated many of the
molecular interactions crucial for connecting the cytoskeletal
Development of Appendages
networks of the basal cells with the extracellular filamentous Skin appendages (hair, nails, sweat and mammary glands in
networks important in matrix adhesion (Fig. 1-3). On the mammals, and feathers and scales in birds and reptiles) all

Normal EB simplex Junctional EB Dystrophic EB

Keratin
filaments Basal
keratinocytes

Plectin

Lamina
Laminin 5 lucidia
Anchoring Basement
filaments membrane
Lamina
densa

Collagen VII
Anchoring fibrils Dermis

Collagen IV

FIG. 1-3 Schematic of the dermoepidermal junction indicating the proteins that are defective in the relevant hereditary bullous diseases (X).
Mutations in genes encoding keratin 5 or keratin 14 cause epidermolysis bullosa (EB simplex). Plectin function is disrupted in EB associated with
muscular dystrophy. One of the subunits of laminin-5 is defective in most forms of junctional EB. However, the β4 subunit of α6β4 integrin is
altered in the form associated with pyloric atresia, and bullous pemphigoid antigen 2 (BPA2) is mutated in generalized atrophic benign EB.
Collagen VII is defective in all forms of dystrophic EB published to date. 9

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 FETAL SKIN DEVELOPMENT

consist of two distinct components: an epidermal component mis, but function transiently until resident epidermal stem
that elaborates the differentiated end-product, such as the hair cells can functionally replace them.133,134
or nail, and the dermal component that regulates specification Maturation of the hair peg into a definitive follicle is a
and differentiation of the appendage. Fetal development of complex process involving the formation of a patent hair canal
these structures depends on rigidly choreographed, collabora- and the elaboration of at least six distinct concentric rings of
tive interactions between early epidermis and dermis.79,118,119 cells.135 The most peripheral ring of ectodermal cells makes up
Defects in dermal induction or specification of the overlying the outer root sheath, whose upper portion is continuous with
ectoderm, or in the ectoderm’s responses to these instructions, the interfollicular epidermis and undergoes a similar process
result in aberrant development, as has been demonstrated in of keratinization. The lower portion of the outer root sheath,
genetic studies and transplant experiments in animal model in contrast, does not form a granular layer or classic stratum
systems.79,118–120 Moreover, the recent demonstration that corneum. The inner root sheath forms just internal to the
defects in human homologs of mouse hairless, LMX1B, and outer root sheath. The cells in this sheath do form a granular
tabby genes result in clinically significant developmental layer through the keratin proteins, and keratin-aggregating
abnormalities in humans confirms the relevance of such products produced here differ from those produced by the
animal studies to our understanding of human skin appendage normal epidermis. Cells in this inner root sheath arise from
development.121–125 self-renewing progenitor cells at the base of the follicle, which
differentiate as they move upward toward the skin surface
surrounding the hair shaft. Likewise, the three internal con-
centric layers of the hair shaft – cuticle, cortex, and medulla
Hair Follicle and Sebaceous (from outer to inner) – arise from the matrix cells at the base
Gland Development of the follicle. These deep matrix cells sit on the basement
Hair follicle formation begins on the head and then spreads membrane ‘mat,’ along the concavity of the hair follicle invagi-
caudally and ventrally in waves, resulting in regularly spaced nation, and as such are in close proximity to the dermal papil-
rows and whorls of follicles.126,127 The first morphologic evi- lae mesenchymal cells.
dence of follicle formation in humans is the focal crowding of By 19–21 weeks’ EGA, the hair canal has fully formed and
small groups of basal keratinocytes at regularly spaced inter- the scalp hairs are visible just above the surface of the fetal
vals, starting between 75 and 80 days on the face and epidermis.127,136,137 They continue to lengthen until 24–28
scalp.126,128–130 This ectodermal structure is called the placode weeks, when they shift from the active growing phase (anagen)
of the pregerm-stage follicle. Slightly later in development, to the short-lived degenerative phase (catagen) and then to the
mesenchymal cell clusters are observed beneath these ecto- resting phase (telogen).3,138 They then re-enter the active
dermal placodes. Although morphologically similar to other growing stage (second anagen), and the first wave of hairs is
dermal fibroblasts, these clustered mesenchymal cells are bio- shed into the amniotic fluid as the new hairs grow out. Cycling
chemically distinguishable based on their continued expres- through active and inactive phases continues for all hairs
sion of certain molecular markers, such as nerve growth factor throughout the life of an individual,139 although cycles for
receptor (NGFR).3 On the trunk at approximately 80 days’ individual hairs become asynchronous postnatally. The main-
EGA, a cluster of basal epidermal cells thickens and begins to tenance of a tight anatomic relationship between dermal
bud downward into the dermis, forming the early hair papilla cells and the cycling ectodermal portion of the hair
germs.130,131 Transplant studies in other species indicate that follicle is critical for follicular self-renewal, and the inability to
ectodermal budding requires an induction signal from the maintain this relationship results in a form of inherited alo-
underlying mesenchymal cells. The cells of the early ectoder- pecia in which hair neogenesis is normal but, after the first
mal bud or placode then respond with their own signal, which resting phase, cycling is aberrant.122
elicits a second mesenchymal signal. This second signal directs Perinatally the second wave of fine lanugo hairs is shed.
the species-specific type of mesenchymal appendage that will With subsequent cycles, hairs increase in diameter and coarse-
ultimately develop.79,119 ness, forming first vellus and then adult-type terminal hair
The next stage of hair development involves further prolif- shafts on the scalp and brow.138 During adolescence, vellus
eration and resulting downward elongation of the ectodermal hairs of androgen-sensitive areas undergo a similar transition
bud, forming the so-called hair peg.126 At 12–14 weeks’ EGA to terminal-type hair follicles.
the hair peg develops a widened bulb at its base that flattens Sebaceous gland maturation occurs in parallel with that of
and then invaginates, engulfing the subjacent clustered mes- the follicle proper and begins between 13 and 16 weeks’
enchymal cells, which become the follicular dermal papilla. In EGA.140 Lipogenic cells produced by the outer proliferative
addition to the widened bulb at the base, two other bulges form layer of the sebaceous gland progressively accumulate lipid/
along the length of the developing follicle, which is now termed sebum until they terminally differentiate, which results in
the bulbous hair peg (see Fig. 1-2).126,132 The uppermost bulge their disintegration and the release of their products into the
is the presumptive sebaceous gland, and the middle bulge, upper portion of the newly formed hair canal.141,142 The syn-
which forms at approximately one-third the distance from the thesis and secretion of sebum is accelerated in the second and
follicular base, is the site of the future insertion of the arrector third trimesters under the influence of the maternal steroids,
pili muscle and is the location of multipotent stem cells, which and the glands themselves become hyperplastic.143,144 This
give rise to all the progenitors necessary for regeneration of the stimulated activity by the sebaceous glands is believed to be
lower portion of follicle during postnatal follicular cycling, as responsible for the common condition known as neonatal
well as to cells capable of replenishing the overlying epidermal acne. In the absence of exogenous maternal hormones, these
covering in the event of extensive surface wounds or burns. glands become quiescent during the first few months of life
Recent lineage studies indicate that progeny of the follicular and again increase in activity during the hormonal changes of
10 stem cells do not take up permanent residence in the epider- adolescence.143

Ch001-X3432.indd 10 11/26/2007 10:42:42 AM

 Combined Dermoepidermal Structures

nail plate, reside on the ventral (deeper) side of the proximal

Nail Development invagination. At around 11 weeks, the dorsal surface of the
The first evidence of nail formation is delineation of the flat nail bed begins to keratinize, a process similar to subsequent
surface of the future nail bed on the dorsal digit tip at 8–10 keratinization of the embryonic epidermis.146–149 In the fourth
weeks (Fig. 1-4),10,145 slightly earlier than the initiation of hair month, the definitive nail plate grows out distally from the
follicle development. Along the proximal boundary of the early proximal fold, replacing the embryonic cornified layers, and
nail field a wedge of ectoderm buds inward at an oblique angle completely covers the nail bed by the fifth month. Keratiniza-
to the surface, forming the proximal nail fold. The presump- tion of the nail resembles that of the epidermis except that
tive nail matrix cells, which will give rise to the differentiated nail terminal differentiation, like hair shaft differentiation,

B
E

FIG. 1-4 Nail development. The developing nail from 65 to 85 days’ EGA, by scanning electron and light microscopy. The nail field boundaries
are marked by folds seen clearly in A, B and E. The lines delimited by arrows indicate the plane of the section taken for the accompanying
histologic sections. C, D and F show the increasing thickness and differentiation of the epidermis forming the presumptive nail plate.
Reproduced with permission from Schachner LA, Hansen RC (eds) Pediatric dermatology, 2nd edn. Edinburgh: Churchill Livingstone, 1995. 11

Ch001-X3432.indd 11 11/26/2007 10:42:42 AM

 FETAL SKIN DEVELOPMENT

involves the synthesis of distinct keratins and keratin- dark cells characteristic of apocrine glands are distinguishable.
aggregating proteins normally not expressed in epidermis.150–152 At birth, the secretory portions of nonvolar sweat glands
The keratins found in hairs and nails provide greater structural remain high in the dermis but postnatally extend progressively
stability and rigidity than those in epidermis. down to the subcutis. The apocrine gland functions transiently
in the third trimester and then becomes quiescent in the
neonate,144,159 whereas the eccrine gland does not appear to
Eccrine and Apocrine Sweat
function in utero but progressively reaches functional maturity
Gland Development postnatally.160–164
The first morphologic indicators of palmoplantar eccrine gland
development are the formation of large mesenchymal bulges
or pads on the volar surfaces of the hands and feet between
Ectodermal Appendages: Clinical Relevance
55 and 65 days’ EGA, and the induction of parallel ectodermal Genetic studies in mice have suggested that mutations in the
ridges overlying these bulges between 12 and 14 weeks (Fig. genes that direct early regional patterning of the mammalian
1-5).153,154 The curves and whorls that these ridges adopt are embryo can have a profound impact on later skin appendage
intimately related to the size and shape of the embryonic volar specification and differentiation.82,83,165,166
pads and result in the characteristic dermatoglyphic patterns, One such gene, LMX1B, which encodes a homeobox-
or ‘fingerprints,’ which can be visualized on the surface of the containing transcription factor, acts several stages before the
digit tips in the fifth month.154,155 In contrast to those of most initiation of appendageal downgrowths and is important in
other animal species, the volar mesenchymal pads in humans distal limb patterning.166 Experimental ablation of LMX1B
regress by the third trimester. function in mice results in the transformation of dorsal limb
Individual eccrine gland primordia bud at regularly spaced musculoskeletal elements and dermal structures to a more
intervals along the ectodermal ridges, elongating as cords of ventral (volar side) phenotype. Viewed from the side, Lmx1b
cells into the pad mesenchyme. By 16 weeks, the glandular mutant mouse limbs appear perfectly symmetrical, with the
regions at the terminal portion of this downgrowth have paw pads present on both the ventral and dorsal aspects. Muta-
formed, and the secretory and myoepithelial components tions in LMX1B have been observed in at least some people
become discernible. Canalization of the dermal components with the autosomal dominant disease nail–patella syndrome.121
of the glands occurs by loss of desmosome adhesion along the These patients display a much less dramatic limb phenotype,
innermost ectodermal surfaces with maintenance of lateral characterized by aberrant or absent development of the nails
adhesion between cells of the duct and gland walls. This and patellae (elbows). This milder effect on dorsal limb struc-
process is complete by 16 weeks, whereas the opening of the tures reflects the fact that individuals with nail–patella syn-
epidermal portion of the duct by vesicular fusion and autolysis drome are heterozygotes. Thus they carry a single defective
and keratinization of the wall are not complete until 22 weeks’ copy of LMX1B, together with a wild-type copy, resulting in
EGA.156,157 Although the primary ectodermal ridges are estab- only partial loss of gene function.
lished quite early in embryonic development, secondary ridges Several other genes have been identified that appear to regu-
form at later stages and the complexity of the undulating DEJ late skin appendage formation. Positional cloning strategies
increases further at late fetal stages and postnatally with the have been used to identify genes affected in several different
formation of dermal papillae protruding into the overlying types of ectodermal dysplasias, a heterogeneous group of dis-
epidermis. orders defined by their involvement of hair, nails, glands,
In contrast to volar eccrine glands, interfollicular eccrine and/or teeth (see Tables 1-1 and 1-2). The most common type
glands and apocrine glands do not begin budding until the fifth of ectodermal dysplasia, anhidrotic (hypohidrotic) ectodermal
month of gestation.136,158 Apocrine sweat glands, like seba- dysplasia, is caused by mutations in the EDA or EDAR
ceous glands, usually bud from the upper portion of a hair genes, which encode a ligand/receptor pair related to TNF
follicle, whereas eccrine sweat glands arise independently. signaling components.125 The gene encoding MSX1, another
Over the next several weeks, the glandular cords of cells elon- homeobox-containing transcription factor, has been shown
gate. By 7 months EGA the clear cells and mucin-secreting to be mutated in familial tooth agenesis, which affects not
only tooth development but also the formation of nails and
hair.167,168
Studies in mice suggest that other classic embryonic pat-
terning genes play a direct role in epidermal appendage devel-
opment, including genes encoding components of the Notched,
Wnt, and Sonic hedgehog signaling pathways.118,169 The impor-
tance of such genes in human skin homeostasis has already
been demonstrated by the finding that PATCHED is the tumor
suppressor gene mutated in nevoid basal cell carcinoma
(Gorlin) syndrome, and that it and other genes of the pathway
are frequently mutated in spontaneous basal cell carcino-
mas.170–174 Indeed, several genes involved in tumor formation
FIG. 1-5 Sweat gland development. Plantar epidermis from the digit are critical regulators during embryonic development (Table
of a late first-trimester human fetus showing a multilayered epidermis
and the primary epidermal ridges (arrows) that will develop into sweat
1-5). Finally, it is important to consider potential teratogenic
glands and ducts. Reproduced with permission from Schachner LA, effects on normal skin appendage development. Dilantin, for
Hansen RC (eds) Pediatric dermatology, 2nd edn. Edinburgh: example, can cause broadening of the nail associated with
Churchill Livingstone, 1995. distortions in the underlying distal phalange.
12

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 Acknowledgments

TABLE 1-5 Skin development

Melanocytic regulators
KIT growth factor Piebaldism
PAX3 transcription factor Waardenburg syndrome 1,3
MITF transcription factor Waardenburg syndrome 2A
SNA12 transcriptional repressor Waardenburg syndrome 2D
(zn finger, Snail homolog,
Neural crest)
SOX10, Endothelin-3, transcription factor; G-protein Waardenburg syndrome 4
EDNRB coupled receptor & ligand
PTPN11 (SHP2) tyrosine phophotase 2C LEOPARD syndrome
MYO5 organelle movement Griscelli syndrome
LYST lysosomal trafficing Chediak-Higashi
TYR tyrosinase Oculocutaneous albinism, 1A & 1B
TYRP1 tyrosinase-related protein Oculocutaneous albinism, 3
MATP Memb asso transporter prot Oculocutaneous albinism, 4
AP3B1 prot trafficing to lysosomes Hermansky Pudlak 2
DTNBP1 biogenesis of lysosomes Hermansky Pudlak 7
BLOC1S3 biogenesis of lysosomes Hermansky Pudlak 8

PRENATAL DIAGNOSIS OF SEVERE can be made using cells obtained from CVS at 8–10 weeks’
EGA, or amniocentesis at 16–18 weeks’ EGA.9 The obvious
CONGENITAL SKIN DISORDERS advantages of these procedures is that they can be performed
A number of inherited skin disorders are compatible with in early in the pregnancy with minimal risk to the mother and
utero survival but are life-threatening or result in severe mor- fetus.
bidity after birth. Often these disorders can be diagnosed Fundamental knowledge of those skin disorders whose eti-
during the first or second trimesters of pregnancy. Candidates ologies are genetic is crucial for the practicing pediatric derma-
for prenatal testing include those fetuses with an affected tologist. Awareness of the resources available for both diagnosis
sibling or other family member. Importantly, the need for and treatment of those fetuses suspected of having an inher-
prenatal testing depends on the familial relationship, the mode ited disorder is equally as important and must frequently be
of inheritance of the disorder in question, and in some cases reviewed as our understanding of the molecular bases for
the sex of the fetus. DNA from parents and from both affected genetic abnormalities evolves. Data on genetic test availability,
and unaffected siblings should be analyzed before conception provided by both commercial and research laboratories, are
to determine the exact mutational event responsible for the provided by GeneTest (http://www.genetests.org), a database
disorder in the relevant pedigree, and the likelihood that the for healthcare providers. Information regarding the identity of
fetus will in fact inherit the disease.175 With this in mind, genes critical for specific disorders, as well as whether labora-
prenatal and genetic counseling should be a critical component tories exist that conduct relevant testing, can also be accessed
of early interventional care of infants affected with severe through the website for Online Mendelian Inheritance in Man
genodermatoses. (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM&i
Until recently, prenatal diagnosis of inherited disorders has tool=toolbar).178 It is only through physicians’ awareness of
relied on fetal skin biopsies performed between 19 and 22 the different genodermatoses, as well as their understanding
weeks’ EGA.176,177 The procedure is carried out under ultra- of normal fetal skin development, that the need for evaluation
sound guidance, and multiple biopsies must be taken, although can be recognized, the necessary therapies and supports pro-
the number of biopsies and the sites from which they are taken vided, and the patients best served.
depend on the disorder for which the fetus is at risk. In
some disorders, such as those in which keratinization of the
interfollicular dermis is not yet complete, analysis of the devel-
ACKNOWLEDGMENTS
oping appendageal structures is required for accurate diagno- The authors are grateful to Angela Christiano, Karen
sis.177 Fortunately, because of the identification of the genetic Holbrook, and William Larsen for their thought-provoking dis-
mutations responsible for many of these disorders, diagnosis cussions and insights into human genetics and embryology.
13

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 FETAL SKIN DEVELOPMENT

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 FETAL SKIN DEVELOPMENT

92. Mau U, Kendziorra H, Kaiser P, et al. 108. Skolnik EY, Marcusohn J. Inhibition of EDA gene: evidence for a membrane-
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 2
Structure and Function of
Newborn Skin
Anthony J. Mancini and Leslie P. Lawley

The skin of the newborn serves a pivotal role in the transition reveals several unique features that have increased our under-
from the aqueous intrauterine environment to extrauterine standing of fetal skin development. The outermost compart-
terrestrial life and is integral to the vital functions of mechani- ment of the skin, the epidermis, arises from surface ectoderm
cal protection, thermoregulation, cutaneous immunosurveil- and at about the third week of fetal life consists of a single
lance, and maintenance of a barrier that prevents insensible layer of undifferentiated cells that becomes two-layered by
loss of body fluids. The anatomy and function of skin are most around 4 weeks.8 The outer layer of cells, the periderm, is
easily understood by dissecting the individual compartments found only in developing skin and is transiently present, even-
(stratum corneum, epidermis, dermoepidermal junction (DEJ), tually undergoing a series of apoptotic cellular events as the
dermis and subcutaneous tissue) and their component cell epidermis becomes multilayered and the stratum corneum,
types. Specialized structures found within these compart- the outermost layer of flattened, nonnucleated skin cells, is
ments, such as pilosebaceous units, sweat glands, nerves, and forming.9 By 24 weeks of gestation the periderm is largely
vascular networks, play an essential role both anatomically absent,8,9 and the epidermis shows considerable progressive
and functionally in cutaneous homeostasis in the neonate. maturation, which is largely complete by 34 weeks.10 A thin,
The anatomy of these compartments and structures of the hydrophobic layer of the periderm may persist for several days
skin, and the physiologic processes involved in their functions, postnatally and may participate in protective and thermoregu-
are the focus of this chapter. latory functions.11
Human skin consists of three layers: epidermis, dermis, and The epidermis is a stratified epithelium, the number of cell
subcutaneous fat (Fig. 2-1). All elements of skin are derived layers varying between different body regions. The various
from either ectoderm or mesoderm, the former giving rise to layers, from the dermal side toward the skin surface, are
the epidermis and other cutaneous epithelial components.1 A termed the stratum basale, stratum spinosum, stratum granu-
brief description of fetal skin development is helpful in under- losum, and stratum corneum. In areas of thicker skin, such
standing the structure and function of newborn skin, and is as the palms and soles, the stratum lucidum is interposed
incorporated into some of the following discussions of the between the granular and corneal layers. These epidermal
various compartments and structures. A more thorough review layers are shown in Figure 2-2.
of cutaneous embryology is the focus of Chapter 1. Individual cells within the epidermis are referred to as kera-
tinocytes, so named for the intermediate-sized filament pro-
teins (keratins) that are synthesized within them. Keratins are
STRATUM CORNEUM AND EPIDERMIS the major structural proteins of the epidermis and its append-
The most obvious clinical difference between the skin of the ages, constituting up to 85% of the total protein of fully dif-
term newborn and that of an adult is the presence of the moist, ferentiated epidermal keratinocytes.12 They have been divided
greasy, yellow-white substance called vernix caseosa, which is into types I and II based on their acidic or basic nature, respec-
a coating comprising a combination of sebaceous gland secre- tively, and are frequently configured in specific pairs of a type
tions, desquamated skin cells, and shed lanugo hairs.2,3 The I and a type II protein as obligatory heteropolymers.13 Termi-
vernix caseosa has an important role in maintaining hydration nal differentiation of the epidermis involves the sequential
and pH balance, and preventing infection during the first few expression of different proteins, including the keratins, in the
days of life.4,5 Certain components of the innate immune basal and spinal layers.14 An important function of the kera-
system, termed antimicrobial polypeptides (see later this tins is imparting mechanical integrity to epithelial cells. Muta-
chapter, Cutaneous Immunosurveillance, Langerhans’ Cells, tions in the genes encoding these proteins have been confirmed
and Cytokines), have been isolated in the vernix and probably as the basis of several inherited skin defects, such as the
play an important role in surface defense in the newborn.4,6,7 simplex form of the mechanobullous disease epidermolysis
This coating persists for the first several days of postnatal life, bullosa.12
eventually disappearing completely to reveal the more typical, The stratum basale consists of a single layer of cells, the
moderately dry newborn skin. basal portions of which are in contact with the dermis and
The structure of term newborn skin is histologically similar contribute to the DEJ. The cells of the basal layer are cuboidal
to that of older individuals, whereas premature infant skin to columnar in shape and are anchored to the underlying 19

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 STRUCTURE AND FUNCTION OF NEWBORN SKIN

Epidermis

Eccrine duct Pilosebaeous unit

Sebaceous gland
Hair follicle
Blood vessels

Dermis

Eccrine gland

Subcutaneous fat

FIG. 2-1 Basic anatomy of the skin, which is composed of three major divisions: epidermis, dermis, and subcutaneous fat. Adnexal structures
include pilosebaceous units and eccrine ducts and glands (shown), and apocrine glands (not shown). (Courtesy of Randall Hayes.)

Stratum corneum
Stratum lucidum
Stratum granulosum

Stratum spinosum

Stratum basale

Melanocyte
FIG. 2-3 Histologic appearance of normal skin. The basal portion of
the epidermis has an undulating surface, resulting in rete ridges
(arrowhead) interposed between dermal papillae (p).
Dermis

FIG. 2-2 The cell layers of the epidermis. Note the interspersed producing cells (melanocytes), which are discussed in more
distribution of melanocytes in the basal cell layer. (Courtesy of Randall detail below, under Melanocytes and Pigmentation of the
Hayes.) Skin.
The stratum spinosum consists of the cells between the
stratum basale and the stratum granulosum and forms the
dermis by cytoplasmic processes. The stratum basale has bulk of mammalian epidermis. The keratinocytes in this layer
an undulating surface inferiorly, forming projections called are polyhedral in shape and have numerous tiny, spiny projec-
rete ridges, which lie interposed between the dermal papillae tions spanning the intercellular space between contiguous
of the superficial (papillary) dermis (Fig. 2-3). The basal cell cells.15 These projections are composed ultrastructurally of
layer contains cells that eventually replace those continually desmosomes, which form communication junctions between
lost from the epidermis through terminal differentiation, the cells. Keratinocytes of the spinous layer become larger,
maturation and desquamation. Interspersed among the cells flatter, and more desiccated as they progress from the basal
20 in the basal cell layer are the dendritic, pigment (or melanin)- layer toward the skin surface. Also present in this layer are

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 Stratum Corneum and Epidermis

Langerhans’ cells, bone marrow-derived cells that are involved is lacking in preterm infants.35–39An acceleration of skin matu-
in cutaneous immunosurveillance through antigen process- ration may occur postnatally in preterm infants, although in
ing and presentation (see Cutaneous Immunosurveillance, extremely low-birthweight infants (23–25 weeks’ gestational
Langerhans’ Cells and Cytokines). age) complete development of a fully functional barrier may
The stratum granulosum comprises a thin layer of darkly require up to 8 weeks.36,37,40 Recent studies support the long-
stained keratinocytes at the outermost surface of the stratum held notion that the shift from an aqueous to an air environ-
spinosum. The dark appearance of these cells is due to the ment, and hence water flux, may be an important factor in
presence of keratohyalin granules, which are composed of an this acceleration of barrier formation.41 Nonetheless, during
electron-dense protein (profilaggrin) and keratin intermediate the period of postnatal maturation large transepidermal water
filaments.16 Profilaggrin is subsequently converted to filaggrin, losses contribute to the morbidity of the preterm infant, and
a protein involved in the aggregation and disulfide bonding of therefore a major focus of past studies has been the develop-
keratin filaments,17,18 and it has been suggested that kerato- ment of a therapeutic strategy to accelerate epidermal barrier
hyalin serves to form a matrix that provides structural support maturation or augment its function, including the use of semi-
by linking keratin filaments to one another.15 The granular cell permeable membranes42–45 or topical emollients.46,47Premature
layer is also where lamellar bodies (Odland bodies, membrane- infant skin and barrier maturation are discussed in more detail
coating granules) are produced.19 These intracellular organelles in Chapter 4.
participate in the formation of the epidermal permeability In addition to the prevention of insensible water losses
barrier through the production and discharge of lipid sub- across the skin by the epidermal barrier, the epidermis and
stances into the intercellular corridors of the stratum stratum corneum of the newborn provide important protection
corneum. against toxicity from exposure to ultraviolet rays (UVR), and
In areas of thicker skin, such as the palms and soles, the this protective effect may be greater for UVB than for UVA
stratum lucidum is present as a layer with a clear hyaline radiation.48 As previously noted, melanin is primarily respon-
appearance. At this level one can visualize transitional cells sible for UVR protection, although the ‘protein barrier’ of the
that exhibit marked degeneration of the nucleus and other stratum corneum may augment this cutaneous function.49
organelles and, ultramicroscopically, keratin filaments and Epidermal lipids may also play a role in protection from UVR.
keratohyalin granules, which are abundant but not yet as Another function of the superficial skin layers is protection
compact as in the stratum corneum.15 against microorganisms, which are blocked from invasion
The stratum corneum, or cornified layer, is composed of across the skin by an intact stratum corneum. In addition to
several layers of flattened, nonnucleated keratinized cells (cor- such physical factors, the antimicrobial qualities of skin may
neocytes) arranged in an overlapping fashion. The thickness be related to the relative dryness of the stratum corneum, the
of this layer varies by body region, being thinnest on the face presence of skin surface lipids, and the degree of epidermal
(especially over the eyelids) and genitalia, and thickest on the cellular differentiation.49–52 Skin is also a vital participant in
palms and soles. It is now widely accepted that the epidermal the process of neonatal thermoregulation (discussed in more
permeability barrier resides in the stratum corneum and serves detail later) through regulation of cutaneous blood flow and
the vital functions of preventing excessive transepidermal evaporative water loss.
water loss (TEWL) and preventing penetration of a variety of Percutaneous absorption of substances across neonatal skin
substances.20–24 requires passage through the stratum corneum and epidermis,
The formation of the epidermal barrier is accomplished diffusion into the dermis, and eventual transfer into the sys-
through the lipid secretions of lamellar bodies, which include temic circulation. Transfer across the stratum corneum and
free fatty acids, ceramides, and cholesterol. These lipids are epidermis may be through the intercellular corridors (favoring
deposited in the intercellular interstices within the stratum nonpolar or hydrophobic compounds) or via a transcellular
corneum. This arrangement has been likened to ‘bricks and route (which favors polar or hydrophilic substances).53 Hair
mortar,’ where the corneocytes represent the bricks and the follicles and eccrine sweat ducts may serve as diffusion shunts
intercellular lipids represent the mortar.25 Although these for certain substances (i.e. ions, polar compounds, very large
lipids represent only about 10% of the dry weight of the stra- molecules), which would otherwise traverse the stratum
tum corneum26 their location and composition are vital, and corneum slowly (because of their large molecular weight).54
cutaneous barrier function is dependent on both the genera- The rate-limiting step of percutaneous absorption seems to be
tion of sufficient quantities of these lipids and their strategic diffusion through the stratum corneum,54 and hence the effec-
secretion and organization into lamellar bilayer unit struc- tiveness of the epidermal permeability barrier correlates
tures.24,25,27–29 In fact, the epidermis is equipped with the neces- inversely with percutaneous absorption. Percutaneous absorp-
sary machinery to autonomously regulate its lipid-synthesis tion, although continuously being explored in terms of its
apparatus in response to specific barrier requirements.30–32 The therapeutic applications, may contribute to systemic absorp-
development of a functional barrier has been shown to be tion and potential toxicity after topical application of some
closely correlated with normal ontogenesis and does not appear substances to newborn skin, especially in preterm infants or
to be disrupted by somatic growth retardation.33 Hence, more those with cutaneous damage.36 Importantly, although the
mature infants, even those who are small for gestational age, barrier function of intact skin in the term infant is usually
have a competent epidermal barrier.34 normal, the surface area-to-weight ratio is greater than in older
The epidermis and stratum corneum in the full-term infant children and adults. Caution should therefore be exercised in
are well developed, and the barrier properties are excellent.35 the use of topical agents in any newborn, with extra caution
Conversely, premature infants have greater skin permeability and a thorough risk–benefit analysis being employed in the
and a more poorly functioning barrier. Histologically, the term case of premature infants or any neonate with a compromised
infant has a well-developed epidermis, which is several layers skin barrier. Percutaneous absorption is discussed in more
thick, and a well-formed stratum corneum.2,10 This maturity detail in Chapter 5. 21

Ch002-X3432.indd 21 11/26/2007 10:43:29 AM

 STRUCTURE AND FUNCTION OF NEWBORN SKIN

form of epidermolysis bullosa (EB) termed generalized atrophic

DERMOEPIDERMAL JUNCTION
benign EB, and has recently been described in a rare variant
The dermoepidermal junction (DEJ) is an important site of of EB simplex.58–62
attachment in skin, occurring at the interface between the α6β4 integrin is a membrane glycoprotein component of the
basal epidermis and the papillary dermis. It appears that the hemidesmosome, and defects in this integrin have been identi-
various components of the DEJ are expressed in term newborn fied in a subset of patients with junctional EB in combination
skin in a manner similar to that in adults, without apparent with pyloric atresia.63–66 Laminin-5 is a glycoprotein localized
differences in their quantity or associations.2 For reasons that mainly to the lamina densa and lower lamina lucida,67 and is
are poorly understood, however, skin appears to be more fragile also associated predominantly with hemidesmosomes.68 Muta-
during the newborn period, even in term infants, as evidenced tions in the genes encoding various chains of laminin-5 have
by blisters or erosions developing in situations that do not been identified in patients with the lethal (Herlitz) junctional
cause blisters later in life (e.g. erosions due to diapering, type of EB.69–72
sucking blisters on fingers and hands, and disease states such Type IV collagen predominates in the lamina densa region,
as bullous syphilis). whereas type VII collagen, which is also known as the epider-
Specialized structures called hemidesmosomes assist in molysis bullosa acquisita (EBA) antigen, is situated in the zone
anchoring the basal keratinocytes to the underlying plasma beneath the lamina densa. EBA antigen was so named because
membrane. Ultrastructurally the DEJ can be broken down into it was first defined by circulating autoantibodies in the sera of
several planes, including (from the epidermal side to the patients with EBA, an acquired autoimmune blistering
dermal side) the inferior portion of the basal keratinocyte; an disease.73 The dystrophic forms of inherited EB have been
empty-appearing, electron-lucent clear plane known as the shown to be a result of defects in the gene encoding type VII
lamina lucida; a thin, dark, electron-dense layer known as the collagen.74
lamina densa; and the sublamina densa fibrillar region16,55 (Fig.
2-4). Each of these layers contains individual components that
function harmoniously in concert to create cohesion between
DERMIS AND SUBCUTANEOUS FAT
the epidermis and the underlying dermis. Defects in, or anti- The dermis of human skin consists primarily of connective
bodies directed against, some of these components have been tissues, including proteins (collagen and elastic tissue) and
etiologically linked to cutaneous disease. ground substance. This compartment lies between the epider-
Major constituents of the DEJ include bullous pemphigoid mis superiorly and the subcutaneous fat inferiorly and forms
(BP) antigens, α6β4 integrin, laminin-5, type IV collagen, and a resilient and flexible layer that envelops the entire organism.
type VII collagen. The BP antigens are large glycoproteins with It is divided into superficial (papillary) and deep (reticular)
both intracellular (BP antigen 1) and transmembrane (BP components, which are anatomically divided by a thin plexus
antigen 2) components. BP antigen 2, also known as collagen of blood vessels. Although differentiation between these dermal
type XVII, extends from the basal keratinocyte across the compartments can be ascertained on the basis of the size of
lamina lucida into the lamina densa,56 and autoantibodies the collagen fiber bundles in adult skin, this criterion is less
directed against it have been found in the sera of patients with helpful in newborn skin, where there is a more gradual transi-
BP, pemphigoid gestationis, mucous membrane pemphigoid, tion in fiber bundle size.2 Structures found within the dermis,
linear IgA disease, lichen planus pemphigoides, and recently, which are discussed in different sections of this chapter,
pemphigoid nodularis.57,58 Reduced or absent expression of BP include the cutaneous appendages (pilosebaceous units, eccrine
antigen 2 is found in patients with a hereditary junctional and apocrine sweat glands), as well as nerves, blood vessels,
and lymphatics.
Collagen is the major constituent of mammalian dermis
and accounts for approximately 75% of the dry weight of the
Desmosome skin.16 The collagens are a family of related, yet individually
distinct, structural proteins, and in the skin they provide
Basal keratinocyte tensile strength and elasticity. Types I and III collagen are
the major collagens found in human dermis, and smaller
Hemidesmosome
amounts of types IV (a primary component of the basement
membrane as noted above), V, VI, and VII are also present.75
Lamina lucida
Eighty to 90% of dermal collagen is type I. Type III collagen
was initially termed fetal collagen because of its predominance
Lamina densa in fetal tissues, where it accounts for over half of total skin
collagen. However, synthesis of type I collagen accelerates
during the postnatal period, and eventually the ratio of type
I to type III collagen increases, such that in adult skin it
Sublamina densa
fibrillar region and
is around 5:1–6:1.76 Abnormalities in collagen synthesis or
papillary dermis posttranslational processing may result in clinical disease,
including osteogenesis imperfecta and the Ehlers–Danlos
syndromes.
Elastic fibers play an important role in the structure and
FIG. 2-4 Depiction of the ultrastructure of the dermoepidermal
junction (DEJ). Hemidesmosomes assist in anchoring the basal
function of skin, providing elasticity and resilience. They
keratinocyte to the underlying plasma membrane. Planes of division consist of two components: elastin, which is a connective
within the DEJ include the lamina lucida, lamina densa, and sublamina tissue protein, and elastic fiber-associated microfibrillar com-
22 densa fibrillar region. (Courtesy of Randall Hayes.) ponent, a complex of glycoproteins.75 Elastic fibers are distrib-

Ch002-X3432.indd 22 11/26/2007 10:43:29 AM

 Pilosebaceous Units, Apocrine Glands, and Nails

uted in the papillary and reticular dermis. Fibers in the papillary a cephalocaudad fashion.86,87 In some full-term infants, and
dermis have been subdivided into elaunin fibers, which are especially in premature infants, the skin surface is covered
oriented parallel to the DEJ, and oxytalan fibers, which connect with lanugo hairs, which are soft, fine hairs with limited
the elaunin fibers to the DEJ.1 It has been demonstrated that growth potential.2 These hairs are usually shed by term, or
elastic fibers are distributed in the term newborn dermis in a shortly thereafter, and are replaced by vellus hairs, which are
manner similar to that of the adult, albeit with a decreased eventually replaced on the scalp by coarse terminal hairs. The
elastin content in the papillary dermal bundles, and with a majority of hairs present at birth are synchronized in their
finer fiber diameter in the reticular dermis.2 The most widely growth phase,3,88 although this synchrony of growth is dis-
recognized disease related to abnormalities in elastin produc- rupted within a few months and may result in a period of
tion is cutis laxa, a heterogeneous group of disorders featuring temporary alopecia.88 The growth of a hair follicle is cyclic, the
lax skin and occasional systemic involvement in the form of stages being divided into anagen (active growth), catagen (tran-
hoarseness, emphysema, hernias, and diverticulae.77 sitional involution), and telogen (resting) phases. The typical
The ground substance of the dermis is an amorphous mate- length of each of these phases is 2–5 years, 3 days, and 3
rial that surrounds and embeds the fibrous and cellular com- months, respectively.87 No new hair follicles are formed after
ponents found in this compartment. Glycosaminoglycans birth.
(GAGs), which are long chains of aminated sugars, and pro- The hair follicle is organized into a series of concentric cel-
teoglycans (PGs), which are large molecules consisting of a lular compartments, the details of which are beyond the scope
core polypeptide linked to GAGs, are major constituents of of this chapter. The structure of a pilosebaceous unit is depicted
ground substance.1,16 Major GAGs and PGs in the dermis are in Figure 2-5. Longitudinally, the hair follicle can be divided
chondroitin sulfate, dermatan sulfate, heparin/heparin sulfate, into three zones: the infundibulum, extending from the
chondroitin 6-sulfate, and hyaluronic acid (hyaluronan).1,16,78 opening of the follicle to the entrance of the sebaceous duct;
These components are capable of retaining large amounts of the isthmus, extending from the entrance of the sebaceous
water and may also play a role in binding growth factors and duct to the insertion of the arrector pili muscle; and the infe-
providing structural support, anticoagulation, and adhe- rior segment, which forms the remainder of the follicle from
sion.1,79,80 Hyaluronic acid has been demonstrated in large the insertion of the pili muscle to the base. A subpopulation
amounts in fetal dermis and amniotic fluid and is thought by of hair follicle keratinocytes has been identified in the upper
some to be associated with the rapid wound healing without follicle near the insertion site of the arrector pili.89,90 This area
scarring that has been observed to occur in fetal wounds.81 has been termed the bulge, and these cells may be involved
These observations have been applied to the study of diabetic not only in the regeneration of the anagen hair follicle, but
ulcers, where hyaluronic acid levels have been shown to be also in the long-term maintenance of the epidermis.91 Within
decreased, leading to the hypothesis that application of this the specialized environment of the bulge are multipotent stem
substance may induce healing.82 Fibronectin is a large glyco- cells, Merkel cells, and melanocytes which are thought to
protein also found in the dermis and is associated with a interact, leading to the differentiation of stem cells into the
variety of putative functions, including organization of the components of the hair follicle, sebaceous gland and epider-
extracellular matrix, wound healing, attachment, and mis.92–96 The exact signaling and control of these stem cells is
chemotaxis.1,16 not known, but adhesion molecules, epidermal growth factor,
The subcutaneous fat is an important layer, playing a role nerve growth factor, and platelet-derived growth factor are all
in shock absorption, energy storage, and maintenance of body felt to play a role.94 The integrity of the hair shaft is related to
heat. The individual cells in the subcutaneous fat – adipocytes its protein constituents, including the intermediate filament
– form lobules that are separated by fibrous septa. The fibrous
septa contain neural and vascular elements and connect deeper
with the fascia of underlying skeletal muscle. In contrast,
brown fat is a distinct type of adipose tissue present only in
newborns that plays a vital role in neonatal thermoregulation
(discussed in more detail later) through the oxidation of fatty
acids.83 Brown fat makes up 2–6% of the neonate’s total body
weight and is found primarily in the scapular region, the medi- Infundibulum
astinum, around the kidneys and adrenal glands, and in the
axilla.84 The nonshivering thermogenesis that occurs in this
Sebaceous
tissue appears to be regulated by the enzyme-uncoupling
gland
protein thermogenin, which serves as a protonophore through Isthmus Arrector pili
the mitochondrial membrane, enabling high rates of cellular Follicle muscle
respiration and proton conductivity.85 Brown fat is depleted
over time and is virtually absent in adults.
Inferior
segment
PILOSEBACEOUS UNITS, APOCRINE GLANDS,
AND NAILS
FIG. 2-5 The pilosebaceous unit, divided into three zones: the
Hair Follicles infundibulum, extending from the opening of the follicle to the
entrance of the sebaceous duct; the isthmus, extending from
The earliest hair follicles begin to form at 9–12 weeks’ gesta- the entrance of the sebaceous duct to the insertion of the arrector
tion86 primarily in a facial location, and the bulk of the remain- pili muscle; and the inferior segment, extending from the insertion
ing hairs start developing around 16–20 weeks, progressing in of the arrector pili muscle to the base. (Courtesy of Randall Hayes.) 23

Ch002-X3432.indd 23 11/26/2007 10:43:29 AM

 STRUCTURE AND FUNCTION OF NEWBORN SKIN

hair keratins and high-sulfur proteins, and to the strong disul-

Proximal nail fold Nail bed
fide bonding between these proteins.87 In neonates, hair may
be a source of valuable clinical information, the utility of neo- Matrix Cuticle Nail plate
natal hair shaft analysis as a marker for intrauterine exposure
to drugs of abuse having emerged as a valuable tool over the
last decade.91–100

Bone
Sebaceous Glands
Sebaceous glands begin to develop between 13 and 15 weeks
of fetal life.101 They are nearly always associated with hair fol-
licles and are found diffusely in the skin, except on the palms,
soles, and dorsal feet.102 The locations of the most prominent
glands are the face and scalp, and in term neonates may be
quite evident over the nose, forehead, and cheeks. Modified
glands are found in the skin of the nipples and areolae (Mont-
gomery’s tubercles), on the labia minora and prepuce (Tyson’s FIG. 2-6 The nail unit. The hard nail plate consists of cornified cells
glands), on the vermilion border of the lips (Fordyce’s condi- and is produced by the mitotically active cells of the nail matrix, which
tion), and in the eyelids (meibomian glands). Sebaceous glands is situated underneath the proximal nail fold. (Courtesy of Randall
are well formed at birth and are quite active during the neo- Hayes.)
natal period, when they are stimulated by transplacentally
derived steroid hormones and possibly by endogenous steroid
production.3 This sebaceous activity in the newborn is reflected
by the common finding of neonatal acne. Sebum, the sub-
ECCRINE GLANDS AND
stance produced by the holocrine sebaceous glands, is a com-
posite of triglycerides, wax esters, squalene, cholesterol, and
NEONATAL SWEATING
cholesterol esters and serves a role in lubrication of the follicle Eccrine sweating is a physiologic response to increased body
and epidermal surface.1 Sebum levels sharply decline over the temperature and is the most effective means by which humans
first year of life,103 putatively in response to diminished levels regulate their body temperature through evaporative heat
of circulating hormones. The glands then remain relatively loss.106 Gestational age, postnatal age, and body site are all
quiescent, producing only small amounts of sebum, until important variables with regard to eccrine glands, and much
puberty.2 of what is known about the process of neonatal sweating has
been learned from studies of the normal physiologic eccrine
gland responses of term and preterm neonates to various
Apocrine Glands sweat-inducing stimuli.
The apocrine glands are limited in distribution and are found Eccrine sweat glands first appear during fetal development
primarily in the axillae, areolae, mons pubis, labia minora, at 14 weeks and are initially limited to the volar surface of the
scrotum, perianal area, external ear canal, and eyelids (Moll’s hands and feet.107 They then appear in the axillae and eventu-
glands).102 Their function in humans is unclear, although they ally in a generalized distribution, with a full complement of
may serve as scent glands. Apocrine glands remain small until anatomically normal glands present by the 28th week of gesta-
puberty, when they enlarge and begin the process of secreting tion, although functionally the glands are immature until 36
a milky white fluid. Body odor in postadolescent individuals weeks of gestation.108 The total number of eccrine sweat glands
is related to bacterial action on these secretions. is formed before birth97 and is estimated to be between 2 and
4 million.107
The eccrine sweat gland consists of two segments: a secre-
The Nail tory coil and a duct. The secretory coil is composed of secretory
The nail acts as a hard, protective covering over the distal end cells and myoepithelial cells, the latter being contractile cells
of the digit and may have served a function in evolution to with smooth muscle-like characteristics.107 The duct is com-
assist in grasping small objects. The nail unit is depicted in posed of two cell layers, the basal and luminal ductal cells,
Figure 2-6. The nail plate consists of cornified cells with a high which are involved in secretion and reabsorption of solutes.
protein (primarily keratin) content and is produced by the Components of eccrine sweat include water, sodium, chloride,
matrix, a cellular zone situated underneath the proximal nail potassium, urea, lactate, and ammonia.107 Although newly
fold at the base of the nail. The nail plate is situated on top formed sweat is isotonic, reabsorption of water and solutes
of the nail bed, a highly vascular zone. The lateral nail folds occurs in the duct such that the expelled product is hypotonic.
consist of skin that envelops the lateral borders of the nail Evaporation of sweat from the surface of skin removes 0.58
plate. The average growth rate of the human fingernail is calorie of heat for each gram of water that evaporates.109
0.10–0.12 mm/day and appears to be greatest during the Eccrine sweat glands are innervated anatomically by fibers
second decade of life.104 Toenails, which grow at a slower of the sympathetic nervous system, although functionally they
rate, may appear to be abnormal or ‘ingrown’ in newborns are under cholinergic influence, and acetylcholine is the major
as a result of relative nail plate hypoplasia with a bulbous neurotransmitter released from the periglandular nerve end-
distal phalanx.105 Despite their abnormal appearance, these ings.107 Circulating catecholamines can also have a stimula-
nails eventually grow out and take on a more normal tory effect on eccrine sweat production,109 as can a variety of
24 appearance. other peptides or neurotransmitters.

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 Nerves, Vascular Networks, and Thermoregulation

Sweating can be induced by pharmacologic stimulation and fetal development.2,127,128 Studies suggest that Merkel cells may
by emotional or thermal stress, and all mechanisms appear to actually be trophic for developing nerves and therefore play an
be developed to some extent at birth in term infants. Levels of inductive role in the development of the human cutaneous
sweat production in response to the intradermal injection of nerve plexus.129 Specialized sensory receptors are present to
pharmacologic agents have been demonstrated to bear a direct varying degrees at birth, including Pacinian corpuscles, which
relation to gestational age,110–113 as well as to birthweight.110 are well developed and abundant in palm and sole skin, and
Thermal stress-induced sweating, although present in infants, Meissner’s corpuscles, which are not fully formed and undergo
appears to require a greater thermal stimulus in neonates than continued morphologic changes with age.2
in adults, and this response also appears to be less developed The vasculature of human dermis comprises two plexuses
in premature infants,113–117 increasing with increasing post- that parallel the skin surface: one in the lower dermis (deep
natal age.115 However, the thermal stimulus of sweating is an plexus) and one just beneath the papillary dermis (superficial
important contributor to increased insensible water loss in plexus).102 These two systems are connected by intercommu-
certain infants at risk, such as those treated with phototherapy nicating vessels, and vertical vessel arcades project superiorly
for hyperbilirubinemia118 and those under radiant warmers.119,120 from the superficial plexus toward the epidermis to form papil-
The core temperature at which sweating begins in full-term lary loops (Fig. 2-7). This subpapillary plexus also gives rise to
newborns has been estimated at around 37.2°C.121 vessels that infuse the periadnexal structures.102 The cutane-
’Emotional sweating’ also appears to be well developed at ous vascular system also contains arteriovenous shunts, or
birth in full-term but not premature neonates.108 In one study, glomi, which are specialized anastomoses that assist in the
skin conductance after heel prick for routine blood testing rose regulation of skin blood flow and thermoregulatory shunt-
sharply, and to a greater extent, in infants of more advanced ing.3,114 The cutaneous capillary network is fairly disordered at
gestational ages,122 supporting the role of postconceptual age birth and assumes a more orderly network pattern by the
in maturation of the sweating response to emotional stress. second week of life,130 with continued development until
Another study using auditory stimuli revealed that the sym- around 3 months.131
pathetic nervous system innervating the eccrine glands devel- Vasomotor tone is under the control of a complex series of
oped over the first 10 weeks of life.123 neurogenic, myogenic, and pharmacologic mechanisms,3 and
The process of neonatal sweating, therefore, appears to the ability to control skin blood flow is now known to be well
develop early anatomically in fetal life and functionally at later developed in neonates.132 It was previously suggested that skin
stages, and the sweating response appears to be well developed blood flow and total peripheral blood flow both correlate
at birth in term but not preterm infants. Hypotheses on the inversely (and decrease) with increasing birthweight, gesta-
potential mechanisms for progressive postnatal maturity of tional maturity, and postnatal age, along with the develop-
the sweating response include anatomic development of the ment of increasing peripheral vascular resistance.133 However,
sweat gland, functional development of the gland, or nervous studies of capillary blood cell velocity (CBV) in full-term
system maturation.115 infants have demonstrated a correlation between CBV and
postnatal age, making the significance of previous microvas-
NERVES, VASCULAR NETWORKS, cular findings in the neonate unclear.134
Thermoregulation, which maintains an equilibrium between
AND THERMOREGULATION heat production and heat loss, is a crucial requirement in the
The cutaneous neural and vascular networks both develop neonate for maintenance of optimal core body temperature. It
early in the fetus, and their architecture becomes organized is a complex physiologic process under the control of the
into adult patterns with increasing postnatal age.2 Nerve net- nervous (most importantly the hypothalamus) and endocrine
works in the skin contain both somatic sensory and sympa-
thetic autonomic fibers and function as innervation for arrector
pili muscles, cutaneous blood vessels, and sweat glands, as
well as serving as receptors for touch, pain, temperature, itch,
and mechanical stimuli. Large myelinated fibers, which are
cutaneous branches of musculoskeletal nerves, innervate the
skin in a pattern similar to that of vascular supply, whereas
sensory nerves follow segmental dermatomes, which often Superficial
vascular
show some overlap. Although cutaneous nerve fibers in the
plexus
neonate are similar in structure and distribution to those in
the adult, ultramicroscopic examination has revealed a higher
percentage of unmyelinated fibers with bundling of axons,
suggesting cytoarchitectural immaturity or incomplete
growth.124
Deep
Sensory cutaneous nerves may end freely or in encapsulated vascular
terminals. Free nerve endings in skin represent the most plexus
important of sensory receptors and include penicillate fibers
found in a subepidermal location in hairy skin,125 multiple
types of free endings in digital (nonhairy) skin,126 and papillary
FIG. 2-7 Vasculature of the skin, which is composed of the superficial
nerve endings found at the orifice of hair follicles.16 Free nerve plexus and the deep plexus with intercommunicating vessels. The
endings may also be associated with Merkel cells, neurosecre- superficial plexus gives rise to vertical vessel arcades that project
tory cells of uncertain biologic significance that are of epithe- superiorly into the dermal papillae and form papillary loops. (Courtesy
lial derivation and which become scarce in human skin after of Randall Hayes.) 25

Ch002-X3432.indd 25 11/26/2007 10:43:29 AM

 STRUCTURE AND FUNCTION OF NEWBORN SKIN

systems. Although the thermoregulatory response is present the basal layer, as well as more superficially, where melanin
in both term and preterm neonates, it is more pronounced in serves a protective role by absorbing and scattering ultraviolet
term infants.135 The primary contributors to thermogenesis are radiation (UVR).16
muscles (voluntary and involuntary, or ‘shivering’ thermogen- Two forms of melanin are present in human skin: eumela-
esis), sweat glands, blood vessels, and adipose tissue.136 Heat nin, which is brown, and pheomelanins, which are red and
loss, or thermolysis, is accomplished by flow of heat from the yellow.115,142 Differences in native skin pigmentation among
center of the body to the surface and, subsequently, flow of individuals are related to the concentration, as well as the
heat from the body surface to the environment.136 Heat trans- distribution and retention, of melanin in the basal cell layer,
fer to the surroundings can be accomplished through conduc- rather than to the absolute number of melanocytes.1,143,144
tion (thermal exchange between the body surface and objects Although melanocytes in newborn skin are quantitatively
with which it is in contact), convection (heat loss from mass comparable to those in older individuals, melanin production,
flow of moving air over the body surface), or radiation (elec- and hence skin pigmentation, is relatively decreased during
tromagnetic heat loss to cool surfaces within the environ- the neonatal period,2,3 with gradual darkening over several
ment). Water evaporation, the fourth mechanism of heat loss, months following birth. Several disorders of either increased
is discussed in the section on neonatal sweating. or decreased pigmentation, as well as proliferation of melano-
Thermal stimuli providing information to the hypothala- cytes, are seen in the newborn period. These include disorders
mus are transmitted from skin thermal receptors, as well as such as albinism, piebaldism, café au lait macules, congenital
from deeper receptors present in the abdominal cavity and nevi, and others. Disorders of pigmentation and melanocytes
central nervous system.136,137 In general, increased environ- are discussed in Chapters 21 and 22.
mental temperature results in cutaneous arteriolar vasodilata-
tion and heat dissipation, whereas cold stress leads to
vasoconstriction, with resultant decreased skin blood flow and CUTANEOUS IMMUNOSURVEILLANCE,
reduced heat loss from the body core. Heat production in the
neonate is accomplished primarily through nonshivering ther-
LANGERHANS’ CELLS, AND CYTOKINES
mogenesis, which utilizes the increased number of mitochon-
dria, increased glycogen stores, and abundant blood supply of
Cutaneous Immunosurveillance
brown fat.137 The primary mechanism utilized by the over- While participating in the important roles of physical protec-
heated neonate to dissipate heat is evaporative water loss tion, barrier function, and thermoregulation, the skin also
through sweating. occupies a niche in the immunologic system of the host as a
Although temperature regulation is developed to some peripheral immune organ. Various models and terms have
extent in most infants, they are susceptible to both cold and been used to describe the immunologic capacities of the skin,
heat stress. Transition out of the stable thermal environment including skin-associated lymphoid tissues (SALT), skin
of the uterus, as well as birth trauma, malformations, drugs, immune system (SIS), dermal microvascular unit (DMU), and
and respiratory deficiency, may predispose the newborn to dermal immune system (DIS).145,146 SALT are composed of
hypothermia, whereas birth trauma and exogenous sources of epidermal Langerhans’ cells and keratinocytes, as well as
heat may lead to hyperthermia.136 Studies of both full-term dermal endothelial cells and the skin-draining lymph nodes,
and preterm infants reveal a decreased ability to vasoconstrict and are an important system in the induction of immunity
blood vessels in the extremities following exposure to cool and tolerance.146 The broader terminology of the SIS refers to
temperatures, further predisposing infants to hypother- the entire complex interplay of immune response-related
mia.121,138 Thermoregulation is a multifaceted process, which systems in the skin, including cellular components and
at times may be inadequate in the maintenance of the homeo- humoral factors,146,147 and both dermal and epidermal
thermic state in the neonate. An understanding of these pro- components.
cesses is therefore vital for providing appropriate thermal These immunologic systems in the skin provide cutaneous
support to such infants. immunosurveillance, which functions in the prevention of the
development of cutaneous neoplasms and mediates against
persistent infections with intracellular pathogens.148 Cellular
MELANOCYTES AND PIGMENTATION OF components include keratinocytes, antigen-presenting cells
(APCs), monocytes and macrophages, granulocytes, mast cells,
THE SKIN lymphocytes, and endothelial cells, whereas humoral constitu-
As mentioned, interspersed among the basal layer cells are the ents include antimicrobial peptides, complement proteins,
dendritic, melanin-producing cells called melanocytes. These immunoglobulins, cytokines, and prostaglandins.146 Antimi-
cells first appear between a gestational age of 40 and 50 days crobial peptides and proteins are an important innate cutane-
and migrate to the skin from the neural crest.139 Whereas ous defense mechanism against microbial intruders. They
melanocytes are found in both basal and suprabasal locations have a broad-spectrum killing activity, and their presence in
during embryogenesis, neonatal skin reveals a more limited both amniotic fluid and vernix caseosa has been well docu-
distribution restricted to the basal epidermal layer.140,141 mented, suggesting that effective innate immune protection
Melanin is manufactured within organelles called melano- begins during fetal and early neonatal life.4,6,149,150 Human anti-
somes, which are formed in melanocytes and transferred to microbial peptides include the cathelicidin and β-defensin
neighboring keratinocytes via dendritic connections. Each families.
melanocyte is in contact with roughly 36 keratinocytes, an Characterization of lymphocyte populations within normal
association that is referred to as the epidermal melanin unit. human skin has revealed that they are predominantly T cells,
The transfer of melanin from the melanocyte to the keratino- with 90% of cells clustered around postcapillary venules or
26 cytes within this unit results in pigment being distributed in adjacent to cutaneous appendages.147,151 Intraepidermal local-

Ch002-X3432.indd 26 11/26/2007 10:43:30 AM

 References

ization of T lymphocytes accounts for less than 2% of skin dendritic cells, which also contribute to the surveillance func-
lymphocytes normally present. B lymphocytes are not present tion of the immune system and initiation of the primary
in normal human skin, but may be found in mucosal immune response. These cells were also shown to express high
locations. levels of MHC class II molecules, as well as factor XIIIa, and
are isolated primarily from the dermis.160 Some dermal den-
dritic cells may acquire the ultrastructural characteristics of
Langerhans’ Cells LCs and therefore may be precursors of these epidermal
The cell that sets the SIS apart from others is the Langerhans’ APCs.160
cell (LC). This APC resides in the epidermis and is involved
in skin allograft rejection, delayed hypersensitivity reactions,
and specific T-cell responses.152 LCs are derived from the bone
Cytokines
marrow and migrate via a hematogenous route to the skin. In addition to the role of such cellular components in cutane-
They are present in the fetus as early as 16 weeks’ gestation, ous immunity, a complex interplay with several humoral
with early restriction to the basal layer and eventual distribu- factors is also present, including the biologic proteins known
tion among suprabasal cells.153 as cytokines. These autocrine, paracrine, endocrine, exocrine,
The function of the LC was unclear until the 1970s, when and intracrine proteins include the interleukins (ILs), inter-
surface Fc receptors, major histocompatibility complex (MHC) ferons (IFNs), colony-stimulating factors (CSFs), tumor necro-
class II molecules, and C3 receptors were described on its sis factors (TNFs), and growth factors (GFs).147,154 They are
surface,148 suggesting an immunologic role. It is now well produced by various cell types, including keratinocytes, which
accepted that the epidermal LC is involved in antigen process- have been demonstrated to be capable of secreting several types
ing and presentation in a variety of skin-induced immune of cytokine.147
responses against a variety of antigens, including contact aller- Cytokines have multiple biologic functions and act on target
gens, alloantigens, tumor antigens, and microorganisms.154 cells by binding to specific receptors. The result of such binding
These cells have been found to have positive staining for other is signal transduction to the cell interior followed by activation
characteristic surface markers, including CD1a and S100 of various second-messenger pathways and eventual altered
proteins and membrane-bound adenosine triphosphatase gene expression and cell function.154 For instance, on exposure
(ATPase).154 Although the exact function of the CD1a glyco- to contact allergens LCs may show enhanced migration after
protein remains unclear, relatively weak expression of the induction of local IL-1β production, ultimately resulting in
antigen on LCs from neonatal skin has been demonstrated155 activation and expansion of allergen-specific T-cell popula-
and may partially explain why neonatal donor skin demon- tions,146 whereas IL-10 inhibits the ability of LCs to stimulate
strates extended survival compared to adult donor skin after T cells.152 Cytokines are involved in many cutaneous pro-
transplantation in animal models.156–158 Ultrastructurally, LCs cesses, both physiologic and pathologic, the details of which
are found to contain Birbeck granules, distinctive cytoplasmic are beyond the scope of this chapter. Although not clearly
organelles with central striations and a characteristic ‘tennis elucidated, the secretion, activity, and effector functions of
racket’ appearance on thin sections.152 Although the exact cytokines in neonates may differ from those in adults. An
function of these granules is unknown, it has been suggested example is the hypothalamic response to IL-1, also known as
that they may be involved in receptor–ligand interactions and endogenous pyrogen, in newborns. The synthesis of pro-
surface antigen trafficking.159 staglandins in response to this protein normally shifts the
LCs are a member of the dendritic family of cells, which are thermoregulatory set-point, resulting in fever, but this respon-
stellate cells with cytoplasmic extensions, or dendrites. Other siveness is decreased in the neonate, which may account for
dendritic APCs are present in human skin, including dermal the attenuated fever response in the setting of infection.142

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1974; 128: 511–514. Pediatr 1991; 33: 121–134. 152. Hogan AD, Burks AW. Epidermal
121. Karlsson H, Hanel SE, Nilsson K, et 137. Thomas K. Thermoregulation in Langerhans’ cells and their function in
al. Measurement of skin temperature neonates. Neon Network 1994; 13: the skin immune system. Ann Allergy
and heat flow from skin in term 15–22. Asthma Immunol 1995; 75: 5–12.
newborn babies. Acta Paediatr 1995; 138. Karlsson H, Olegard R, Nilsson K. 153. Drijkoningen M, de Wolf-Peters C,
84: 605–612. Regional skin temperature, heat flow Van Der Steen K, et al. Epidermal
122. Gladman G, Chiswick ML. Skin and conductance in preterm neonates Langerhans’ cells and dermal dendritic
conductance and arousal in the nursed in low and in neutral cells in human fetal and neonatal skin:
newborn. Arch Dis Child 1990; 65: environmental temperature. Acta an immunohistochemical study.
1063–1066. Pediatr 1996; 85: 81–7. Pediatr Dermatol 1987; 4: 11–17.
30

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 References

154. Stingl G, Hauser C, Wolff K. The skin tissue. Int Arch Allergy Appl transplants in mice. Transplantation
epidermis: an immunologic Immunol 1986; 80: 274–277. 1984; 38: 84–86.
microenvironment. In: Fitzpatrick TB, 156. Silvers WK. Studies on the induction 159. Hanau D, Fabre M, Schmitt DA,
Eisen AZ, Wolff K, et al. (eds) of tolerance of the H-Y antigen in mice et al. Appearance of Birbeck granule-
Dermatology in general medicine, 4th with neonatal skin grafts. J Exp Med like structures in anti-T6 antibody-
edn. New York: McGraw-Hill, 1993; 1968; 128: 69–83. treated human epidermal Langerhans
172–197. 157. Silvers WK, Collins NH. The behavior cells. J Invest Dermatol 1988; 90:
155. Kowolenko M, Carlo J, Gozzo JJ. of H-Y-incompatible neonatal skin 298–304.
Histologic identification of cellular grafts in rats. Transplantation 1979; 160. Nestle FO, Nickoloff BJ. Dermal
differences that may contribute to 28: 57–59. dendritic cells are important members
the reduced immunogenicity of 158. Kowolenko M, Gozzo JJ. Comparative of the skin immune system. Adv Exp
transplanted neonatal versus adult study of neonatal and adult skin Med Biol 1995; 378: 111–116.

31

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Exploring the Variety of Random
Documents with Different Content
[Inhoud]
 XIV.

»Je hebt een pracht van een vrouw, Conrad,” zei Guillaume. »Ik heb
nog nooit een tweede gezien, zoo lief, zoo vriendelijk.”

»Dat schijnt Cor ook te denken,” zeide de gelukkige echtgenoot

kortaf, »dadelijk heeft ze haar meegenomen naar die hoek-canapé
en haar mond staat geen oogenblik stil.”

»Waarom sta je dat toe, Coen? Als ik je was, liet ik haar geen
oogenblik met de prinses alleen! Zij heeft haar zondagsch humeur
van daag niet, van morgen bij het kerkhouden liet zij de juffrouw
een preek voorlezen van wel twaalf bladzijden lang, en toen Jantje
van August en mijn Njo daarbij in slaap vielen, kregen zij voor
vandaag huisarrest op droge rijst, kassian!”

»Maar hoe kun je dat toelaten? vraag ik op mijn beurt.”

»Jij zult ook wel toegeven, als je zoover bent. Ik kan dat gezanik
niet uitstaan; je begrijpt dat Toetie of Kitty wel zorgen zullen dat de
kinderen het noodige krijgen. Ik kan die eeuwige ruzie niet velen.
Apaboleh boeat?” 1

»Dat is jelui lijfspreuk, dat heeft August me ook al gezegd.”

»Maar jij bent pas getrouwd, je vrouw weet nog van niets. Hoe
minder zij met Corona omgaat, hoe beter.”

»’t Kan me niets schelen!”

»Heb je nog de bokkenpruik op? Beken toch dat Cor goed voor je
uitgezocht heeft. Leek Toetie maar half op haar! Zeg eens, wat is dat
een flinke vent die Thoren, vind je niet?”

»Ik kan er niet over oordeelen, ik heb hem nog niet gesproken.”

»Hij kan van alles, maar het meeste schik geeft het mij, als ik zie
hoe hij Cor aandurft! Gisteravond heeft zij na lang bidden eindelijk
viool gespeeld; Portias accompagneerde haar, zie je, ’t klonk
prachtig, ik kon niet anders zeggen en hij gaf haar toch een
compliment dat geen compliment was. Ik dacht een oogenblik
[87]dat zij de viool stuk zou slaan op zijn hoofd, maar ze hield zich in,
en van morgen wenschte zij hem nauwelijks goeden morgen!”

»Als ieder zoo bang niet was voor haar, zou zij niet zooveel durven.”

»Ik geloof dat zij papa erg opstookt tegen Portias; de arme kerel
krijgt toch niet meer dan alles vrij en f 50.”

»Hij klaagt toch niet.”

»Wel neen, hij zei me gisteren. »’t Doet me genoegen; papa en

Corona zullen langzamerhand overtuigd raken, dat ik mijn Kitty wou
hebben alleen omdat ik haar lief had, en niet omdat zij de dochter
van de rijke Gérans is.” Zoo iets moest Akkeveen overkomen, die
heeft nooit genoeg naar zijn zin. Maar vertel me nu eens wat van je
vrouw! Hoe prettig voor je dat het zoo uitgevallen is; ze is niet alleen
mooi maar goed bovendien. ’t Doet mij pleizier voor jou, je hebt het
verdiend aan Kitty.”

De goede Guillaume was geen scherp opmerker en het somber

zwijgen van zijn broer op dien gelukwensch viel hem niet op; er
kwamen een paar kleine jongens langs, hij pakte er een beet, wierp
dien in de hoogte, ving hem met de schouders op en draafde de
voorgalerij zoo door tot bij de canapé, waar Corona en Hermelijn
nog zaten.
»Heb je geen moeite om al die kinderen te onderscheiden?” vroeg
Hermelijn.

»Ik ken mijn eigen er nauwelijks uit,” antwoordde hij lachend. »Laat
eens kijken, is dat er een van mij, óf is ’t een broertje of een neefje.
Hoe heet je, vent?” en hij keek naar boven.

»Herman.”

»Dien heb ik niet, dat is een zoon van August, geloof ik! Die kneuter
daar is zijn oom, een heuveltje in vergelijking van Dora August.”

»En de uwe?”

»Lientje, daar komt ze aan. ’t Is No. 3 van de zes, mijn jongste is elf
weken; ja, de klapperboomen zitten hier vol kleine Gérantjes, men
heeft ze maar voor het plukken.”

»Iteko,” riep Corona, die opgestaan was en naar de binnengalerij

wandelde; zij had een lange, slepende grijze peignoir aan met
donkerroode opslagen gegarneerd, een bloedkoralen kam in de hoog
opgestoken haren, bloedkoralen groot als duiveneieren om hals en
armen.

»Zeg me toch eens, wat voor wonderlijke naam dat is?” zei
Hermelijn.

»Iteko, bedoelt u? Wel, dat is Margaretha Jacoba, heb ik eens

gehoord. ’t Is een goed mensch die juffrouw! Zij leert de kinderen
van alles, en bemoeit zich niet met onze zaken, Corona behandelt
haar als een meid en als een koningin.”

»Iteko,” vroeg Corona, toen het bultje voor haar stond, »waar blijft
Margot van morgen?” [88]
»Zij is met meneer Philip, meneer Portias en meneer Thoren uit
rijden gegaan.”

»Zonder mijn verlof op Zondag. ’t Is goed! Zeg haar dat zij vandaag
de kamer niet verlaat.”

»Ook niet voor het eten?”

»Neen.”

Op hetzelfde oogenblik kwam van den achterkant het viertal het erf
oprijden. Margot, die zich dol geamuseerd had, omdat »meneer
Thoren zoo aardig kon zijn” had dicht bij huis plotseling
gewetenswroegingen gekregen.

»Niet daar boven langs, onder langs, dan komen wij niet van voren
aan,” bad zij.

»En waarom dan, juffrouw Margot?” vroeg Thoren.

»Ze is bang voor Cor,” verklapte Philip, »zij heeft haar geen
permissie gevraagd.”

»Ik ook niet,” zei Portias, »en jij Philip?”

»O bij de jongens komt het er niet op aan,” sprak het meisje

weemoedig. »Maar voor de meisjes is zij zeer streng.”

»Kom, het zal zoo erg niet wezen; zullen wij haar ontevredenheid
niet tarten?”

»Och neen, neen, doe het niet! Ze is vandaag toch niet goed
gehumeurd.”

»Niet, en waarom?”
»Omdat u haar gisteravond geen mooi compliment heeft gegeven
over haar vioolspelen,” zeide het meisje schalksch lachend.

»Foei Margot, foei enfant terrible!” verweet Portias haar.

»Kom, je zoudt me nog ijdel maken Margot, waarom zou juffrouw

Corona vragen naar mijn meening; als het nu nog die van Portias
was.”

»O, dat is oudbakken brood, ’t is een straatdeun,” verklaarde deze

oprecht.

»Gaan we nu door den klappertuin?”

»Zullen wij de kleine meid haar zin geven, Portias?”

»Ik ben geen kleine meid meer!”

»Neen, een aardige, groote heks.”

»Och ja, laat ons maar links inslaan, Thoren.”

Nauwelijks kwam Margot, die er in haar lange zwarte amazone met

haar rijhoedje op, reeds geheel als een volwassen dame uitzag, de
trap der achtergalerij op of Iteko kwam haar tegen.

»Foei Margauw,” begon zij op haar zoetsappigsten toon, »hoe heeft

u dat kunnen doen?”

»Weet Cor …”

»Ja en nu mag u den heelen dag niet uw kamer verlaten.”

Margot had verscheidene prettige plannetjes voor den Zondag en nu

werd daaraan op zoo onverwachte wijze een eind gemaakt.
»Cor is een gek!” riep zij, en vergetend dat zij gaarne voor een
verstandige, groote meid werd aangezien, wierp zij haar hoed [89]en
zweep op den grond en begon hardop te schreeuwen en te
stampvoeten, terwijl zij in haar kamer verdween.

»Ze zijn allemaal hetzelfde, die inlandsche kinderen,” mompelde

juffrouw Iteko, hoed en zweep gedwee opnemend.

Juist kwam Thoren ook binnen.

»Hoorde ik Margot daar niet aangaan?” vroeg hij.

»Och ja, zij is wat verdrietig mijnheer, zij heeft kamerarrest

gekregen.”

»Omdat ze uit rijden is geweest?”

»Ik denk het wel mijnheer.”

Thoren van Hagen en Portias gingen naar de voorgalerij en maakten

hun opwachting bij de dames; Corona was statig en koel en
verwaardigde ze nauwelijks met een blik; Thoren van Hagen sprak
haar evenmin aan en onderhield zich met Hermelijn.

Hij zat tegenover haar op een klein tabouret en vroeg hoe het
Indische leven haar beviel; Conrad stond op eenige stappen afstand
en luisterde zonder het te willen doen blijken.

»Java is een paradijs,” sprak zij bitter, »maar niet ieder kan het
waardeeren.”

»Nu, ik blijf voorloopig hier.”

Corona hief ’t hoofd op en zelfs Conrad’s aandacht scheen opgewekt.

»Hier blijven Iwan?” vroeg Hermelijn.

»Ja, ik heb een verrukkelijk plekje gevonden, waar het goed is te
rusten; daarvoor reis ik de aarde rond om er een plaats te vinden,
waar ik gaarne zou blijven, tot … het mij verveelt.”

»En waar is die bevoorrechte plek?” vroeg Corona scherp.

»Bij het meer Ngaroe, in het huis van Bremmers,” haastte Philip zich
te zeggen.

»Kinderen moeten wachten tot hun iets gevraagd wordt: Hou je stil,”
beval Corona.

»De jongeheer heeft het beter gezegd dan ik het zou kunnen. Dat
namen onthouden is mijn kracht niet; ja, ’t is een heerlijk romantisch
punt, ik zal ’t huis huren en laten inrichten.”

»Wie weet voor hoe korten tijd?”

»Men moet het oogenblik vasthouden, ’t gaat zoo snel voorbij. Ik

vind dien inval kostelijk en zou hem niet willen verliezen; morgen ga
ik naar de hoofdplaats en vandaar naar Samarang om meubels en
een piano te koopen.”

»Hij is niet wijs,” mompelde Corona binnensmonds en zocht toen

haar vader op, die rustig in den anderen hoek der galerij zijn courant
las.

»Papa,” sprak zij, »is het huis van Bremmers nog niet verhuurd?”

»Neen kind, wie zou het willen huren?”

»Ik hoor, de mijnheer, die u uit Samarang mee heeft gebracht. Staat
u dat toe?” [90]
»Verhuren zal ik ’t hem niet, maar hij kan het bewonen als hij het
verlangt.”

»Doe me pleizier en weiger ’t hem.”

»En waarom? Thoren van Hagen is een ontwikkeld, aangenaam

mensch, een goede omgang voor je broers.”

»Doe ’t niet!”

»Maar Corona, geef een reden op!”

Zij beet zich op de lippen; iets boosaardigs glimde in haar oogen,

maar dadelijk sloeg zij ze neer en antwoordde niets anders dan:

»U moet het zelf weten, als er ongelukken van komen.”

»Kom, kind, wees verstandig! Wat voor kwaad zou het geven?”

Hij zette zijn lectuur voort, en zij verwijderde zich.

Intusschen gaf Thoren met vuur een beschrijving van het plekje dat
hem geboeid had.

»’t Lijkt een tooversprookje zoo romantisch, zoo wild; verbeeld u,

Hermelijn, een meer groen als een smaragd, omsloten door hooge
rotsen aan eene zijde, waaruit slingers van woekerplanten met
groote, pluimachtige bloemen bevallig neerhangen en dikke boomen
zich door de spleten wringen om dan hun takken droomerig in het
water te laten slepen; eilandjes, die groote bonte bouquetten lijken,
verstrooid over het water, aan de andere zijde hooge waringins en
alang-alang, die het in gele planken opgetrokken paviljoen, bijna
geheel verschuilen. Uw villa is mooi, maar de mijne wint het toch!”

»Altijd even grillig, Iwan!”

»Och ja, met grilligheid bevind ik mij het beste; ik hou niet van lang
vastgestelde plannen, van uitgewerkte levensprogramma’s, van
wissels op de toekomst. Elke dag brengt zijn eigen lief en leed.”

»Gelukkig, die zich de weelde veroorloven kan er grillen op na te

houden,” zei Hermelijn glimlachend.

Juist werden zij voor de lunch geroepen, Thoren naderde Hermelijn

van nabij en vroeg fluisterend:

»Meen je werkelijk dat ik gelukkig ben?”

»Wel neen, zeker niet, men mag immers niet gelukkig zijn op aarde.”

»O Hermelijntje, wat heb je vorderingen gemaakt in levenswijsheid,”

dacht Iwan, maar sprak het niet uit.

’t Was een gezellige rijsttafel, niettegenstaande twee derden het

stilzwijgen niet verbraken; Corona was plotseling levendig en
spraakzaam geworden zelfs tegen Thoren, die het geheele
gezelschap iets mededeelde van het vuur, dat uit zijn gesprekken en
blikken ontsprong.

»Mag ik u een gunst verzoeken?” vroeg hij over de tafel heen aan
Corona bij het dessert. [91]

»Als ik die mag weigeren?”

»Een slecht begin, maar ik roep mijnheer uw vader op mijn hand. Is

het niet wreed, dat bij het eerste familiemaal waarbij een nieuwe
schoonzuster aanzit, een der zusjes afwezig moet blijven?”

»Wie is dat?” vroeg de oude heer de Géran rondziende.

»Juffrouw Margot.”
»Dat ondeugende kind; maar ik wil vandaag genade voor recht laten
gaan, nu zal zij wel in ontoonbaren toestand zijn en niet eens
verlangen hier in ’t openbaar te verschijnen, maar van middag mag
ze zich kleeden Iteko, en aan het diner komen.”

»Op de barmhartigheid der Koningin,” riep Thoren van Hagen zijn

glas opheffend, »voor haar, die genade voor recht laat gaan!”

En toen allen van tafel opstonden na het maal, zeide hij zacht tot
Corona:

»Ik blijf u dankbaar voor die gunst, de eerste, die ik u heb gevraagd.
Moge dat een goed voorteeken blijken!”

»Waarvan?”

»Van uw goedgunstigheid voor het vervolg!”

Hij zag haar aan met zulk een blik, dat Corona plotseling alles om
haar heen zag wentelen; zij kreeg een gevoel zooals zij nimmer nog
had ondervonden, haar oogen flikkerden, haar hand beefde, en
zonder een woord te spreken, verliet zij hem.

»Iteko!” vroeg zij in haar kamer gekomen, »wat zeg je van Thoren’s
plan?”

»Wel juffrouw, wat zou ik er van zeggen. Hij is vrij zich te vestigen,
waar hij wil. En ’t is hier heel mooi.”

»Ik zou willen weten wat hem drijft hier te blijven.”

»Ik heb mijn vermoedens.”

Tot Iteko’s groote verwondering deed Corona geen verdere vragen

meer.
 Wat kan men er aan doen? ↑
1
[Inhoud]
 XV.

»Zullen wij wat samen gaan praten, Hermine?” vroeg Kitty aan hare
schoonzuster, terwijl Conrad, Guillaume en Philip zich naar de
bijgebouwen begaven, vermoedelijk naar de stallen.

In het groote huis was het wel de gewoonte dat ieder na de rijsttafel
zijn weg ging, maar aan slapen deed het jongere geslacht, op enkele
uitzonderingen na, niet veel.

Corona ging lezen of werken aan het handwerk, dat zij met vuur
steeds begon om het later door Iteko te doen voltooien; Kitty en
Portias trokken zich in hun paviljoen terug, de kinderen,
[92]waaronder zelfs Margot en Philip, kregen les in de ruime, geheel
naar de eischen ingerichte schoolkamer, of mochten er zondags
onder Iteko’s waakzaam oog, den tijd korten met allerlei spellen; de
heeren wierpen zich echter bijna altijd in de armen van Morpheus als
zij tenminste geen bepaalde werkzaamheden te vervullen of tochten
door de koffietuinen te maken hadden.

Hermelijn volgde haar zuster naar het paviljoen, waarvan de kleine

buitengalerij geheel met bloemen gevuld was. Achter het bevallige
gordijn van groen klimop met de witte en blauwe klokjes stond een
alleraardigste kleine divan met een tafeltje er voor.

»Daar ontbijten we, als Corona het toestaat,” zeide Kitty met
schitterende oogen.

»Altijd en overal Corona,” sprak Hermelijn geërgerd.

Kitty dwong haar met zacht geweld neer te zitten en toen den arm
om haar hals slaande, vroeg zij deelnemend:
»Zeg me de waarheid Hermine, ben je ongelukkig?”

Hermelijn zag haar met groote starende oogen aan en vroeg terug:

»Zie ik er dan zoo ongelukkig uit?”

»Dat weet ik niet. Dat kan ik niet beoordeelen, maar toen je uit den
wagen stapte, toen waren je oogen heel anders. Is Conrad niet goed
voor je?”

»Zeer goed!”

»Neen, dat zou je niet zoo zeggen. Toen ik pas getrouwd was, o
toen had ik een gevoel of alles mij onverschillig werd, alles behalve
José, of er niemand op de wereld was dan hij. Nu is ’t ook nog wel
zoo, maar natuurlijk men raakt er meer aan gewoon.”

Hermelijn zuchtte.

»Dat weet ik ook! Ik heb ’t zelfde gehad toen ik pas getrouwd was,
in Holland namelijk.”

»Waarom heeft Conrad je dan getrouwd, als hij niet van je hield, als
hij niet lief voor je wilde zijn.”

Verwonderd zag Hermelijn Kitty aan; zij wist van niets, zwijgend had
Conrad het offer gebracht, waarvan zij de bittere gevolgen droeg.

»Vertel mij alles Kitty,” verzocht zij, »’t is beter dat ik alles weet, ’t
zal gemakkelijker gaan mijn rol te spelen als één weet dat het een
rol is. Ja, Conrad en ik leven als geslagen vijanden, we spreken
elkaar niet aan, hij heeft me gezegd dat hij me haat evenals Corona.
Dat was zijn declaratie,” ging zij bitter voort. »De brieven die hij me
schreef waren valsch; zeg, werd er een meisje ooit meer bedrogen
dan ik?”
»O, die Corona,” zuchtte Kitty.

»’t Is schandelijk maar wat moet ik doen? Ik kan toch niet weigeren
bij Conrad te blijven en de spot worden van geheel Indië, waar de
familie de Géran algemeen bekend is? Een ding blijft me over:
geduldig wachten, en dat is het juist wat mij zoo zwaar [93]valt. Nu
denkt Corona, nu ik tevredenheid huichel, dat haar list gelukt is, dat
hij toe heeft gegeven, dat ik reden heb haar te bedanken voor mijn
schitterende positie; zij vermoedt niet, hoe rampzalig ik ben.”

Kitty begon te schreien.

»Ach, ik weet het lieve zuster, ’t is zoo akelig, ongelukkig te zijn, ik

weet het bij ondervinding; ik zal je later vertellen, hoe slecht wij
geweest zijn, maar we hielden zooveel van elkaar en er was geen
hoop om anders haar toestemming te krijgen. Ik wilde dat zij zelf
iemand lief kreeg, dan zou ze eens ondervinden hoe ongelukkig zij
anderen maken kan.”

»Ik wensch haar niets toe; dat zij niet verder in mijn leven taste, ’t
heeft reeds ongeluk genoeg veroorzaakt.”

»Maar is er nu niets aan te doen Hermine, niets? Wil Conrad dan

niet inzien, hoe lief je bent? Ik zou ’t hem willen zeggen, maar hij
wordt dadelijk zoo driftig.”

»Zeg hem niets Kitty; laten wij het samen uitmaken, mijn trots
beveelt me tegenover allen behalve jou de gelukkige vrouw te
blijven, maar aan den anderen kant moet ik Corona toch doen
voelen, hoe haar plannen slechts strekten tot mijn ongeluk.”

»Dat verdient zij ook! Durf je het zeggen?”

»Het durven?” en Hermelijn’s lippen krulden zich trotsch, »het

durven, meen je, dat ik haar vrees, die vrouw zonder hart?”
»Dat moet je niet zeggen Hermine, daarvoor ken je haar niet
genoeg. Cor heeft wel degelijk een hart en een goed hart ook.”

Hermelijn dacht aan Corona’s uitval op dien morgen tegen goede

harten, maar Kitty vervolgde:

»Zooals zij voor me geweest is, zooals zij dag en nacht op mij
gepast heeft toen ik klein en ziekelijk was, hoe lief zij mij altijd
aankleedde en niets voor mij te mooi of te duur vond, dat kan ik niet
vergeten. Nooit kreeg ik van haar een kwaad woord, alle avonden
kwam ze mijn klamboes 1 sluiten na mij een nachtkus te hebben
gegeven. Ach, ze was zoo goed, zoo lief! Je lacht er om Hermine! Je
kunt het je niet begrijpen, maar ’t is toch zoo! Al is zij soms scherp
en onbillijk, zij meent het zoo goed.”

»’t Eerste goede wat ik van haar hoor! Wat is ze dan veranderd!”

»Alleen tegen mij, en ik heb ’t verdiend. Waarom moest ik ook juist

Portias lief krijgen, dien zij niet lijden mocht, of neen, dat deed ze
vroeger niet. Zij had heel iets anders voor mij gedroomd, die goede
Corona maar ik, domoor, moest een armen muziekmeester hebben,
kost wat kost! Als zij van iemand houdt dan heeft ze alles voor hem
over.”

»Dan schijnt ze al heel weinig van Conrad te houden.”

»Zij meende het goed, zeg ik je, en waarlijk wat kon die nare
[94]jongen meer verlangen dan zoo’n allerliefst vrouwtje? Hij is met
blindheid geslagen, maar voor alle broers en zusters is zij goed, zelfs
voor Akkeveen, dien zij niet kan uitstaan en, zooals zij de moeder
van de kleintjes verzorgd heeft in haar laatste ziekte, ofschoon zij
volstrekt niet met haar overweg kon, dat is boven alle beschrijving.
Neen Hermine, ik begrijp ’t wel, je hebt heel veel grieven tegen
Corona, maar haar heelemaal veroordeelen mag je niet, zoolang je
haar niet beter kent.”

»Maar ben je de eenige niet, Kitty, die zoo goed van haar denkt?”

»Och, ze zijn allemaal bang voor haar, dat is zoo, maar ze weten ook
dat als ze werkelijk iets noodig hebben, zij altijd van goeden wille is
hen te helpen. De helft van August’s kinderen heeft zij voor haar
rekening genomen; als er een Javaan ziek is dan gaat zij hem
bezoeken, voor de kraamvrouwen laat zij versterkend voedsel koken,
we lachen er haar om uit, want die zijn dikwijls zoo raar, ze lusten
het niet of doen er sambel in; ze doet zich slechter voor dan ze is.
Wij zijn niet allemaal lieve menschen, Hermine, er zijn akelige
jongens bij en vervelende meisjes, maar dat verzeker ik je, wij
hebben gevoel en dat kan niet van ieder gezegd worden. Daar heb
je nu bijvoorbeeld Akkeveen, die man is zoo droog als een hout, hij
kan Dolly zien sjouwen en hoort haar kinderen huilen zonder zich te
verroeren, dat zou geen van ons kunnen.”

»Zelfs Conrad niet?”

»Conrad is misschien de beste van ons allen. Wanneer je mekaar

leerdet kennen, Hermine, zou je stellig gelukkig worden.”

»Ik wanhoop aan geluk!”

»Kom, dat heb ik ook gedaan en nu ben ik zoo dol gelukkig; wil je
ons huisje zien, wij hebben niet veel want Corona wou niets voor mij
doen, maar Portias heeft er zoo’n pleizier in alles netjes te
arrangeeren.”

Hermelijn volgde haar naar de kamer, die op de binnengalerij

uitkwam; een zwarte piano, zwarte meubels met rotting zittingen,
een gewone mat vormden wel een groot contrast, met de
weelderige inrichting van het hoofdgebouw, maar toch bracht het
geheel den aangenaamsten indruk voort, zoo smaakvol was alles
geschikt.

Fraaie gravuren uit het leven der beroemde componisten, de laatste

droom van Weber, de storm van Händel, Glück bij Marie Antoinette
en Mozart’s sterfbed, versierden de muren, afgewisseld door busten
van Beethoven en andere componisten; op een lessenaar, waarover
muziekpapier uitgespreid lag, stond een metronome, een vioolkast,
en een ruiker bloemen; overal zag men bloemen in sierlijke
hangmandjes, in vazen en potten.

»Hoe vind je ons nestje?” vroeg Kitty met stralende oogen.

»Ik kan me begrijpen, hoe gelukkig je hier bent,” antwoordde

Hermelijn weemoedig. [95]

»Om negen uur gaan wij gewoonlijk naar de kamer, maar dan
blijven we nog lang op, José speelt zoo mooi of componeert, en ik
houd hem gezelschap, dat zijn de prettigste uren van den dag. De
menschen vinden het eentonig dat wij hier zoo in de wildernis
wonen maar je weet niet hoe heerlijk, hoe rustig wij met ons tweeën
leven, zonder vrees van gestoord te worden.”

»Ja, het kan heerlijk zijn,” zuchtte de arme Hermelijn.

»Als Conrad dat wilde inzien maar hij is altijd erg koppig geweest, en
hij wantrouwt je, omdat je een nicht van Corona bent, maar ik ben
er zeker van dat je altijd, zoo ’t noodig is, je man gelijk zult geven
zelfs tegenover haar.”

»Ik dank je, Kitty, je hebt mij het best beoordeeld. We zullen
vriendinnen worden.”
»Maar laat Cor het niet merken dat wij ’t eens zijn, ’t zou voor ons
beiden niet goed wezen.”

Dien avond werd er muziek gemaakt; voor ’t eerst weerklonk

Hermelijn’s lieve stem in de tropische lucht, die Ngaroengan
omringde; zelfs haar schoonvader luisterde en Guillaume was in de
wolken en fluisterde Conrad telkens toe:

»Gelukkige kerel, wees niet ondankbaar! Wat een verschil met mijn
Toetie!”

Corona was verrukt, zij zag er recht blijde uit en eens zelfs vergat zij
zichzelf zoozeer, dat zij Conrad zacht vroeg:

»Ben je mij nu niet dankbaar, dat ik je zoo’n vrouw heb bezorgd?”

»Ik had er je niet om gevraagd,” was het norsche antwoord.

Thoren van Hagen deed ook zijn spel hooren, waaronder Conrad zich
verwijderde: eerst was het Corona’s plan niet te spelen, maar na een
vraag, over de wijnmerken die zij voor te dienen had fluisterde Iteko
haar toe:

»Als ik u een raad geven mag juffrouw de Géran, laat u niet bidden
en speel.”

»Waarom?”

»Omdat hij anders denken zou dat u het liet om hem.”

»Wat een verbeelding!”

Toch volgde Corona den raad op en speelde waarlijk uitstekend. Zij

oogstte niet veel bijval in, maar was tevreden, want Hermelijn zeide
haar eenvoudig:
»U speelt zeer goed!”

»Zulk een compliment stel ik op prijs,” verklaarde zij met een

zijdelingschen blik op Thoren van Hagen.

»Hermelijn spreekt mijn meening uit,” zeide deze, »en gister avond
heb ik ’t zelfde reeds gezegd.”

Toen Conrad met zijn vrouw huiswaarts reed, zeide hij plotseling na
lang stilzwijgen:

»Is dat de mode in Holland, dat de heeren jonggetrouwde

[96]vrouwen bij den naam noemen al zijn ze geen familie van hen en
omgekeerd?”

»Wie deed ’t dan?”

»Die kwast en u.”

»Bedoel je Thoren van Hagen?”

»Ja.”

Een scherp antwoord zweefde om Hermelijn’s lippen. »Welk recht

hebt ge mij dat te verbieden tegenover den vriend mijner jeugd, die
mij meer achting en eerbied betoont, dan gij, mijn man?” Maar zij
weerhield zich en zeide met groote krachtsinspanning zoo zacht en
vriendelijk mogelijk:

»’t Is goed Conrad. Ik wist niet dat het je onaangenaam was, maar
’t zal voortaan niet meer gebeuren.”

In de eenzaamheid overwoog zij nogmaals zijn uitval en dacht:

»Zou ’t waar zijn, wat sommigen beweren, dat daar, waar jaloezie
zich vertoont, de liefde niet ver af is?”
 Gordijnen. ↑
1
[Inhoud]
 XVI.

Den volgenden dag vertrok Thoren van Hagen naar de hoofdplaats

en van daar naar Samarang; hij bleef acht dagen weg en kwam
terug eenige uren nadat een groote vrachtwagen, door karbouwen
bespannen, hoog met meubels opgeladen voor het kleine huis bij
het Ngaroemeer kwam stilhouden.

Natuurlijk was de geheele kolonie de Géran vervuld van de

bijzonderheid, dat een Hollander, zoo pas uit Europa aangekomen,
zich op hun grondgebied kwam vestigen en zich inrichtte of hij er
voor goed wilde blijven.

»Maar, beste Thoren,” vroeg de oude heer de Géran, »ben je

voornemens hier je leven te eindigen?”

»Te eindigen mijnheer, dat staat niet in mijn macht want ik ben
tegen zelfmoord.”

Hermelijn alleen kon vermoeden, welke treurige beteekenis die

woorden in zijn mond hadden.

»Maar of ik het hier zal doorbrengen is nog de groote vraag.

Misschien blijf ik hier jaren, misschien een maand.”

De jonge Gérans en Portias koesterden de grootste belangstelling in

Thoren’s doen en laten, hij had hun harten geheel gewonnen.

»Die meubels zijn heel solide,” verzekerde Guillaume, die van alles
verstand scheen te hebben.
»Maar niet mooi. ’t Is ongelukkig hoe weinig men in Indië [97]nog
aan vormen doet,” zeide Portias, die om de ingepakte piano
drentelde als een mug om de kaars.

»Ik heb genomen, wat er was,” sprak Thoren van Hagen, »ik wil niet
zeggen dat ze mij erg aanstaan, maar voor de binnengalerij heb ik
de modellen geteekend, dan kunnen ze die in djatihout uitvoeren,
dat eikenhout het meest nabij komt. Jonge juffertjes meubelen moet
ik hier niet hebben.”

»Ik ben benieuwd hoe je piano is, Thoren!”

»Niet kwaad, Portias, een mollige toon, ik had liever een vleugel
gehad, maar die was er niet.”

»Je hadt op een vendutie moeten wachten.”

»Die misschien juist plaats heeft als ik er weer aan denk op te

breken.”

»Nu, dat doe je zoo gauw niet, ’t zal je hier stellig veel te goed
bevallen.”

»’t Is me wat lekkers,” bromde Akkeveen, die ook een kijkje kwam
nemen, ofschoon hij al een paar maal had gevraagd of die vreemde
snoeshaan iets achter zijn voorhoofd mankeerde. Een verstandig
mensch ging zich niet begraven in zoo’n wilde boel als die ellendige
negorij.

»Wacht tot het regenmousson is, vriend! Dat alle goten stroomen,
dat je dak lekt, de meubels bederven, dat het meer niets is dan
borrelend water dagen lang, dat je niet rijden, niet loopen, niet
wandelen kunt.”

»Meent u dat ik mij binnenshuis niet zal kunnen amuseeren?”

»Maar je kon voor hetzelfde geld je in Amsterdam, Brussel of Parijs
installeeren, een leven leiden als een prins, eten in de eerste
restaurants, uitgaan met wie je wilt, gij, die zakken vol geld en geen
blokken aan je beenen hebt. Een ander moest in je plaats zijn!”

»Elk zijn smaak, Akkeveen; een volgend jaar eens weer wat anders.”

»Nu, niemand maakt me wijs dat hij er geen bedoelingen mee

heeft,” bromde Akkeveen, »hij zal toch geen idées hebben op de
groote Cor?”

Thoren van Hagen was zelf druk in de weer met de kisten

openslaan, de meubels ontpakken, de schilderijen ophangen en hij
had er bijzonder slag van ook de jonge Gérans aan het werk te
zetten, daar hij de voorzichtigheid van den mandoer 1, die van
Samarang meegekomen was, slecht vertrouwde. Allen stonden
verbaasd over de wijze, waarmede hij zich met het maleisch wist te
redden, na zulk een kort verblijf in Indië.

Hij was in een lichtblauwe kiel gekleed, en als hij naar buiten ging
met zijn grooten stroohoed op, zag hij er meer uit als een
Amerikaansche planter dan als een zoo pas uit Europa aangekomen
oud-officier. [98]

Alle Gérans kwamen hem achtereenvolgens bezoeken, zelfs August.

Zij moesten altijd een paar maal in de week op het groote huis
verslag geven van hun werk en kwamen dan van hun respectieve
woningen naar »beneden;” nu was er een reden te meer om een
extra-verschijning te maken en den nieuwen gast in zijn doen en
laten te bespieden.

»Wel mijnheer August,” sprak Thoren, »hoe bevalt u de inboedel?”

»Jammer, de witte mieren zullen opeten.”

»Witte mieren, zijn die dan hier.”

»Overal witte mieren, vooral onder tapijten.”

»Nu, we zullen er wel raad op weten. De buitengalerij ga ik eens

behangen.”

»Tjitjak 2 maken toch de behangsel kapot.”

»Maar ik kan die ellendige witte muren niet zien. Als ik ze eens
beschilderde, Portias.”

»Dan zal ik u helpen,” riep Philip, die een kist met glaswerk uitpakte,
»ik heb heel veel verf.”

»De vocht bederft toch de verf.”

»Kom, mijnheer August, wees niet zoo zwaartillend.”

»Dat is hij altijd,” zeide Portias, »hij ziet niets dan de schaduwzijde
van de dingen.”

»Vindt u dat geen mooi gezicht op het meer?”

»Kan wel, maar ongezond, alle menschen gaan dood hier.”

»Hebben hier al zooveel gewoond?”

»Je bent de derde, Thoren; toevallig zijn er twee gestorven, maar

die kwamen er ziek aan.”

»En over Bremmers’ dood hangt een sluier.”

»Ik woon vroeger ook hier maar Poppie wil niet langer.”

»Omdat het ongezond was?”

»Neen, zij ziet gendroewo 3, en toen ze moet bevallen, is zij bang,
dat die steelt het kind.”

»Nou, daar was niet veel aan verloren, één van de tien,” merkte
Akkeveen boosaardig aan.

»Wij verliezen toch niet graag één!” zei August met een overtuiging,
die aan het banale woord zekere kracht gaf.

»En vooral niet per gendroewo, dat spreekt.”

»Nu, als die gendroewo voor niets anders te vreezen is, dan kan ze
hier gerust komen.”

»U moet niet zoo praten, als zij hoort of de kalang!”

»Wie is dat?”

»De roode hond, een allerdwaast bijgeloof.”

»Niet dwaas; als u ziet die roode hond, u wordt ongelukkig.”

»Kom, mijnheer August, je bent toch wijzer.” [99]

»Ik zeg maar, wat de menschen vertellen.”

»Als iemand den rooden hond ziet, wordt hij ongelukkig in zijn
liefde,” vertelde Guillaume, »maar de Gérans zijn allen zoo gelukkig
in hun keuzen, daar zij die zelf niet doen, dat de roode hond hun
nooit verschijnt.”

»Conrad ziet hem, toen hij nog jong is!”

»Conrad? Nu, dan is die roode hond het grootste leugenbeest ter
wereld, want hij heeft de mooiste vrouw gekregen, die op God’s
aardbodem leeft.”
»Apa boleh boeat! Mooi, is niet alles.”

»Wel neen, Poppie kan nog meer dan mooi zijn.”

»Poppie is een goede vrouw, maar je weet August:

»Darie mana datang linta?

Darie kali toeron di sawak,
Darie mana dateng tjinta?
Darie mata toeron di atti.” 4

»En zoo zal het met Conrad gaan, al heeft hij ook honderdmaal den
rooden hond gezien.”

»Ik zal het er maar op wagen; woont de kalang hier in de buurt?”

»Hij woont overal en nergens, hij sluipt door de bosschen en schuilt

in de alang-alang, hij verschrikt de tijgers en doet de vogels
wegvliegen.”

»En hoe ziet hij er zoowat uit?”

»Donkerrood met oogen van vuur.”

»Nu, dan zal ik hem wel kennen als ik ’t dier tegenkom!”

»Wees maar blij als je dat monster ziet en hoop dan dat die
voorspelling uitkomt, want liefde brengt niets dan last en dwang.”

»Hoe kan je dat weten, Ak?” vroeg Portias leuk. »Die legende van
den rooden hond is niet onaardig, ik heb beproefd er een kleine
opera van te maken. De Indische opera, ziedaar een veld, dat nog
geheel braak ligt.”

»En dat jij wilt ontginnen?”

»Trachten tenminste. Mijn vermogens zijn zwak, ik weet het, maar
mijn wil is goed en als de bezieling maar eens komt!”

»O zie, wat een beeldige bloemenvaas!” riep Philip bewonderend,

een Boheemsch kristallen horen opheffend, die op zilveren voetstuk
stond.

»Goed voor dames,” zei August.

»Wel, wie weet voor welke schoone dame Thoren het bestemt!” riep
Guillaume. [100]

»’t Is het eenige artistieke ding, dat ik in de toko’s kon vinden; de

gravures zijn afgezaagde platen of opera-decoraties, die aan den
Bijbel ontleend heeten of muziek of schilder- of dichtergroepen even
geaffecteerd van opzet als ordinair van opvatting. Nergens iets
nieuws of oorspronkelijks.”

»Ik ga naar huis, het zal regenen. Bonjour gezelschap! ’t Is een

genot eens ergens te kunnen komen, waar wij zeker zijn Corona niet
aan te treffen.”

»Wat niet is kan komen!” mompelde Guillaume, maar Thoren van

Hagen, die anders een bewonderenswaardig gehoor had, scheen het
niet te hooren.

»Denk je dat het regenen gaat, Gus?”

»Neen, mooi weer!”

»Altijd in de contramine; wil je hem iets laten goedkeuren, Thoren,

begin er dan kwaad van te spreken.”

»Wat is uw Jansje een mooi kind, meneer August.”

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