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 © Springer-Verlag Berlin Heidelberg 2014 This work is subject to copyright. 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Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) 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 VII 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