(Ebook) The Pediatric Upper Limb: Published in

association with the Federation of European Societies

for Surgery of the Hand by Piero Raimondi, Guy Foucher,
Steven E.R Hovius ISBN 9781841841342, 184184134X Pdf
Download

https://ebooknice.com/product/the-pediatric-upper-limb-published-in-
association-with-the-federation-of-european-societies-for-surgery-
of-the-hand-4397862

★★★★★
4.9 out of 5.0 (51 reviews )

DOWNLOAD PDF

ebooknice.com
 (Ebook) The Pediatric Upper Limb: Published in association
with the Federation of European Societies for Surgery of the
Hand by Piero Raimondi, Guy Foucher, Steven E.R Hovius ISBN
9781841841342, 184184134X Pdf Download

EBOOK

Available Formats

■ PDF eBook Study Guide Ebook

EXCLUSIVE 2025 EDUCATIONAL COLLECTION - LIMITED TIME

INSTANT DOWNLOAD VIEW LIBRARY

 We believe these products will be a great fit for you. Click
the link to download now, or visit ebooknice.com
to discover even more!

(Ebook) Biota Grow 2C gather 2C cook by Loucas, Jason; Viles,

James ISBN 9781459699816, 9781743365571, 9781925268492,
1459699815, 1743365578, 1925268497

https://ebooknice.com/product/biota-grow-2c-gather-2c-cook-6661374

(Ebook) Matematik 5000+ Kurs 2c Lärobok by Lena Alfredsson, Hans

Heikne, Sanna Bodemyr ISBN 9789127456600, 9127456609

https://ebooknice.com/product/matematik-5000-kurs-2c-larobok-23848312

(Ebook) SAT II Success MATH 1C and 2C 2002 (Peterson's SAT II

Success) by Peterson's ISBN 9780768906677, 0768906679

https://ebooknice.com/product/sat-ii-success-math-1c-and-2c-2002-peterson-
s-sat-ii-success-1722018

(Ebook) Master SAT II Math 1c and 2c 4th ed (Arco Master the SAT
Subject Test: Math Levels 1 & 2) by Arco ISBN 9780768923049,
0768923042

https://ebooknice.com/product/master-sat-ii-math-1c-and-2c-4th-ed-arco-
master-the-sat-subject-test-math-levels-1-2-2326094
(Ebook) Cambridge IGCSE and O Level History Workbook 2C - Depth
Study: the United States, 1919-41 2nd Edition by Benjamin
Harrison ISBN 9781398375147, 9781398375048, 1398375144,
1398375047
https://ebooknice.com/product/cambridge-igcse-and-o-level-history-
workbook-2c-depth-study-the-united-states-1919-41-2nd-edition-53538044

(Ebook) Rethinking European Welfare: Transformations of European

Social Policy (Published in association with The Open
University) by Janet Fink, Gail Lewis, John Clarke ISBN
9780761972792, 076197279X
https://ebooknice.com/product/rethinking-european-welfare-transformations-
of-european-social-policy-published-in-association-with-the-open-
university-1869578

(Ebook) Contemporary Issues Related to Management of the Upper

Limb in Tetraplegia, An Issue of Hand Clinics by Albert A.
Weiss, Mary Jo Mulcahey ISBN 9781416058151, 141605815X

https://ebooknice.com/product/contemporary-issues-related-to-management-of-
the-upper-limb-in-tetraplegia-an-issue-of-hand-clinics-1394718

(Ebook) Nerve Tendon and Other Disorders (Surgery of Disorders

of the Hand and Upper Extremity) by Raoul Tubiana, Gilbert Alain
ISBN 9781853174940, 1853174947

https://ebooknice.com/product/nerve-tendon-and-other-disorders-surgery-of-
disorders-of-the-hand-and-upper-extremity-2136742

(Ebook) Neurorehabilitation of the Upper Limb Across the

Lifespan: Managing Hypertonicity for Optimal Function by Jodie
Copley, Kathy Kuipers ISBN 9780470670316, 0470670312

https://ebooknice.com/product/neurorehabilitation-of-the-upper-limb-across-
the-lifespan-managing-hypertonicity-for-optimal-function-5151498
Prelims 23/4/02 9:48 am Page i

The Pediatric Upper Limb

Prelims 23/4/02 9:48 am Page iii

The Pediatric
Upper Limb

Edited by

Steven ER Hovius MD PhD

Professor of Plastic and Reconstructive Surgery
University Hospital Rotterdam
Rotterdam, The Netherlands
in collaboration with
Guy Foucher
Piero L Raimondi

Published in association with the

Federation of European Societies
for Surgery of the Hand

MARTIN
DUNITZ
CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742

© 2002 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government works

Version Date: 20130325

International Standard Book Number-13: 978-1-4822-0753-8 (eBook - PDF)

This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to
publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors
or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors,
authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guid-
ance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to
the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions
and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, pro-
cedures or diagnoses should be independently verified. The reader is strongly urged to consult the drug companies’ printed instructions,
and their websites, before administering any of the drugs recommended in this book. This book does not indicate whether a particular
treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make
his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted
to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in
this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in
any future reprint.

Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by
any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in
any information storage or retrieval system, without written permission from the publishers.

For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.
com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-
profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy
license by the CCC, a separate system of payment has been arranged.

Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and
explanation without intent to infringe.
Visit the Taylor & Francis Web site at
http://www.taylorandfrancis.com

and the CRC Press Web site at

http://www.crcpress.com
Prelims 23/4/02 9:48 am Page v

CONTENTS

List of contributors vii 8 Thumb polydactyly 75

Introduction xi Alain Gilbert with Michael A Tonkin
and Steven ER Hovius
1 Syndromic hand anomalies 1
Raoul CM Hennekam 9 Symbrachydactyly 91
Steven ER Hovius, Teun JM
2 Clinical genetics of the upper limb 9 Luijsterburg with Guy Foucher,
Esther de Graaff, M Jeljte van Chantal MAM van der Horst and
Baren and Peter Heutink Simon PJ Kay

3 Classification and related 10 Camptodactyly 103

pathoembryology of congenital upper Ulrich Lanz with Guy Foucher, Rolf
limb differences 21 Habenicht, Susanne Kall and
Teun JM Luijsterburg, Christl Hans-Martin Schmidt
Vermeij-Keers and Steven ER Hovius
11 Thumb hypoplasia: a spectrum of
4 Grip development in the growing congenital disorders 133
child 39 Guy Foucher, Jose Medina, Giorgio
Margreet ter Schegget Pajardi and Ricardo Navarro

5 Psychological behaviour of the child 12 Radial club hand 153

with a congenital difference of the Paul J Smith and Gillian D Smith
upper limb 47
Eileen Bradbury 13 Cerebral palsy 183
Caroline Leclercq, Giorgio Pajardi,
6 First approach to a child with a Jole Colombelli, Paolo Zerbinati and
congenital difference of the upper Maurizio Calcagni
limb 57
Luc De Smet 14 Volkmann’s ischaemic contracture 197
Piero L Raimondi, Roberto M
7 Syndactyly 65 Cavallazzi and Steven ER Hovius
David M Evans with Bruno C Coessens
and Rolf Habenicht
Prelims 23/4/02 9:48 am Page vi

vi CONTENTS

15 Replantation and revascularization of 16 Effect of growth on pediatric hand

the upper extremity in children 209 reconstruction 225
Panayotis N Soucacos, Marios Vekris Alain Gilbert
and Alexandros E Beris
Index 233
Prelims 23/4/02 9:48 am Page vii

LIST OF CONTRIBUTORS

Alexandros E Beris Guy Foucher

Professor of Orthopaedics Professor, Department of Orthopedics
Department of Orthopaedic Surgery Las Palmas University
School of Medicine Gran Canaria, Spain
University of Ioannina
15 C. Trikoupi str, Alain Gilbert
Ioannina 45332, Greece Institut de la Main
6, square Jouvenet
Eileen Bradbury 75016 Paris, France
Alexandra Hospital
Mill Lane Esther de Graaff
Cheadle Department of Clinical Genetics
Cheshire SK8 2PX, UK Erasmus University
PO Box 1738
Maurizio Calcagni 3000 DR Rotterdam, The Netherlands
Hand Surgery Unit
Multimedica Hospital, Milan, Italy Rolf Habenicht
Abteilung Handchirurgie
Roberto M Cavallazzi Kinderkrankenhaus Wilhelmstift
Reparto di Chirurgia Plastica e della Mano Liliencronstrasse 130
Ospedale di Legnano 22149 Hamburg, Germany
20025 Legnano, Italy
Raoul CM Hennekam
Bruno C Coessens Pediatrics and Clinical Genetics
Centre Hospitalier Universitaire Brugmann Academisch Medisch Centrum
Place a Van Gehuchten 4 Meibergdreef 9
1020 Bruxelles, Belgium 1105 AZ Amsterdam, The Netherlands

Jole Colombelli Peter Heutink

Hand Surgery Unit Department of Clinical Genetics
Multimedica Hospital, Milan, Italy Erasmus University
PO Box 1738
David M Evans 3000 DR Rotterdam, The Netherlands
The Hand Clinic
Oakley Green Chantal MAM van der Horst
Windsor SL4 4LH, UK Department of Plastic Surgery
Academisch Medisch Centrum
Meibergdreef 9
1105 AZ Amsterdam, The Netherlands
Prelims 23/4/02 9:48 am Page viii

viii CONTRIBUTORS

Steven ER Hovius Ricardo Navarro

Department of Plastic and Reconstructive Professor of Orthopedics
Surgery Department of Orthopedics
University Hospital Rotterdam Las Palmas University
Dr. Molewaterplein 40 Gran Canaria, Spain
3015 GD Rotterdam, The Netherlands
Giorgio Pajardi
Susanne Kall Head, Department of Hand Surgery
Klinik für Plastische Hand- und Milan University - Plastic Surgery Institut
Wiederhestellungschirurgie Multimedica Hospital, Milan, Italy
Klinikum Oststadt
Podbielskistrasse 380 Piero L Raimondi
30659 Hannover, Germany Casa di Cura S Maria – Multimedica
Viale Piemonte, 70
M Jeltje van Baren 21053 Castellanza, Italy
Department of Clinical Genetics
Erasmus University Margreet ter Schegget
PO Box 1738 European Federation of Hand Therapists
3000 DR Rotterdam, The Netherlands Zuideinde 6
9497 PS Donderen, The Netherlands
Simon PJ Kay
Department of Plastic Surgery Hans-Martin Schmidt
St James’s University Hospital Anatomisches Institut der Universität Bonn
Leeds, UK Nussallee 10
53115 Bonn, Germany
Ulrich Lanz
Klinik f(r Handchirurgie Luc de Smet
Salzburger Leite 1 Universitaire Ziekenhuizen Leuven
97616 Bad Neustadt, Germany UZ Pellenberg
Weligerveld 1
Caroline Leclercq 3212 Lubbeck (Pellenberg), Belgium
Institut de la Main
6, square Jouvenet Gillian D Smith
75016 Paris, France Clinical Hand Fellow
Department of Plastic and Reconstructive
Teun JM Luijsterburg Surgery
Research Institute Plastic and Reconstructive Great Ormond Street Hospital for Children
Surgery Great Ormond Street
Erasmus University Rotterdam – HEE 1253 London WC1 3JH, UK
P.O. Box 1738
3000 DR Rotterdam, The Netherlands Paul J Smith
Consultant Hand Surgeon
Jose Medina Department of Plastic and Reconstructive
Hand Surgeon Surgery
Department of Orthopedics Great Ormond Street Hospital for Children
Las Palmas Great Ormond Street
Gran Canaria, Spain London WC1 3JH, UK
Prelims 23/4/02 9:48 am Page ix

CONTRIBUTORS ix

Panayotis N Soucacos Christl Vermeij-Keers

Professor, Department of Orthopaedic Surgery Research Institute Plastic and Reconstructive
University of Ioannina Surgery
Ioannina 45110, Greece Erasmus University Rotterdam – HEE 1253
P.O. Box 1738
Michael A Tonkin 3000 DR Rotterdam, The Netherlands
Department of Hand Surgery and Peripheral
Nerve Surgery Paolo Zerbinati
Royal North Shore Medical Centre Hand Surgery Unit
St. Leonards, NSW 2065, Australia Multimedica Hospital, Milan, Italy

Marios Vekris
Lecturer of Orthopaedics
Department of Orthopaedic Surgery
School of Medicine
University of Ioannina
Ioannina, Greece
Prelims 23/4/02 9:48 am Page xi

INTRODUCTION

It has become a tradition to publish a book that the first consultation, are touched on. Clearly it
includes papers of the presentations from the is impossible to cover all subjects. Therefore we
instructional courses of every meeting of the have chosen to present the more common
Federation of European Societies for Surgery of problems together with case presentations and
the Hand (FESSH). This series has already discussions. In this way this instructional course
covered the subjects of wrist instability, stiff book distinguishes itself from the classical
joints, finger bone and joint injuries, and brachial textbook, in that it does not purport to be
plexus injuries. The eighth FESSH meeting in ‘complete’, although there are some insightful
2002 in Amsterdam is devoted to the subject of and in-depth presentations on technique.
the ‘Pediatric Upper Limb’. The selected subjects are syndactyly,
An intriguing part of any problem concerning polydactyly, thumb hypoplasia, camptodactyly,
the upper extremities encountered in childhood is symbrachydactyly and radial dysplasia. Diseases
the influence of growth and the great variety in that are less common and quite difficult to treat,
congenital differences. Treatment is particularly such as cerebral palsy, Volkmann’s ischemic
challenging in the latter group and creativity is a contracture and replantations and revasculariza-
necessity. It is also clear that a sound knowledge tions in children are subjects that cannot be
of pathoembryology, pathological anatomy, grip omitted when dealing with the paediatric upper
development and psychosocial behaviour is extremity. Fractures in children and obstetrical
necessary in order to guide these children, with brachial plexus injuries have been dealt with in
the help of their parents, through their develop- earlier books in this series and are therefore not
ing years. The emphasis on early treatment in included here. A logical closing to the book, as
these children requires an insight into multifari- stated earlier, covers the problems encountered
ous and complex problems, and one is constantly with growth in the paediatric upper limb.
having to justify and re-evaluation one’s desire to This book took a little more than a year to
help and treat a patient—‘primum nil nocere’— complete and to this end the editors wish to
and in view of this, renowned experts were express their gratitude to the authors for their
invited to participate in this book. continued support, commitment and splendid
With respect to congenital differences, the contributions and without the help of the
topics of syndromology, clinical genetics, publishers—Martin Dunitz—particularly that of
pathoembryology, grip development, psycholog- Robert Peden and Clive Lawson, the production
ical behaviour and the approach to the child at of this book would never have been possible.

Steven ER Hovius
ch01 23/4/02 10:39 am Page 1

1
Syndromic hand anomalies
Raoul CM Hennekam

An isolated hand anomaly is a frequently occur- from cell biology and developmental biology in
ring finding in daily practical care, and often the field should allow a classification of
forms a challenge for the clinician in reaching the syndromic hand anomalies that is based on the
right diagnosis, and inherent to this, the right pathogenesis. Such a classification has already
prognosis, therapeutic regime and genetic been used for isolated cases of syndactylism and
counselling to both the patient and their polydactylism by Winter and Tickle (1993), but
relatives—a diagnostic process that often can now be considerably expanded (Table 1).
depends solely on localized symptoms and the However, such a classification should be consid-
expertise of the investigator. ered provisional due to the rapid further expan-
However, a high percentage of patients with sion of our knowledge on the subject.
congenital hand anomalies also show symptoms
elsewhere, mainly in the craniofacies, which can
be extremely helpful in reaching the right
diagnosis. As with the limbs, the craniofacies
Table 1 Provisional classification of syndromic hand
share a greater susceptibility to any kind of anomalies by pathogenetic background
congenital anomaly, not only as malformations,
but also disruptions, deformations and morpho- Pathogenic factor Example
logical variations (Gorlin et al 2001). This can be
Vascular disturbance Hypoglossia–hypodactyly
attributed in part to their developmental
Apoptosis Bartsocas–Papas syndrome
complexity, the extended period of morphogen- Signalling gene Smith–Lemli–Opitz syndrome
esis, and the exposure of the craniofacies and Ligand Spondylocostal dysostosis
limbs beyond the protection of the body wall Trans-membrane receptor Gorlin syndrome
(Stevenson and Meyer 1993). Nearly all human Tyrosine kinase Apert syndrome
G protein Allbright syndrome
teratogens and chromosome anomalies affect Transcription factor Greig syndrome
both the limbs and the outer parts of the body Structural gene Marfan syndrome
and the same holds for single gene mutations—
Winter and Baraitser’s London Dysmorphology
Database (1999) lists 1889 dysmorphologic
entities that have at least one limb symptom.
A complete overview of all syndromic limb
defects cannot be provided in a single chapter Basic principles
and this necessitates a choice in subjects. In the
past such a review would have been based on Orthopaedic, plastic, and reconstructive sur-
an anatomical classification such as that of geons are not always familiar with the terminol-
Temtamy and McKusick (1978), the International ogy used in molecular and developmental
Clearinghouse for Birth Defects Monitoring biology, so a few basic principles are
Systems (Rosano et al 2000), or the EUROCAT summarised for clarity. Furthermore, our
registration (Stoll et al 1998). However, the increased understanding of the pathogenesis in
recent advances in molecular biology, not only congenital anomalies has revealed several
in limb development but also within the field of unexpected relationships; these are also
syndromology, and the application of knowledge discussed.
ch01 23/4/02 10:39 am Page 2

2 THE PEDIATRIC UPPER LIMB

Human genome lateral mesoderm gives rise to the blood, vascu-

lature and heart.
The entire human genome contains approxi-
mately three billion nucleotides (DNA base pairs)
that together encode for 35 000–45 000 different
Neurulation
genes. These genes are packed together in 23
pairs of chromosomes, in such a way that every Neurulation is the next stage in embryonic devel-
human somatic cell nucleus contains the entire opment following gastrulation and corresponds
human genome. Every individual gene can to the formation of the neural tube by closure of
produce one or more transcription products, the neural plate, directed by the underlying
namely, proteins that exhibit structural, regula- notochord. The neural plate is a region of early
tory or enzymatic activity. The original idea of a embryonic ectodermal cells, known as the
single gene producing a single protein with a neuroectoderm that lies directly above the
single function, and thus any mutation of a notochord. During neurulation, these neuroecto-
single gene causing a specific single disorder has dermal cells change shape, fold in on themselves
now been completely abandoned. We now know (the neural fold) and fuse to form the neural
that a single gene may cause different disorders, tube. The neural tube gives rise to the brain,
that a single disorder may be caused by spinal chord, and the ganglia.
mutations in different genes, and that a single
gene may have different functions with time, for
instance acting prenatally as a developmental Limb bud
gene and postnatally as a tumour suppressor
The limbs of vertebrates start as outgrowths of
gene.
mesenchymal cells surrounded by a simple
epithelium. The tip of the limb is thicker and is
called the apical ectodermal ridge (AER). The
distal region is referred to as the progress zone;
Gastrulation it depends upon the AER and contains cells in
During the embryonic development of most active proliferation. There has been extensive
animals a complex and coordinated series of study of positional information within the limb
cellular movements occur at the end of cleavage. bud that has determined, for example, the proxi-
During gastrulation the three embryonic axes mal-distal pattern of bone development and the
(dorso-ventral, cranio-caudal and medio-caudal) anterior-posterior specification of digits.
are established (or become apparent if they have
been established before depending on the
species). The details of these movements, called Organogenesis
gastrulation, vary from species to species, but
Organogenesis is the formation of the organs as
usually result in the formation of the three
they appear in the adult. Initially one or more
primary germ layers—the ectoderm, mesoderm,
groups of cells occupy or migrate into a territory
and the endoderm. The ectoderm gives rise to
that will later form that specific organ (anlagen).
the surface epithelia and the nervous system,
These cells proliferate, undergo morphogenetic
and the endoderm to the gut and related organs.
changes (morphogenesis) and then differentiate
The mesoderm is immediately patterned in an
into the specialized cells that form the various
axial chord, the notochord, which leads to the
tissues (histogenesis) of the organ.
formation of the neural tube (neurulation). On
both sides of the notochord, the paraxial
mesoderm segments in a cranio-caudal direction
Morphogenesis
to form somites—epithelial spheres that later
differentiate from the ventral sclerotome to form Morphogenesis is the process of shape forma-
the axial skeleton, and from the dorsal dermo- tion—a process that is responsible for producing
myotome to form skeletal muscle and the the complex shapes of adults from a simple ball
dermis. Lateral to the somites, the intermediate of cells that was derived from division of the
mesoderm forms the urogenital system, and the fertilized egg.
ch01 23/4/02 10:39 am Page 3

SYNDROMIC HAND ANOMALIES 3

Embryonic induction is a rare event that can be more easily observed

in cultured cells. In newts for example, the
Embryonic induction is the process by which
pigmented cells of the iris trans-differentiate to
differentiation in one tissue is influenced by its
form lens cells if the existing lens is removed. In
proximity to another tissue, arising for example
vertebrates, smooth cells of the oesophagus
during gastrulation. One of the best-known
trans-differentiate to form skeletal muscle.
examples is the induction of the neural tube in
the ectoderm by the underlying chordo-
mesoderm. In order to respond to inducing
signals (secreted or membrane-bound signalling Signalling cells
molecules) responding cells must be competent,
Developmental processes are regulated by a
that is, they must express receptors and post-
network of signal transduction pathways that
receptor intracellular signalling molecules that
relay and integrate information from outside the
allow translation of the inducing signals to the
cell through a receptor in the cell membrane to
nucleus.
the nucleus to regulate the expression of target
genes. These extracellular signals are usually
‘ligands’, such as diffusible growth factors or
Determination extracellular proteins, which bind to membrane
receptors (Fig. 1). There is also a propagation of
Once a cell has committed to a particular path of information from the nucleus outwards to alter
differentiation, even though there may be no structures in the cytoplasm, to modify the cell’s
morphological features that reveal this move, responsiveness to signals from the outside and
determination is said to have occurred. Generally to affect the activities of neighbouring or distant
there is a first phase where, in response to induc- cells.
ing signals, responding cells activate the Many receptors in cell membranes exhibit
transcription of determination genes. If the enzymatic kinase activity, which catalyzes the
induction signals are withdrawn, these genes transfer of a phosphate group from adenosine
may be deactivated; this phase of determination triphosphate to the side chains of substrate
is thus reversible, but after a certain period amino acids. Such phosphorylation causes
(usually a few hours) determination genes act on subtle changes in the conformation of the
other genes (and frequently on their own substrates altering their enzymatic activity or
promoter) and determination becomes regulatory properties. With changes in such
irreversible from the original inducing signals. protein activity, signals are propagated into
circuits or networks. The function of proteins can
also be altered by conformational changes.
Some proteins act as transcription factors, which
Differentiation
increase or decrease transcription of specific
Differentiation is a process in the development genes within chromosomal DNA. This leads to
of a multi-cellular organism in which cells qualitative and quantitative changes in protein
become specialized for particular functions. synthesis. The overall effect of these signalling
Differentiation requires selective expression of pathways and their regulation of gene expres-
portions of the genome and the fully differenti- sion is to control cell proliferation, migration,
ated state may be preceded by a stage in which differentiation and programmed cell death
the cell is already programmed for differentiation (apoptosis). The coordinated control of groups of
but is not yet expressing the characteristic cells is fundamental in the formation of complex
phenotype (determination). structures.

Trans-differentiation Cascades
Trans-differentiation is the change of a cell or In embryology genes seldom, if ever, function
tissue from one differentiated state to another. It alone. Usually embryogenesis is regulated by
ch01 23/4/02 10:39 am Page 4

4 THE PEDIATRIC UPPER LIMB

Figure 1

Developmental processes are

regulated by networks of signal
transduction pathways that relay
and integrate information from
outside the cell through a mem-
brane receptor to the nucleus, thus
regulating the expression of target
genes (Breugem et al 2001).

complex signalling cascades, in which the the same time in SIX3 (located on chromosome
function of one gene product (protein) is depen- 2p21) and ZIC2 (located on chromosome 13q32)
dent on the function of another. It becomes in patients with holoprosencephaly (Muenke and
increasingly clear that differences in phenotypic Beachy 2001), and mutations in two different
expression of mutated genes are at least in part genes of the five genes (all located on different
determined by the functioning of the other genes chromosomes) are known to cause Bardet-Biedl
involved in the cascade. Indeed in several disor- syndrome (Katsanis et al 2001). The occurrence
ders mutations have now been found in two or of mutations in different genes on different
more different groups within the same cascade, chromosomes within the same patient was first
which can explain the differences in clinical regarded with disbelief, but now provides a new
symptoms within families. Examples of such insight in the principle of monogenic entities; it
differences are mutations in genes Sonic may well be that monogenic entities are uncom-
Hedgehog (located on chromosome 7q36) and at mon, and most entities are in fact polygenic.
ch01 23/4/02 10:39 am Page 5

SYNDROMIC HAND ANOMALIES 5

Sonic Hedgehog Holoprosencephaly Figure 2

The human Sonic Hedgehog–

N-Sonic Hedgehog attached to Cholesterol Smith–Lemli–Opitz syndrome Gli–CREB pathway and associated
links to human disorders. The
pathway has been simplified to
Patched-1 Gorlin syndrome those genes where human disor-
Basal cell carcinoma ders are known. The regulatory
Medulloblastoma mechanisms (such as the stimula-
tion or suppression of genes) are
not indicated. A more extensive
Patched-2 Basal cell carcinoma
review of the pathway can be
Medulloblastoma
found elsewhere (Villavicencio et
al 2000).
Smoothened Basal cell carcinoma
Medulloblastoma

Gli-1 Glioblastoma
Rhabdomyosarcoma
Osteosarcoma
Basal cell carcinoma

Gli-3 Greig syndrome

Pallister–Hall syndrome
Postaxial polydactylism type A

CBP Rubinstein–Taybi sydrome

TWIST Saethre–Chotzen syndrome

A well-known example of a signalling cascade syndrome, in which a disturbance of the choles-

is the Sonic Hedgehog–Gli–CREB pathway terol metabolism can give rise to different
(Fig. 2). Mutations in genes within this pathway symptoms such as polydactylism, heart defects,
often give rise to syndromes that are accompa- absence of the callosal body, and sex reversal
nied by limb defects. Indeed the phenotypes may (Kelley and Hennekam 2000). A disturbance at
resemble each other to a great extent, such as another step of the same cholesterol metabolism
the hand and facial anomalies found in Greig can lead to a completely different clinical picture
syndrome, Rubinstein–Taybi syndrome, and such as that found in desmosterolosis
Saethre– Chotzen syndrome (Fig. 3). The occur- (Waterham et al 2001). The co-occurrence of
rence of these mutations in genes all acting congenital anomalies and a metabolic disorder
within the same pathway may contribute to the has already been reported in other entities such
apparent phenotypic resemblances. as in Zellweger’s syndrome (Goldfischer et al
1973), but at that time it was not realized that this
was a general principle—that a congenital disor-
der can also be caused by a disturbance in
Metabolic disorders and congenital
human metabolism.
anomalies
The prototypic symptoms of a metabolic disor-
der are a child who shows no symptoms at birth
Cancer and congenital anomalies
and who shows an increasing delay in develop-
ment and/or physical problems in later life. It has In the past congenital anomalies and tumours
become clear that many metabolic disorders can were thought to belong to different groups and
in fact cause congenital anomalies (Gorlin et al to be pathologically unrelated. In the last decade
2001). A major example is the Smith–Lemli–Opitz however, an increased incidence of specific
ch01 23/4/02 10:39 am Page 6

6 THE PEDIATRIC UPPER LIMB

tumours in several syndromes has been

reported, such as leukaemia in Noonan
syndrome and CFC syndrome (Van de Berg and
Hennekam 1999), medulloblastoma in
Rubinstein–Taybi syndrome (Miller and
Rubinstein 1995), and Wilms tumour in
Beckwith–Wiedemann syndrome (Wiedemann
1997). Several entities that show both congenital
anomalies and tumours were in fact already long
known, such as Down syndrome (leukaemia),
a MEN2b syndrome (thyroid carcinoma), and
Gorlin syndrome (basal cell carcinoma). In
addition, in several pathways it has been found
that mutations in one gene of the pathway can
give rise to a tumour while mutations in another
gene of that same pathway may cause a malfor-
mation syndrome. The Sonic Hedgehog–
Gli–CREB pathway is a good example in this
respect (Fig. 2).
This has all added proof to the general princi-
ple that a developmental gene has different
functions at different moments in human life and
thus mutations can cause different types of
disorders depending on time. A mutated gene
can cause a congenital anomaly if the function
(or another related function) is disturbed in later
life. This has had a great impact on the surveil-
lance of children with congenital anomalies—the
increased risk of developing cancer in several
specific disorders has led to careful follow-up
b programmes and our growing awareness of such
risks will undoubtedly have a knock-on effect
when dealing with other disorders.

Conclusion
Modern molecular genetics and developmental
biology have provided us with better tools to
understand the symptoms displayed in children
and adults with congenital anomalies. It has also
provided us with unexpected insights into the
pathogenesis of the disorders and revealed
relationships that were considered unlikely to
c
exist in the past.
Figure 3 We should not forget, however, that careful
clinical observations are crucial. In patients with
Three examples of syndromes resulting from a disturbance congenital hand anomalies this means that the
of different genes within the Sonic Hedgehog–Gli–CREB
surgeon will investigate the hands of the child or
pathway. (a) Greig syndrome (mutation in Gli-3), (b)
Rubinstein–Taybi syndrome (mutation in CBP), (c) adult carefully and keep detailed systematic
Saethre–Chotzen syndrome (mutation in TWIST). records. It also means that everyone with a
ch01 23/4/02 10:39 am Page 7

SYNDROMIC HAND ANOMALIES 7

congenital hand anomaly deserves a careful associated with major congenital anomalies: clinical
investigation of other parts of the body by and epidemiological study from the International
someone (usually a pediatrician or clinical Clearinghouse for Birth Defects Monitoring Systems,
geneticist) who is aware of the symptoms that Am J Med Genet 93:110–16.
might be present. Without this the affected
Stevenson RE, Meyer LC (1993) The Limbs. In:
person will not obtain what we all pursue— Stevenson RE, Hall JG, Goodman RM, eds, Human
optimal care. Malformations and Related Anomalies (Oxford
University Press: New York) 699–804.

Stoll C (1998) Classification of limb defects, Am J Med

References Genet 77:439–41.

Breugem C, Van der Horst CC, Hennekam RCM (2001) Temtamy SA, McKusick VA (1978) The Genetics of
Towards the understanding of vascular malformations, Hand Anomalies (Alan R Liss: New York).
Plastic Reconstr Surg 107:1509–23.
Van den Berg H, Hennekam RCM (1999) Acute
Goldfischer S, Moore CL, Johnson AB et al (1973) lymphoblastic leukaemia in a patient with cardiofacio-
Peroxisomal and mitochondrial defects in the cerebro- cutaneous syndrome, J Med Genet 36:799–800.
hepatorenal syndrome, Science 182:62–64.
Villavicencio EH, Walterhouse DO, Iannaccone PM
Gorlin RJ, Cohen MM Jr, Hennekam RCM (2001) (2000) The Sonic Hedgehog–Patched–Gli pathway in
Syndromes of the Head and Neck, 4th edn (Oxford human development and disease, Am J Hum Genet
University Press: New York). 67:1047–54.

Katsanis N, Ansley SJ, Badano JL et al (2001) Triallelic Waterham HR, Koster J, Romeijn GJ et al (2001)
inheritance in Bardet–Biedl syndrome, a Mendelian Mutations in the 3beta-hydroxysterol delta24-reductase
recessive disorder, Science 293:2256–59. gene cause desmosterolosis, an autosomal recessive
disorder of cholesterol biosynthesis, Am J Hum Genet
Kelley RI, Hennekam RCM (2000) The Smith–Lemli– 69:685–94.
Opitz syndrome, J Med Genet 37:321–35.
Wiedemann HR (1997) Frequency of Wiedemann–
Miller RW, Rubinstein JH (1995) Tumours in Beckwith syndrome in Germany; rate of hemihyper-
Rubinstein–Taybi syndrome, Am J Med Genet plasia and of tumours in affected children, Eur J
56:112–15. Pediatr 156:251.

Muenke M, Beachy PA (2001) Holoprosencephaly. In: Winter RM, Baraitser M (1999) The London
Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Dysmorphology Database (Oxford University Press:
Kinzler KW, Vogelstein B, eds, Metabolic and Molecular Oxford).
Bases of Inherited Disease (McGraw-Hill Publishers:
New York) 6203–30. Winter RM, Tickle C (1993) Syndactylies and
polydactylies: embryological overview and suggested
Rosano A, Botto LD, Olney RS et al (2000) Limb defects classification, Eur J Hum Genet 1:96–104.
ch02 23/4/02 8:05 am Page 9

2
Clinical genetics of the upper limb
Esther de Graaff, M Jeltje van Baren and Peter Heutink

Introduction Many of the genes involved in limb formation

have been identified in the chicken and mouse.
In the past decade rapid advances have been These organisms have been used extensively to
made in the identification of human genes that study embryonic development and much insight
play a role in upper limb malformations. It is only has been gathered from manipulation of limb
10 years ago that the first gene associated with development. However, our insight in limb
a human limb malformation was identified—in development is far from complete.
the Greig cephalopolysyndactyly syndrome, To identify new genes involved in limb forma-
characterized by digital malformations and a tion, several approaches can be used, such as
peculiar skull shape; mutations were detected in interaction studies with known proteins to
the GLI3 gene (Vortkamp et al 1991). Now, many identify their binding partners. One of the most
more mutations responsible for upper limb powerful methods of finding genes involved in
malformations have been found in a large limb development is the identification of genes
number of genes, elucidating the understanding responsible for hereditary limb malformations.
of normal limb development. The most frequently used strategy for the
In humans, malformations of the upper limb identification of disease-causing genes in
occur in approximately 1 in 626 new-borns (Flatt humans is positional cloning. In this procedure,
1994). These malformations occur isolated, the chromosomal localization of the disease
meaning that no other abnormalities are seen in gene is determined first. Some diseases are
the patient, or they are found in combination associated with gene defects caused by chromo-
with other hand and/or foot malformations, or somal abnormalities, which can be detected with
as part of a syndrome. In all cases, the cause of a microscope. Unfortunately, only a minority of
the malformation(s) may be genetic, environ- cases shows these obvious abnormalities.
mental, or a combination of these factors. Therefore, the genomic localization of the
Although most inherited hand malformations disease is more frequently done by linkage
are single gene disorders, patients from a single analysis. This method is based on the rationale
family often show a range of phenotypes that all affected family members must share a
indicating that other genes and/or the environ- genomic region, which contains the mutated
ment play a role in the phenotypic variability of gene, whereas the unaffected individuals are less
the disorder. likely to share this region. The exact procedure
Defects in limb formation are not always due of linkage analysis falls outside the scope of this
to genetic causes. Restriction of blood flow to the chapter; excellent reviews can be found in most
developing limb, for instance, leads to limb textbooks on human genetics (e.g. Human
reduction abnormalities such as truncation or Molecular Genetics by Strachan and Read 1999).
oligodactyly. A well-known cause of limb trunca- The disease region identified by linkage analysis
tions and other defects was the use of thalido- often contains more than one gene. Mutation
mide, better known as Softenon, in the 1970s. analysis of these genes in patients is performed
Thalidomide is an inhibitor of angiogenesis to identify the mutation causing the limb
(blood vessel formation) and this inhibition was malformation. Such a positional cloning project
probably the cause of the limb malformations. is a considerable task, which involves close
ch02 23/4/02 8:05 am Page 10

10 THE PEDIATRIC UPPER LIMB

cooperation of GPs, clinical geneticists and The proximodistal axis

molecular biologists in order to find as many
affected and unaffected family members as Human transversal limb malformations are most
possible, obtain blood samples for DNA analysis likely caused by defects in differentiation along
and perform the study. the proximodistal axis. Cells at the tip of the limb
In order to understand how genetic alterations bud form the apical ectodermal ridge (AER)—a
can lead to malformations of the upper limb, an thin, tightly packed band of epithelial cells which
overview will be given of the genetics of normal signals to the underlying mesoderm to promote
limb development. outgrowth of the limb. The AER runs along the
boundary between the dorsal and ventral side of
the limb (Fig. 1a) and it specifies the proxi-
modistal outgrowth. The AER keeps the underly-
ing mesenchymal cells in an undifferentiated and
Development of the limb highly proliferative state—the progress zone. As
outgrowth continues, cells at the proximal side
Development of the human upper limb initiates leave this zone and differentiate (Fig. 1b). By this
approximately 26–28 days after fertilization, time, their fate is specified: cells that leave the
when a thickening, the limb bud, becomes visible zone first, specialize and condense to form the
at the flank of the embryo (Fig. 1a). At around primordia of the humerus. In contrast, cells that
52–54 days of gestation the upper arm and hand leave the zone later differentiate into the primor-
are almost fully patterned and developed, with dia of the radius and ulna, the wrist bones, and
full separation of the digits (Fig. 1d). Therefore, lastly the digits (Figs 1b and c) (Summerbell et
in a 25-day interval a large cascade of genetic al 1973).
and cellular interactions results in the patterning The importance of the AER in the proximodis-
and development of the limb. Patterning is the tal development of the limb has been demon-
term used to describe the emergence of spatial strated in chick embryo experiments. Removal of
biological organization during development— the AER from chicken limb buds, and subsequent
'telling' the cells to become a radius, phalanx, culturing of these embryos to allow further
tendon, or muscle. It should be noted that the development, resulted in transverse limb malfor-
development of the lower limb resembles that of mations. Earlier removal of the AER results in the
the upper limb, albeit with a two-day delay. The absence of most of the upper limb, whereas later
majority of factors involved in development of removal only resulted in absent hands, with
the upper and lower limbs are shared and it is normal formation of the humerus and
therefore not surprising that malformations of ulna/radius (Saunders 1948).
the hand are frequently accompanied by similar The most likely candidate molecules regulating
malformations of the feet. limb bud outgrowth are members of the fibrob-
It is generally believed that the three- last growth factors (FGF) family. Several FGFs
dimensional organization of the upper arm is are expressed in the site important for proxi-
determined by the skeletal pattern laid out early modistal outgrowth—the AER. Fibroblast growth
during limb development. The patterning of the factor-8 and FGF-2 are expressed throughout the
muscles, blood vessels, and nerves occurs AER and FGF-4 is expressed in the posterior two-
slightly later and follows the skeletal pattern thirds of the ridge (for a review see Cohn and
(Chevallier et al 1977, Christ et al 1982). Tickle 1996). Fibroblast growth factor-8 is first
The signals involved in the patterning are expressed prior to the formation of the AER, in
derived from three different signalling centres. a broad strip of cells along the distal end of the
The combination of these signals results in a limb and later becomes restricted to the ridge
three-dimensional coordinate system, telling (Fig. 2a). Removal of FGF-8 in knockout mice
each individual cell its positional information and results in the transverse limb malformation as
what specific cell type to become. The growth of was seen with removal of the AER. Most impor-
this three-dimensional structure is coordinated tantly, when removal of the AER is followed by
through three different axes, which will each be application of any of these FGFs, outgrowth is
discussed later (D’Amato et al 1994). restored. Thus, FGFs are both sufficient and
ch02 23/4/02 8:05 am Page 11

CLINICAL GENETICS OF THE UPPER LIMB 11

essential for limb outgrowth (Moon and

Anterior
Capecchi 2000, Lewandoski et al 2000 and refer- a Dorsal
ences therein).
AER
Proximal Distal

The anteroposterior axis

The anteroposterior (A/P; thumb-little finger) axis
Posterior
in the developing limb is established by another Ventral
signalling centre, the zone of polarizing activity
(ZPA), located at the posterior side of the limb
bud (Fig. 1a). When cells from this side of a chick
limb were transplanted to the opposite side of
another bud, an entire set of additional digits b
developed, in approximately a mirror image of Distal
the normal set (Saunders and Gasseling 1968).
This outcome indicates that digit patterning
involves a morphogen—a secreted molecule
whose concentration varies along the AP-axis
Humerus
and cells exposed to a high concentration (i.e.
Radius
near the site of expression) respond differently c
than cells exposed to a lower concentration (i.e. Proximal Distal
cells further away). This hypothesis was
supported by the finding that when the ZPA was
separated from the rest of the limb by an impen-
etrable barrier, preventing the diffusion of the Ulna
morphogen, the anterior structures did not form.
At first it was thought that this morphogen was
Dorsal
retinoic acid, as application of retinoic acid could Anterior
substitute for the ZPA, inducing mirror image
duplications when applied to the anterior side of
d
the limb bud. However, the ZPA does not contain
retinoic acid in concentrations high enough to Proximal Distal
activate downstream patterning genes. The ZPA
secrete Sonic hedgehog (SHH), and application
of SHH protein to the anterior margin of the limb
bud leads to polydactyly of the anterior digits. In
addition, in mouse mutants with preaxial Posterior
Ventral
polydactyly, SHH is not only expressed by cells
in the ZPA posteriorly, but also in the anterior
site of the developing limb. This shows that SHH Figure 1
has polarizing activity and that it can take over
Schematic overview of upper arm development. (a) The
the ZPA function. Notably, high concentrations of
progress zone (PZ) is specified at the distal end of the bud
retinoic acid induce SHH expression, which by the apical ectodermal ridge (AER). Anteroposterior infor-
explains the polarizing results of retinoic acid mation is acquired through the zone of polarizing activity
(reviewed in Johnson and Tabin 1997). Loss of (ZPA). Cartilaginous elements are laid out as the limb bud
SHH function mutations results in severe trunca- grows (b, c). The cartilage of the humerus is laid out first
(white), followed by the radius and ulna (black), wrist
tions of the limb in mice, further suggesting that elements and digits (grey). (d) Human hand, 56 days after
SHH is crucial for limb outgrowth (Chiang et al fertilization. At this stage the digits are fully separated. In
1996). b and c: dark grey is precartilage, black is cartilage.
ch02 23/4/02 8:05 am Page 12

12 THE PEDIATRIC UPPER LIMB

The dorsoventral axis buds with a double ventral phenotype (Logan et

al 1997 and references therein). In these mutants,
As described above, the AER forms at the border the AER is formed in the proper place, indicating
between the dorsal and ventral ectoderm. On the that Wnt-7a is not necessary for the formation of
dorsal (back of the hand) side of this border, the AER.
Radical fringe (Rfng) is expressed, whereas on Interestingly, the Wnt-7a mouse mutants also
the ventral (palm) side, the transcription factor lack posterior digits, indicating a role for Wnt-7a
Engrailed 1 (En-1) gene is detected (Fig. 2b). in anteroposterior patterning. Indeed, there
Engrailed 1 expression restricts Rfng expression, appears to be a mutual dependence between the
so that a sharp boundary is maintained in which three signalling axes: expression of SHH in the
the AER is formed. Engrailed 1 also restricts posterior margin induces and maintains expres-
expression of Wnt-7a, another gene expressed in sion of FGFs in the apical ridge and Wnt-7a
the dorsal ectoderm (Fig. 2b). Ectopic expression expression in the dorsal mesenchyme together
of Wnt-7a on the ventral side of the developing with these FGFs maintains SHH expression in the
limb bud leads to dorsalization of the mesoderm, posterior mesenchyme. This feedback loop thus
and absence of Wnt-7a in mice results in limb controls initial proliferation and differentiation of
the limb (Tickle 1995).

HOX genes
How does a cell respond to the positional infor-
V D mation? Candidates for recording these
a
positional values are the HOX genes, which are
AER expressed in overlapping patterns in many
developing tissues. This gene family is named
after the 'homeotic mutation', in which one body
structure replaces another. A good example of
this mutation is the Drosophila mutant
Antennapedia, where legs sprout from a fly's
head where antennae would normally be. The
Anterior mechanical basis for this fly mutant is that the
segment that normally harbours the antennae is
now transformed in a segment that lies more
b V D posterior and normally produces a leg. This is
AER important as it suggested the existence of
control genes responsible for directing the devel-
Rfng opment of large parts of the body (Lewis 1998).
En-1
Wnt-7a HOX genes encode transcription factors,
activating or repressing a large variety of
downstream target genes. The structure of the
genes differs considerably, but all HOX proteins
contain a conserved motif, the homeodomain,
Anterior which is a stretch of 60 amino acids that binds
Figure 2
to specific DNA motifs in promoters of target
genes.
Formation of the AER. (a) In situ hybridization of FGF-8 on In vertebrates, four HOX gene clusters are
the upper limb of an E11.5 murine embryo. FGF-8 expres- found, named HOXA, HOXB, HOXC and HOXD.
sion is restricted to the AER. (b) Schematic representation The order of these genes in each genomic cluster
of the expression of En-1 ventrally and Rfng and Wnt7a
dorsally of the developing murine limb. Note the presence corresponds to their timing and location of
of the AER at the boundary. expression: a more 3' located gene like HOXA1
ch02 23/4/02 8:05 am Page 13

CLINICAL GENETICS OF THE UPPER LIMB 13

is expressed earlier in development than the The HOXD cluster is expressed in an anteropos-
more 5' located gene HOXA13. There are 13 terior way, with HOXD9 expression throughout
homology groups of HOX genes, but not every the limb and HOXD13 in the distal part only (Fig.
cluster contains a gene from every group. For 3; for review see Krumlauf 1994).
example, HOXA11 is homologous to HOXC11
and HOXD11, but there is no HOXB11. In total,
39 HOX genes are known in mammals.
In the developing limb, HOXA and HOXD Genetics of hand malformations
genes are expressed. The HOXA cluster is
expressed in overlapping patterns that run from There is a wide variety of upper limb malforma-
proximal to distal (Fig. 3). The transcript domain tions and a number of classification systems for
of a gene is contained within the domain of the these phenotypes are available. Classification
gene located 3', in such a way that HOXA9 is based on phenotype is the most common
expressed almost throughout the limb bud while system, but this does not always reflect the
HOXA13 is expressed only in the posterior part. molecular basis of the malformation: in families
with the same mutation, the phenotype may
differ considerably. However, a complete molec-
ular classification system is not yet available, and
we will discuss the genetics of hand malforma-
Anterior tions using the classification by Temtamy and
HOXD9 McKusick (1978). This classification is generally
used in clinical genetic studies, and therefore
HOXD9-11 also in molecular biology.
Proximal

The signalling effects of the AER and ZPA in

the development of the limb have been known
HOXD9-13 for several decades (Saunders 1948), but it is
only in the past decade that the molecular basis
of these signals became known. This information
was mostly obtained by experimental work on
mouse and chicken embryos. The explosive
development in molecular understanding in
these experimental systems has recently been
followed by an increasing amount of studies on
human limb malformations. As a result, several
Anterior genes responsible for human hand malforma-
HOXA9 tions have been identified in the past few years
(Table 1), some of which will be discussed
HOXA9-13 below. For a detailed description of the different
Proximal

limb malformations we refer to the cases

described further in this book.

HOXA9-11 Polydactyly
Figure 3
One of the most frequently observed hand malfor-
Pattern of HOX gene expression in the limb bud. mations is polydactyly, with a prevalence of
Schematic representation of HOXA and HOXD expression between 5 and 17 per 10,000 live births (de Walle
in the limb bud. The HOXD genes are expressed in an et al 1992, EUROCAT 1991). Depending on the
anteroposterior pattern whereas the HOXA genes are location of the extra digit, polydactyly is divided
expressed in a similar pattern along the proximodistal axis.
HOXA13 and HOXD13 expression are more restricted than in preaxial, postaxial, and central polydactyly,
HOXA9 and HOXD9, respectively. although it is not clear whether central
ch02 23/4/02 8:05 am Page 14

14 THE PEDIATRIC UPPER LIMB

Table 1 Selection of genes responsible for human congenital malformations that have been localized or identified.

Disorder/syndrome Localization Gene (MIM entry)

Reduction anomalies-isolated
Acheiropody 7q36 LMBR1 200500
Split hand split foot 1 7q21.2–21.3 ? 183600
Split hand split foot 2 Xq26 ? 313350
Split hand split foot 3 10q24 (Dactylin) 600095
Split hand split foot 4 3q27 Tumor protein63 605289
Reduction anomalies-associated
Holt-Oram 12q24.1 TBX5 142900
Schinzel (Ulnar-Mammary) 12q24.1 TBX3 181450
EEC 1 7q11.2–q21.3 ? 129900
EEC 3 3q27 Tumor protein63 604292
Hypoplasia of several segments
Hunter-Thompson dysplasia 20q11.2 CDMP1 201250
Grebe's chondrodysplasia 20q11.2 CDMP1 200700
Brachydactylies-isolated
Brachydactyly A1 2q35–36 IHH 112500
Brachydactyly B1 9q22 ROR2 113000
Brachydactyly C-Haws type 12q24 ? 113100
Barchydactyly C-Robin type 20q11,2 CDMP1 113100
Brachydactylies-associated
Hand-Foot-Genital 7p15–14.2 HOXA13 140000
Trichorhinophalangeal 8q24.12 TRPS 190350
Syndactylies-isolated
Syndactyly I 2q34–36 ? 185900
Syndactyly II (synpolydactyly) 2q31–32 HOXD13 186000
Syndactyly III 6q22–23 ? 186100
Syndactylies-associated
Apert 10q26 FGFR-2 101200
Pfeiffer 10q26 FGFR-2 101600
Pfeiffer 8p11 FGFR-1 101600
Oculodentodigital dysplasia 6q22–23 ? 164200
Polydactylies-isolated
Postaxial polydactyly A1 7p13 GLI3 174200
Postaxial polydactyly A2 13q21 ? 602085
Postaxial polydactyly B ? GLI3 ?
Preaxial polydactyly type II 7q36 ? 174500
Preaxial polydactyly type III 7q36 ? 190605
Preaxial polydactyly type IV 7q36 ? 190605
Preaxial polydactyly type IV 7p13 GLI3 174700
Polydactylies-associated
Smith-Lemli-Opitz type I 11q12–13 DHCR7 270400
Smith-Lemli-Opitz type II 11q12–13 DHCR7 268670
Ellis-van Creveld syndrome 4p16 EVC 225500
Weyers acrofacial dysostosis 4p16 EVC 193530
Bardet-Biedl 16q21 209900
Simpson-Golabi-Behmel Xq26 glypican-3 312870
OFD1 Xp22.3–22.2 CXORF5 311200
McKusick-Kaufman syndrome 20p12 MKKS 236700
Meckel type I 7q22–23 ? 249000
Meckel type II 11q13 ? 603194
Pallister-Hall syndrome 7p13 GLI3 146510
Greig cephalopolysyndactyly syndrome 7p13 GLI3 175700
Acropectoral syndrome 7q36 ? 605967
Townes-Brocks syndrome 16q12.1 SALL1 107480
ch02 23/4/02 8:05 am Page 15

CLINICAL GENETICS OF THE UPPER LIMB 15

polydactyly represents a separate entity. In preax- Interestingly, all PPD type II/III families mapped
ial polydactyly, or PPD, the extra digit is located so far, are linked to this 7q36 locus, despite their
on the thumb side of the hand, with extra thumbs large variability in phenotype (Hing et al 1995).
and/or index fingers. Postaxial polydactyly (PAP) Recently, two more limb disorders were mapped
is a duplication of the little finger. to this region: acheiropody and an acropectoral
Temtamy and McKusick (1978) subdivided the syndrome (Dundar et al 2001, Escamilla et al
postaxial polydactyly in two types. In postaxial 2000). Acheiropody is characterized by bilateral
polydactyly type A, the extra digit is well formed congenital absence of the upper and lower
and articulates with the fifth or an extra extremities and aplasia of the hands and feet,
metacarpal, whereas in type B a rudimentary with no other systemic manifestations; patients
extra fifth digit (pedunculated postminimus) is with the acropectoral syndrome have complex
present that is usually represented by an extra polysyndactyly, in combination with vertebral
skin tag without any bone. Using linkage analy- malformations. Linkage of all these separate
sis, the disease gene was localized to a locus on phenotypes to the same locus suggested that
7p13, and later mutations were detected in the they could be caused by different mutations in
transcription factor GLI3 (Radhakrishna et al the same gene (allelic heterogeneity) or by
1997, 1999). Another family did not link to the mutations in different but closely linked genes
7p13 locus, but to chromosome 13q21–32, and (locus heterogeneity).
was on this genetic basis reclassified as type A2 The critical region, shared by all affected
(Akarsu et al 1996). No locus has been described individuals of the PPD type II/III family, was
for the type B PAP alone. Recently however, a recently reduced to an interval of 450 kb (Heus et
family was described in which type A and B was al 1999). Of all phenotypes linked to this locus, a
found on different limbs of the same individual, mutation has only been detected in the family
which demonstrates that the same gene, GLI3, is with acheiropody. A deletion of the fourth exon
responsible for both types A and B. So-called of the LMBR1 gene was thought to result in the
modifying genes most likely cause the different absence of this protein, of which the function is
phenotype, with PAP B being a milder manifes- unknown (Ianakiev et al 2001). None of the genes
tation of the type A phenotype (Radhakrishna et identified in the critical 450 kb region seemed to
al 1999). The finding of mutations in GLI3 in PAP harbour a mutation for any of the other limb
is not entirely surprising, as GLI3 is one of the malformations.
genes downstream of SHH, the molecule In the PPD and complex polysyndactyly pheno-
involved in determining the anteroposterior axis types, human genetics is aided by mouse genet-
in the developing limb. ics. Preaxial polydactyly in a number of mouse
Following the classification of Temtamy and mutants is caused by ectopic expression of SHH
McKusick (1978) again, preaxial polydactyly is in the anterior (preaxial) side of the developing
subdivided into four types: Type I/thumb limb bud (as opposed to only in the posterior
polydactyly compromises various degrees of side). Interestingly, the SHH gene is located just
duplication of biphalangeal thumbs. This type of outside the critical region containing the defects
PPD is usually sporadic and often unilateral, and on 7q36. One of the mouse mutants, Hemimellic
so far it is unclear whether the malformation is extra toe (Hx) has also been mapped to the
caused by a single gene with reduced penetra- mouse chromosomal locus, harbouring approxi-
tion, or by a combination of several genes (Orioli mately the same genes as the human 7q36 locus.
and Castilla 1999). Preaxial polydactyly type II The limb deformity in this mouse mutant, PPD
(polydactyly of a triphalangeal thumb), type III with tibial dysplasia, is very similar to the pheno-
(polydactyly of an index finger) and type IV type described in one of the families. In addition,
(polysyndactyly, extra digits which are partially the disease gene for a second mouse mutant,
fused) are usually inherited as autosomal Hammertoe (Hm), has been mapped very close
dominant traits (Temtamy and McKusick 1978). to the Hx disease gene. The phenotype in Hm
In 1994, two independent studies reported mice resembles the complex polysyndactyly
linkage of the PPD type II/III (both also called phenotype mentioned earlier (Tsukurov et al
triphalangeal thumb) and type IV to chromosome 1994). In mice, SHH is also located in the vicin-
7q36 (Heutink et al 1994, Tsukurov et al 1994). ity of the murine locus of these Hx and Hm
ch02 23/4/02 8:05 am Page 16

16 THE PEDIATRIC UPPER LIMB

mutants as was found with the human disease by mutations in the homeobox gene HOXD13,
gene and there appears to be a mutation in (Akarsu et al 1996, Muragaki et al 1996). The
sequences upstream of SHH which causes its mutation in HOXD13 does not cause the absence
misexpression at the anterior side of the devel- of the protein, but most likely results in a protein
oping limb. with an altered function. As mentioned before,
HOXD13 is the last HOXD gene activated in the
developing limb and is mainly expressed in the
most posterior distal part of the developing limb,
Syndactyly where also HOXD9–12 are expressed (see Fig. 3).
This corresponds with the finding of poly- and
According to Temtamy and McKusick (1978), the syndactyly in the posterior part of the limb.
syndactyly phenotype has been divided into five Recently a similar mutation was found in a
different types of syndactyly, depending on the mouse mutant, which resulted in the same
parts of digits not separated in the hand and/or phenotype (Johnson et al 1998).
feet. All forms are inherited as an autosomal The similarity in both mutation and phenotype
dominant trait and usually there is uniformity of between human and mouse aided in the identi-
the type of syndactyly within a given pedigree. fication of mutations in the hand-feet-genital
Both syndactyly type IV (complete syndactyly of (HFG) syndrome. The hand-feet-genital (HFG)
all fingers but no bone fusion and associated syndrome is characterized by short thumbs,
with polydactyly) and type V (fusion of the small feet with short big toes and defects of the
metacarpals and metatarsals) are relatively rare, Mullerian duct or its derivatives. The limb
and no linkage to any chromosomal locus has malformations resembled the phenotype found
been found. in a mouse mutant in which a mutation was
The features of syndactyly type III are mainly found in the HOXA13 gene (Mortlock et al 1996)
complete and bilateral soft-tissue syndactyly of and this triggered the search for mutations in the
the fourth and fifth finger, with occasional fusion human HOXA13 gene. In HFG patients a
of the distal phalanges. This phenotype is also mutation was detected at a crucial position for
part of the craniofacial disorder oculodento- DNA binding, most likely producing a non-
digital dysplasia, which is characterized by facial, functional protein that cannot bind DNA
dental, and digital anomalies. Interestingly, both (Mortlock and Innis 1997).
disorders have been mapped to the same locus, So far, mutations have only been found in
on 6q22–23, suggesting that syndactyly type III three human HOX genes. Beside the HOXA13
and oculodentodigital dysplasia may be caused and HOXD13 mutations described above,
by different mutations in the same gene mutations have been found in the HOXA11 gene.
(Boyadjiev et al 1999, Gladwin et al 1997). And whereas the previous two mutations affect
Syndactyly type I is characterized by non- digits and hands only, the mutations in HOXA11
separation involving digits three and four were found in patients with radio-ulnar synosto-
(complete or partial) and may include fusion of sis associated with a blood platelet disorder
the distal phalanges of the third and fourth digit (Thompson and Nguyen 2000). The involvement
and/or second and third toes. Linkage analysis in of radius and ulna as opposed to only digits is
a large German family mapped the disease gene in agreement with the wider and earlier expres-
to 2q34–36 (Bosse et al 2000). Syndactyly type sion of HOXA11 as compared to both HOXA13
II or synpolydactyly (SPD), was mapped to the and HOXD13, of which the expression is
neighbouring locus 2q31–32. Syndactyly type II restricted to the more distal part of the develop-
or synpolydactyly is defined as syndactyly of the ing limb.
third and fourth fingers as well as syndactyly of
toes four and five, associated with polydactyly of
the same fingers and/or toes. Syndactyly type II
or synpolydactyly was the first isolated congen- Brachydactyly
ital hand malformation in which a mutation was
detected (Muragaki et al 1996). Brachydactyly (BD) denotes a group of malfor-
Syndactyly type II or synpolydactyly is caused mations in which the common feature is
ch02 23/4/02 8:05 am Page 17

CLINICAL GENETICS OF THE UPPER LIMB 17

shortening of the digits. All five types are highly ling limb development because they are in a
variable both between and within families. Type unique position to be able to identify affected
A is characterized by shortening or absence of patients and their families, which could be
the middle phalanges. When accompanied by suitable for linkage analysis. In turn, detailed
rudimentary or absent terminal phalanges the clinical descriptions of congenital anomalies
BD is called type B. Brachydactyly type C is affecting the upper extremities will advance the
noted for its widely variable clinical phenotype understanding of the cellular events controlled
both within and between families, featuring by the molecular pathways of limb development
shortness of the second and fifth middle and may help in identifying new genes. With the
phalanges and the first metacarpal. Type D is identification of new genes we will increase our
characterized by short and broad terminal insight into the molecular basis of congenital
phalanges of the thumbs and big toes. In type E, upper arm anomalies, and functional analysis of
shortening of the fingers is mainly in the these gene families and their pathways will
metacarpals and metatarsals. reveal their role in patterning and (normal)
Three different genes have been identified so embryogenesis. In the future, the current
far for three different types of BD (see Table 1). morphological classifications of congenital limb
Interestingly, but not surprisingly, all three genes malformations may be supplemented with
are involved in a later stage of limb develop- genetic ones, possibly providing explanations for
ment, namely the proliferation and differentia- the great clinical variability and overlapping
tion of chondrocytes into bone. Mutation in IHH phenotypes.
leads to a reduced proliferation of chondrocytes
and this explains the shortening or absence of
the middle phalanges in BD type A (Gao et al
2001). A receptor tyrosine kinase, ROR2, is
mutated in the more severe type B. This gene is References
involved in both the initial growth and pattern-
Akarsu AN, Stoilov I, Yilmaz E, et al (1996) Genomic
ing, as well as the proliferating chondrocytes,
structure of HOXD13 gene: a nine polyalanine duplica-
which would explain the more severe phenotype tion causes synpolydactyly in two unrelated families,
(Oldridge et al 2000). Finally, in BD type C, Hum Mol Genet 5:945–52.
mutations have been found in the CDMP1 gene
(cartilage-derived morphogenetic protein-1), Bosse K, Betz RC, Lee YA, et al (2000) Localization of a
which encodes a BMP-like protein (Polinkovsky gene for syndactyly type 1 to chromosome 2q34–q36,
et al 1997). These mutations were found to lead Am J Hum Genet 67:492–7.
to the production of a protein that inhibits
chondrogenesis. The CDMP1 protein can initiate Boyadjiev SA, Jabs EW, LaBuda M, et al (1999) Linkage
and promote chondrogenesis. analysis narrows the critical region for oculodentodig-
ital dysplasia to chromosome 6q22–q23, Genomics
The different phenotypes seen in the three BDs
58:34–40.
can be explained by differences in spatial and
temporal expression of the three genes. Since all Chevallier A, Kieny M, Mauger A (1977) Limb-somite
three genes identified so far in BD are involved relationship: origin of the limb musculature, J Embryol
in chondrogenesis, the genes in the other loci for Exp Morphol 41:245–58.
BD are likely to play a role in bone formation.
Chiang C, Litingtung Y, Lee E, et al (1996) Cyclopia and
defective axial patterning in mice lacking Sonic hedge-
hog gene function, Nature 383:407–13.
Conclusions Christ B, Jacob HJ, Jacob M, et al (1982) On the origin,
distribution and determination of avian limb
Despite the rapid advances made in human mesenchymal cells, Prog Clin Biol Res 110:281–91.
genetics of the upper limb, relatively few specific
human mutations that cause limb abnormalities Cohn MJ, Tickle C (1996) Limbs: a model for pattern
have been identified. Hand surgeons should be formation within the vertebrate body plan, Trends
aware of the basic molecular pathways control- Genet 12:253–7.
ch02 23/4/02 8:05 am Page 18

18 THE PEDIATRIC UPPER LIMB

D’Amato RJ, Loughnan MS, Flynn E, et al (1994) Johnson RL, Tabin CJ (1997) Molecular models for
Thalidomide is an inhibitor of angiogenesis, Proc Natl vertebrate limb development, Cell 90:979–90.
Acad Sci U S A 91:4082–5.
Krumlauf R (1994) Hox genes in vertebrate develop-
de Walle HEK, Cornel MC, Haverman TM, et al (1992) ment, Cell 78:191–201.
EUROCAT, registration of congenital anomalies North
Netherlands, tables 1981–1990, Rijksuniversiteit, Lewandoski M, Sun X, Martin GR (2000) Fgf8 signalling
Department of Medical Genetics, Medical Faculty, from the AER is essential for normal limb develop-
Groningen. ment, Nat Genet 26:460–3.

Dundar M, Gordon TM, Ozyazgan I, et al (2001) A novel Lewis EB (1998) The bithorax complex: the first fifty
acropectoral syndrome maps to chromosome 7q36, J years, Int J Dev Biol 42:403–15.
Med Genet 38:304–9.
Logan C, Hornbruch A, Campbell I, et al (1997) The role
Escamilla, MA, DeMille, MC, Benavides E, et al (2000) of Engrailed in establishing the dorsoventral axis of the
A minimalist approach to gene mapping: locating the chick limb, Development 124:2317–24.
gene for acheiropodia, by homozygosity analysis, Am
J Hum Genet 66, 1995–2000. Moon AM, Capecchi MR (2000) Fgf8 is required for
outgrowth and patterning of the limbs, Nat Genet
EUROCAT (1991), Surveillance of congenital anoma- 26:455–9.
lies, 1980–1988 EUROCAT central registry, Brussels.
Mortlock DP, Innis JW (1997) Mutation of HOXA13 in
Flatt, AE(1994) The Care of Congenital Hand hand-foot-genital syndrome, Nat Genet 15:179–80.
Anomalies, Quality Medical Publishing, St Louis.
Mortlock DP, Post LC, Innis JW (1996) The molecular
Gao B, Guo J, She C et al (2001) Mutations in IHH, basis of hypodactyly (Hd): a deletion in Hoxa 13 leads
encoding Indian hedgehog, cause brachydactyly type to arrest of digital arch formation, Nat Genet 13:284–9.
A-1, Nat Genet 28:386–8.
Muragaki Y, Mundlos S, Upton J, et al (1996) Altered
Gladwin A, Donnai D, Metcalfe K, et al (1997) growth and branching patterns in synpolydactyly
Localization of a gene for oculodentodigital syndrome caused by mutations in HOXD13, Science 272:548–51.
to human chromosome 6q22–q24, Hum Mol Genet 6:
123–7. Oldridge M, Fortuna AM, Maringa M, et al (2000)
Dominant mutations in ROR2, encoding an orphan
Heus HC, Hing A, van Baren MJ, et al (1999) A physi- receptor tyrosine kinase, cause brachydactyly type B,
cal and transcriptional map of the preaxial polydactyly Nat Genet 24:275–8.
locus on chromosome 7q36, Genomics 57:342–51.
Orioli IM, Castilla EE (1999) Thumb/hallux duplication
Heutink P, Zguricas J, van Oosterhout L, et al (1994) and preaxial polydactyly type I, Am J Med Genet
The gene for triphalangeal thumb maps to the 82:219–24.
subtelomeric region of chromosome 7q, Nat Genet
6:287–92. Polinkovsky A, Robin NH, Thomas JT, et al (1997)
Mutations in CDMP1 cause autosomal dominant
Hing AV, Helms C, Slaugh R, et al (1995) Linkage of brachydactyly type C, Nat Genet 17:18–9.
preaxial polydactyly type 2 to 7q36, Am J Med Genet
58:128–35. Radhakrishna U, Blouin JL, Mehenni H, et al (1997)
Mapping one form of autosomal dominant postaxial
Ianakiev P, van Baren MJ, Daly MJ, et al (2001) polydactyly type A to chromosome 7p15–q11.23 by
Acheiropodia Is Caused by a Genomic Deletion in linkage analysis, Am J Hum Genet 60:597–604.
C7orf2, the Human Orthologue of the Lmbr1 Gene, Am
J Hum Genet 68:38–45. Radhakrishna U, Bornholdt D, Scott HS, et al (1999) The
phenotypic spectrum of GLI3 morphopathies includes
Johnson KR, Sweet HO, Donahue LR, et al (1998) A autosomal dominant preaxial polydactyly type-IV and
new spontaneous mouse mutation of Hoxd13 with a postaxial polydactyly type-A/B; No phenotype predic-
polyalanine expansion and phenotype similar to tion from the position of GLI3 mutations, Am J Hum
human synpolydactyly, Hum Mol Genet 7:1033–8. Genet 65:645–55.
ch02 23/4/02 8:05 am Page 19

CLINICAL GENETICS OF THE UPPER LIMB 19

Saunders JWJ (1948) The proximo-distal sequence of malformations, Birth Defects Orig Artic Ser 14, i-
origin of the parts of the chick wing and the role of the xviii:1–619.
ectoderm, J Exp Zool 108:363–403.
Thompson AA, Nguyen LT (2000) Amegakaryocytic
Saunders JWJ, Gasseling MT (1968) Ectodermal- thrombocytopenia and radio-ulnar synostosis are
mesodermal interactions in the origin of limb symme- associated with HOXA11 mutation, Nature Genet
try, In: Fleischmajer RE,, Billingham R, eds, 26:397–8.
Epithlelial-Mesenchymal Interactions (Williams and
Wilkins: Baltimore) 78–97. Tickle C (1995) Vertebrate limb development, Curr Opin
Genet Dev 5:478–84.
Strachan T, Read AP (1999) Human Molecular Genetics
(BIOS Scientific Publishers, Oxford). Tsukurov O, Boehmer A, Flynn J (1994) A complex
bilateral polysyndactyly disease locus maps to chromo-
Summerbell D, Lewis JH, Wolpert L (1973) Positional some 7q36, Nat Genet 6:282–6.
information in chick limb morphogenesis, Nature
244:492–6. Vortkamp A, Gessler M, Grzeschik KH (1991) GLI3 zinc-
finger gene interrupted by translocations in Greig
Temtamy SA, McKusick VA (1978) The genetics of hand syndrome families Nature 352:539–40.
ch03 23/4/02 8:06 am Page 21

3
Classification and related
pathoembryology of congenital upper
limb differences
Teun JM Luijsterburg, Christl Vermeij-Keers and Steven ER Hovius

When a child is born with a congenital difference consistency of the classification is of paramount
of the upper limb, the parents are concerned importance. The consistency of Swanson’s classi-
about the aetiology, treatment, and future fication has been discussed by several authors
prospects of their child. Frequently, aberrations (Cheng et al 1987, De Smet et al 1997, Flatt 1994,
of other body systems are involved, such as the Luijsterburg et al 2000, Ogino et al 1986). For
heart, the craniofacial region, and the lower example, clinical relationships have been demon-
limbs. Explanation of the aetiology, including strated between polydactyly, syndactyly and
potential risks for offspring, may partially calm typical cleft hand (Ogino 1990), and between
the parent’s concerns. Unfortunately, the under- brachysyndactyly, symbrachydactyly, and trans-
lying cause, i.e. a genetic defect and/or a terato- verse deficiency (Miura et al 1994). However,
gen, is often not known. The condition of their these overlapping diagnoses are currently placed
child can often be clarified using knowledge into different categories using Swanson’s classi-
about the mechanisms that may precede the fication, and prevent consistent interpretation.
difference, i.e. the pathogenesis. For groups of hand differences, several clinical
To understand the pathogenesis, a thorough (sub) classifications have been developed in
knowledge of normal embryonic and fetal devel- order to aid the physician in the choice of treat-
opment is required. Morphological changes ment strategy (Bayne and Klug 1987, Blauth 1967,
during normal development are tightly orches- Blauth and Olason 1988, Temtamy and McKusick
trated in time and space, and are influenced by 1978). Nevertheless, problems arise if more
genetic and environmental factors. If those differences are present in one limb, such as radial
changes do not appear at the right time and/or polydactyly and syndactyly. To overcome these
at the right place, or if they do not appear at all, difficulties, a descriptive method has been devel-
aberrations will develop. Interpretation of these oped at the Department of Plastic and
aberrations in general and those of the upper Reconstructive Surgery of the University Hospital
limbs in particular is rather confusing. Rotterdam in The Netherlands. Recording only
In order to assist with the interpretation of the individual aberrations along with knowledge of
observed differences, several classification normal and abnormal embryogenesis, expressed
systems regarding upper limb differences have in terms of morphology and topography, will
been developed (Frantz and O’Rahilly 1961, enable consistent interpretation of the differ-
Swanson et al 1983, Temtamy and McKusick ences.
1978). The most frequently used classification, After introducing the recording form, four
the classification of Swanson et al (1983), is cases (syndactyly, polydactyly, symbrachydactyly,
based on clinical diagnosis and failure during and thumb hypoplasia and radial club) will be
embryogenesis. After establishment and classifi- presented using this descriptive method. Normal
cation of the clinical diagnosis, the underlying embryogenesis will be briefly outlined, and
mechanism should be revealed. Therefore, serves as background to explain the cases on the
ch03 23/4/02 8:06 am Page 22

22 THE PEDIATRIC UPPER LIMB

Figure 1

Recording form.
ch03 23/4/02 8:06 am Page 23

CLASSIFICATION AND PATHOEMBRYOLOGY OF UPPER LIMB DIFFERENCES 23

Figure 2

Manual for the recording form.

Other documents randomly have
different content
Welcome to our website – the ideal destination for book lovers and
knowledge seekers. With a mission to inspire endlessly, we offer a
vast collection of books, ranging from classic literary works to
specialized publications, self-development books, and children's
literature. Each book is a new journey of discovery, expanding
knowledge and enriching the soul of the reade

Our website is not just a platform for buying books, but a bridge
connecting readers to the timeless values of culture and wisdom. With
an elegant, user-friendly interface and an intelligent search system,
we are committed to providing a quick and convenient shopping
experience. Additionally, our special promotions and home delivery
services ensure that you save time and fully enjoy the joy of reading.

Let us accompany you on the journey of exploring knowledge and

personal growth!

ebooknice.com