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Molecular-Pathogenetic Classification of Genetic Disorders of the Skeleton

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Molecular-Pathogenetic Classification of Genetic Disorders of the Skeleton American Journal of Medical Genetics Semin. Med. Genet.) 106:282±293 2001) ARTICLE Molecular-Pathogenetic Classi®cation of Genetic Disorders of the Skeleton ANDREA SUPERTI-FURGA,* LUISA BONAFE , AND DAVID L. RIMOIN Genetic disorders of the skeleton skeletal dysplasias and dysostoses) are a large and disparate group of diseases whose unifying features are malformation, disproportionate growth, and deformation of the skeleton or of individual bones or groups of bones. To cope with the large number of different disorders, the ``Nosology and Classi®cation of the Osteochondrodysplasias,'' based on clinical and radiographic features, has been designed and revised periodically. Biochemical and molecular features have been partially implemented in the Nosology, but the rapid accumulation of knowledge on genes and proteins cannot be easily merged into the clinical±radiographic classi®cation. We present here, as a complement to the existing Nosology, a classi®cation of genetic disorders of the skeleton based on the structure and function of the causative genes and proteins. This molecular±pathogenetic classi®cation should be helpful in recognizing metabolic and signaling pathways relevant to skeletal development, in pointing out candidate genes and possible therapeutic targets, and more generally in bringing the clinic closer to the basic science laboratory and in promoting researchin this®eld. ß 2002 Wiley-Liss, Inc. KEY WORDS: skeleton; genetic disorders; molecular classi®cation; pathogenic classi®cation INTRODUCTION The complexity of skeletal±genetic have also been used. Biochemical data phenotypes has been long appreciated. have been incorporated as they became Genetic disorders of the skeleton are a Although single entities have been des- available. Based on this combination of group of disorders with diverse manifes- cribed in the nineteenth or in the ®rst criteria, more than 200 nosologic enti- tations. Although individually rare, the half of the twentieth century, most ties are distinguished currently. many different forms add to produce a individual entities we know today have signi®cant number of affected indivi- been delineated much more recently. duals with signi®cant morbidity and The criteria used for distinction and The criteria used for distinction mortality. Clinical manifestations in- classi®cation of genetic skeletal disorders and classi®cation of genetic clude short stature, malformation, and have been clinical features such as deformation. The clinical severity differs growth, age at onset of growth retar- skeletal disorders have been between individuals, ranging from dation, presence and nature of altered clinical features such as minor handicaps to death in the neonatal body proportions, and, because of the period. In surviving patients, secondary outstanding role of radiography in de- growth, age at onset of complications of skeletal deformity and ®ning skeletal disease, radiographic cri- growth retardation, presence manifestations in extraskeletal organs teria. The mode of genetic transmission and nature of altered body add to the burden of disease. and speci®c extra skeletal abnormalities proportions, and, because of Andrea Superti-Furga is Professor of Pediatrics at the University of Zurich and Leitender Arzt at the outstanding role of radio- the Division of Metabolism and Molecular Diseases of the University Children's Hospital in Zurich, Switzerland. Dr. Superti-Furga is involved in clinical care, laboratory diagnosis, teaching, and graphy in de®ning skeletal researchin thearea of metabolic and genetic pediatrics. disease, radiographic criteria. Luisa Bonafe , a graduate and board-certi®ed pediatrician from the University of Padova, Italy, has a strong research interest in amino acid and biopterin disorders and in skeletal dysplasias and is currently a postgraduate fellow withDr. Superti-Furga. David L. Rimoin is the Steven Spielberg Chairman of Pediatrics, Director of the Medical The ``Nomenclature and Classi®ca- Genetics±BirthDefects Center and Director of theInternational Skeletal Dysplasia Registry at Cedars-Sinai Medical Center and Professor of Pediatrics and Medicine at UCLA School of tion of the Osteochondrodysplasias'' has Medicine in Los Angeles, California. He is currently President of the American College of Medical been a valuable instrument in de®ning Genetics Foundation and was past President of the American Society of Human Genetics, the existing entities and delineating new American College of Medical Genetics, and the American Board of Medical Genetics. Grant sponsor: Swiss National Science Foundation; Grant number: 31-57272.99; Grant ones. In the 1992 revision [Spranger, sponsor: USPHS NIH.; Grant number: HD 22657; Grant sponsor: The Hartmann-MuÈ ller 1992], the classi®cation was oriented Foundation. toward radiodiagnostic and morpholo- *Correspondence to: Andrea Superti-Furga, Division of Metabolism and Molecular Pediatrics, University Children's Hospital, Steinwiesstr. 75, CH-8032 ZuÈ rich, Switzerland. gic criteria and grouped morphologi- E-mail: [email protected] cally similar disorders into ``families'' of ß 2002 Wiley-Liss, Inc. DOI 10.1002/ajmg.10233 ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS SEMIN. MED. GENET.) 283 disorders based on presumed pathoge- netic similarities. In the 1997 revision Nosology: catalog of de®ned conditions [International Working Group on Con- 3master book, encyclopedia) stitutional Diseases of Bone, 1998], the families of disorders were to some extent .& rearranged based on new etiopathoge- netic information concerning the gene Molecular-pathogenetic Clinical breakdown and/or protein defect in these disorders. breakdown 3help in diagnosis, Those disorders in which the basic 3research, candidate genes, diagnostic algorithms, defect was well documented were re- diagnostic tests, guide to appropriate grouped into distinct families based on pharmacological therapy, # laboratory tests) mutations in the same gene 3e.g., the gene therapy) achondroplasia group, the type 2 col- Radiographic breakdown lagen group, the diastrophic dysplasia 3radiographic features and group). The Nomenclature was focused signs; atlas, computer on the osteochondrodysplasias 3as devel- program for diagnostic opmental disorders of chondro-osseous help) tissue) but neglected the classi®cation of the dysostoses 3malformations of indivi- Figure 1. Classi®cation of skeletal genetic disorders by three categories. dual bones or groups of bones), although certain dysostoses 3e.g., brachydactyly C) were included because they were caused by mutations in genes associated presentations and clinical signs, to be of unprecedented and has turned the with dysplasias. The 1997 revision did, help in the diagnostic approach; and a skeletal system into a unique biologic however, come with the comment that molecular±pathogenetic classi®cation model. The multitude and variety of ``with the rapid evolution of our knowl- based on affected genes and pathoge- genes and proteins calls for a molecular edge concerning developmental genes netic mechanisms. Ultimately, they can and pathogenetic classi®cation. Such a in man, the dysostosis group of disorders be cross-correlated in an electronic classi®cation should assist in the follow- is in dire need of reclassi®cation'' [Inter- database. Books and computer programs ing purposes: national Working Group on Constitu- using a gamut of radiographic signs are tional Diseases of Bone, 1998]. already widely used [Hall and Shaw, Toidentify metabolic pathways active In the 2001 revision,1 the dysostoses * 1994; Taybi and Lachman, 1996]. In this in cartilage and bone, and their regu- have been reviewed and incorporated in article, we present a classi®cation of latory mechanisms. the Nomenclature, which has been genetic disorders of the skeleton based To identify cellular signaling net- called Nosology [Hall, 2002]. At the * on structure and function of the respon- works and gene expression sequences same time, the Working Group believed sible genes and proteins 3Table I). implicated in skeletal development. that the Nomenclature was becoming a By the above mechanisms, to identify hybrid that would not meet clinical * other elements in those systems as criteria 3for example, grouping entities In the 2001 revision, the candidate genes for genetic disorders. such as achondrogenesis 2 and Stickler To facilitate integration of data com- syndrome, which are clinically very dif- dysostoses have been reviewed * ing from spontaneous and genetically ferent, because of their common origin and incorporated in the engineered mouse mutants. in the COL2A1 gene) but also would To help in developing diagnostic not fully re¯ect genetic±molecular cri- Nomenclature, which has * strategies. teria, because those disorders with been called Nosology. To stimulate the design and explora- unknown defect were still grouped by * tion of new therapeutic possibilities. radiographic criteria. The genetic com- To provide a knowledge framework munity might therefore be better served * accessible to physicians as well as to with distinct classi®cations 3Fig. 1): the MOLECULAR± basic scientists and thus to facilitate Nosology as a catalog of de®ned entities PATHOGENETIC communication between clinical 3a sort of master book); a clinical CLASSIFICATION AS A genetics and pediatrics and the basic classi®cation, focused on age-speci®c WORKING INSTRUMENT sciences. 1The Nosology Committee of the Interna- The accumulation of knowledge on tional Skeletal Dysplasia Society met in Oxford on Sept. 4 and
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