Limb Malformations: An Atlas of Genetic Disorders of Limb Development

274 Pages·2014·17.681 MB·English

by  Stefan Mundlos, Denise Horn (auth.)

Stefan Mundlos
Denise Horn
Limb
Malformations
An Atlas of Genetic
Disorders of
Limb Development
123
Limb Malformations
Stefan Mundlos • Denise Horn
Limb Malformations
An Atlas of Genetic Disorders
of Limb Development
Stefan Mundlos Denise Horn
Institut für Medizinische Genetik Institut für Medizinische Genetik
und Humangenetik und Humangenetik
Berlin, Germany Berlin, Germany
ISBN 978-3-540-95927-4 ISBN 978-3-540-95928-1 (eBook)
DOI 10.1007/978-3-540-95928-1
Springer Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014956750
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Foreword
In this book Stefan Mundlos, Denise Horn, and their associates set out to put more order into
a field that Maurice Lamy in his preface to Pierre Maroteaux’ ‘Maladies osseuses de l’enfant’
called ‘chaotic’ because of the multitude of conditions and their bewildering nomenclature. It
focuses on malformations of the limbs – ‘dysostoses’ in today’s nomenclature – and includes
a selection of bone dysplasias with prominent limb involvement. Abnormal limbs have been
described since the battle in Gath “where there was a man of great stature that had on every
hand six fingers and on every foot six toes … also born to the giant” (Old Testament, 2 Sam
21:20). A treasure of malformed limbs can be viewed to this day in the Meckel collection in
Halle/Germany that was started in the mid-18th century by Johann Friedrich Meckel, the el-
der, and brought to blossom by his grandson, Johann Friedrich Meckel, the younger, the very
Meckel, who in 1822 recognized a ‘defective formation in siblings’ that included polydactyly
and now is known as the Meckel syndrome, a highly heterogeneous ciliopathy covered in this
atlas. Ernst Fischer, in his multivolume “Morphologie der Mißbildungen des Menschen und
der Tiere” first published in 1906, a historical ‘must’ for the scholar of malformations, devoted
a large section to developmental limb anomalies. Whereas he and his predecessor pathologists
by trade focused on lethal conditions, the study of dysostoses in children and adults was the
realm of pediatricians including Eugène Apert, Rudolf Pfeiffer, Walter Fuhrmann, Hans-Rudolf
Wiedemann, to name a few. Still, these disorders were too rare to raise wide public interest
or concern.
This changed dramatically with the entrance of thalidomide in the drug marked in 1957, and
the discovery by another pediatrician-geneticist, Widukind Lenz, of its deleterious effects on
early limb development in man. Stefan Mundlos and Denise Horn now come into this tradition
with their pioneering work on limb defects.
Major limb malformations are difficult to categorize and to differentiate on clinical and
radiological grounds. All of them are individually rare and confusing in their complexity and
variability. In these days, the molecular elucidation of many of them helps in their delineation,
and determines the spectrum of their expression. This achievement would not have been pos-
sible without an intricate relationship between clinical medicine and basic science, personalized
by Stefan Mundlos’ broad professional background, realized by the fertile intertwining of the
Institute of Medical Genetics and the Max Planck Institute for Molecular Biology in Berlin,
and documented in this atlas.
The book’s main benefit will be in diagnostics. Taxonomy, the art of organizing vast amounts
of data, is its indispensable tool. Since Geoffroy Saint-Hilaire, in his 1832 ‘Traité de Tératolo-
gie’, differentiated between ectroméliens and syméliens, i. e. reduction and fusion anomalies,
numerous classifications have been proposed. The present one offers a coherent system of
morphological categories and causally determined subcategories. Similarity between actual and
depicted phenotypes will guide the physicians’ quest for molecular confirmation of a suspected
diagnosis.
Is this old-fashioned? Will computational phenotype/genotype analysis make an atlas a relict
of the past? Will we forgo books when digitalized algorhythms have been brought to perfection?
Probably not. Both have their own domains. Computers handle fragments to synthesize entities.
V
VI Foreword
Books present entities that reason analyzes. Through analysis we conceive the commonness of
conditions, understand their basis and genesis, become experts.
As publications go, this atlas probably will be digitalized. Some students will read it as a
book, screen by screen, condition by condition. Others will continue to prefer the compactness
of a book, the rustle of paper, the prospect of leafing through pages to pictures on a screen and
clicks on a keyboard. They all will enjoy the treasure and clarity of its content and the beauty
of its presentation.
Jürgen Spranger
Professor emeritus
Children’s Hospital
University of Mainz/Germany
Preface
Congenital malformations are relatively common among newborns. If recognized early, many
can be treated, and a complete repair can often be achieved. Our knowledge about this diverse
field of medicine has greatly increased over the last decades. We now recognize a myriad of
conditions that can be distinguished on clinical grounds as well as by their molecular causes.
This book concentrates on a subgroup of skeletal diseases, malformations, and growth defects
that predominantly affect the limbs.
Limb malformations are considered a relatively common type of malformation. Because of
their bewildering complexity in phenotypes and their frequent association with other malforma-
tions and clinical symptoms, they are often difficult to diagnose. Furthermore, abnormalities
of the hands are often perceived as stigmatizing, but with adequate and timely surgical and
conservative management, many conditions can be improved or even cured. Beyond the clini-
cal interest, skeletal diseases can serve as a paradigm to understand human genetics. The first
human disorder recognized to follow the principles of Mendelian inheritance was described
by Farabee in 1903. The original pedigree exhibited a classic dominant pattern of segregation
over five generations featuring absent or shortened middle phalanges in the hands and feet,
a condition now termed brachydactyly type A1 (BDA1). As with many other conditions, the
molecular cause of BDA1 has been unraveled, giving us new insights in gene function and basic
mechanisms of skeletal development.
For the patient and family members, limb malformations result in various problems, but
the extent of these depends on the location and size of the reduction and the functional impair-
ment. Some potential difficulties include questions about the recurrence risk within families;
complications with normal development, such as motor skills; the need for assistance with daily
activities; limitations in certain movements, sports, or activities; and potential emotional and
social issues because of physical appearance. To improve a family’s and patient’s situation,
many medical specialists need to be involved, but communication across disciplines is often
hindered by different language and terminology. It is the aim of this book to name, describe, and
categorize limb malformations in order to facilitate their correct diagnosis for improved clinical
care. This book is therefore addressed to medical geneticists, radiologists, pediatricians, hand
surgeons, orthopedic surgeons, and other physicians as well as medical personnel involved in
evaluating and treating patients with abnormal limbs.
In contrast to many other genetic conditions that present with rather uniform features, limb
malformations are multifaceted in their phenotypic appearances and very heterogenous in their
causes. Extreme phenotypic variability and nonpenetrance are common and impose diagnostic
challenges on the clinician. In many other genetic disease groups, such as the skeletal dyspla-
sias, a descriptive approach to classify groups and individual conditions has been very success-
ful, even helping to define molecular abnormalities. In limb malformations similar approaches
have been taken, and numerous systems for classification of upper-limb anomalies have been
proposed. Anatomical classification schemes based on clinical severity can indeed provide use-
ful disease categories that can be used as therapeutic guidelines. However, purely descriptive
terminologies cannot account for phenotypic variability, and when true genetic classifications
based on etiologies are considered, many systems become outdated as our understanding of
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VIII Preface
genetic and developmental pathology expands. For example, a clinical subdivision of split-
hand/foot malformation, polydactyly, or syndactyly based on phenotypic appearance in various
subgroups does not withstand the clinical or molecular reality. Studies of large families have
shown that so-called distinct phenotypes were part of the phenotypic variability; on the other
hand, identical phenotypes were shown to have been caused by different gene defects.
Recent advances in molecular genetics and developmental biology have helped clarify this
confusing complexity. Many conditions can now be assigned to certain gene defects, thereby
opening the possibility of a molecular diagnosis. However, for many conditions the diagnosed
mutation only partially predicts the phenotype with large degrees of variability, even within
families. Thus, a diagnosis has to rely on clinical as well as molecular considerations. Only an
integration of the two aspects can produce a sufficiently validated disease description, nomen-
clature, and disease concept that can be used for diagnostic as well as scientific purposes and
for the benefit of the patient.
This atlas describes most, but not all, conditions with isolated limb involvement and those
syndromes in which abnormalities of the limbs are a consistent and predominant feature. We
have concentrated on conditions in which the molecular cause is known. This approach has been
facilitated by the enormous increase in knowledge in the field, resulting in a nomenclature and
classification that take genetic heterogeneity and clinical variability into account. Whenever
possible, we have tried to demonstrate the degrees of clinical variability that are often observed
in limb malformations. However, due to limitations of space, this has not been possible in all
aspects. The classification used here is clinically oriented and based on phenotypes as well as
on genetic/molecular data. This resulted in eight major groups: 1) acromesomelic dysplasias,
which are conditions that affect bone formation and/or growth, predominantly in the forearm/
leg and hands/feet; 2) brachydactylies, a group of conditions characterized by the shortening or
absence of individual bones of the hands and feet; 3) defects of joint formation; 4) contracture
deformities, conditions in which connective tissue or muscle problems result in the inability to
bend joints; 5) polydactylies, malformations that result in the formation of additional fingers
or toes; 6) syndactylies, in which fingers or toes are fused; 7) reduction anomalies, involving
the absence of part or all of one or more bones; and 8) conditions with macrodactyly or over-
growth of limbs. In some instances we subdivided groups in those conditions with isolated limb
anomalies and those in which limb malformations are associated with other clinical findings.
In addition, subdivisions according to anatomical location have been made, and we sorted
conditions according to their major clinical problem or involvement. Few limb malformations
have isolated defects, and many have features that show overlap among these broad categories.
Obviously, these boundaries are artificial and fluid. Nevertheless, we think they are helpful in
categorizing these conditions and may be useful in making a correct diagnosis.
The phenotypes of limb malformations and their developmental pathogenicity have been
elucidated by many groundbreaking studies on the basic mechanisms of limb development.
Based on this work, many malformations can now be understood from their developmental
point of view, such as the involvement of the hedgehog pathway in many polydactylies. In
the first introductory chapter we give a brief overview of the current concepts of how limbs
develop and how the molecular regulatory network that governs limb development is related to
certain phenotypes. The clinical evaluation of limbs and the diversity of phenotypes and their
interpretation are addressed in the second chapter. In many instances, the clinical evaluation is
not sufficient and a radiological examination is necessary, so basic principles of radiology of the
limb skeleton are presented in the third chapter. Parents may be dismayed by the appearance of
an anomalous hand and may be hoping that surgery can create a “normal” hand. Hand surgery
aims at improving function and cosmetic appearance when possible, and includes counseling
parents about what is and is not possible with surgery. In the fourth chapter, basic principles
of surgery are discussed.
Acknowledgements
Physicians whom we approached to contribute pictures and radiographic films from published
and unpublished cases are acknowledged in the figure legends. We wish to express our gratitude
to colleagues and friends who contributed to this work:
V. Cormier-Daire, Paris; G. Gillessen-Kaesbach, Lübeck; L. Graul-Neumann, Berlin;
R. Habenicht, Hamburg; W. Hülsemann, Hamburg; N. Kantaputra, Chiang Mai; H. Kayserili,
Istanbul; R. König, Frankfurt; I. Kurth, Jena; P. Meinecke, Hamburg; J. Opitz, Salt Lake City;
A. Rajab, Muscat; J. Spranger, Sinzheim; L. van Maldergem, Besançon; D. Wieczorek, Essen;
B. Wollnik, Cologne; B. Zabel, Freiburg.
Our special thanks go to Jürgen Kunze. Many of the clinical figures presented here are from
his collection of clinical cases, generated during his time at the Institute for Human Genetics
in Berlin. We thank Norbert Brieske for excellent photographic work.
IX
Table of Contents
I Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1 Development of the Limbs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Sigmar Stricker and Stefan Mundlos
2 Clinical Assessment and Anthropometry of the Limbs . . . . . . . . . . . . . . . . . . 10
Denise Horn
3 Radiology of the Limb . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Ralph Lachman
4 Surgical Management Principles for Congenital Upper Limb
Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Ulrich Mennen
II Disorders: Polydactyly Isolated . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5 Preaxial Polydactyly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
6 Postaxial Polydactyly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
7 Greig Cephalopolysyndactyly Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
8 Triphalangeal Thumb-Polydactyly Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 36
8 Synpolydactyly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
10 Laurin–Sandrow Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
III Disorders: Polydactyly Associated . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
11 Ellis–Van Creveld Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
12 Short Rib-Polydactyly Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
13 Bardet–B iedl Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
XI