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      Nosology and Classification of Genetic Skeletal Disorders: 2010 Revision


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          Genetic disorders involving the skeletal system arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety. The Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology. In the 2010 revision, 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 were associated with mutations in one or more of 226 different genes, ranging from common, recurrent mutations to “private” found in single families or individuals. Thus, the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene. The Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing technologies; in the delineation of clinical entities and novel disorders, by providing an overview of established nosologic entities; and for scientists looking for the clinical correlates of genes, proteins and pathways involved in skeletal biology. © 2011 Wiley-Liss, Inc.

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          Most cited references 21

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          Genetic heterogeneity in osteogenesis imperfecta.

           D Sillence,  D Danks,  A Senn (1979)
          An epidemiological and genetical study of osteogenesis imperfecta (OI) in Victoria, Australia confirmed that there are at least four distinct syndromes at present called OI. The largest group of patients showed autosomal dominant inheritance of osteoporosis leading to fractures and distinctly blue sclerae. A large proportion of adults had presenile deafness or a family history of presenile conductive hearing loss. A second group, who comprised the majority of newborns with neonatal fractures, all died before or soon after birth. These had characteristic broad, crumpled femora and beaded ribs in skeletal x-rays. Autosomal recessive inheritance was likely for some, if not all, of these cases. A third group, two thirds of whom had fractures at birth, showed severe progressive deformity of limbs and spine. The density of scleral blueness appeared less than that seen in the first group of patients and approximated that seen in normal children and adults. Moreover, the blueness appeared to decrease with age. All patients in this group were sporadic cases. The mode of inheritance was not resolved by the study, but it is likely that the group is heterogeneous with both dominant and recessive genotypes responsible for the syndrome. The fourth group of patients showed dominant inheritance of osteoporosis leading to fractures, with variable deformity of long bones, but normal sclerae.
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            Nosology and classification of genetic skeletal disorders: 2006 revision.

            The objective of the paper is to provide the revision of the Nosology of Constitutional Disorders of Bone that incorporates newly recognized disorders and reflects new molecular and pathogenetic concepts. Criteria for inclusion of disorders were (1) significant skeletal involvement corresponding to the definition of skeletal dysplasias, metabolic bone disorders, dysostoses, and skeletal malformation and/or reduction syndromes, (2) publication and/or MIM listing, (3) genetic basis proven or very likely, and (4) nosologic autonomy confirmed by molecular or linkage analysis and/or distinctive diagnostic features and observation in multiple individuals or families. Three hundred seventy-two different conditions were included and placed in 37 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 215 were associated with one or more of 140 different genes. Nosologic status was classified as final (mutations or locus identified), probable (pedigree evidence), or bona fide (multiple observations and clear diagnostic criteria, but no pedigree or locus evidence yet). The number of recognized genetic disorders with a significant skeletal component is growing and the distinction between dysplasias, metabolic bone disorders, dysostoses, and malformation syndromes is blurring. For classification purposes, pathogenetic and molecular criteria are integrating with morphological ones but disorders are still identified by clinical features and radiographic appearance. Molecular evidence leads to confirmation of individual entities and to the constitution of new groups, but also allows for delineation of related but distinct entities and indicates a previously unexpected heterogeneity of molecular mechanisms; thus, molecular evidence does not necessarily simplify the Nosology, and a further increase in the number of entities and growing complexity is expected. By providing an updated overview of recognized entities with skeletal involvement and of the underlying gene defects, the new Nosology can provide practical diagnostic help, facilitate the recognition of new entities, and foster and direct research in skeletal biology and genetic disorders. (c) 2006 Wiley-Liss, Inc.
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              International nosology and classification of constitutional disorders of bone (2001).

               Lucinda Hall (2002)
              The last International Classification of Constitutional Disorders of Bone was published in 1998. Since then rapid advances have been made in identifying the molecular changes responsible for defined conditions and new disorders are constantly being delineated. For these reasons a further update on the classification is appropriate. It has been expended to not only the osteochondrodysplasias (33 groups) but also genetically determined dysostoses (3 groups). Copyright 2002 Wiley-Liss, Inc.

                Author and article information

                Am J Med Genet A
                Am. J. Med. Genet. A
                American Journal of Medical Genetics. Part a
                Wiley Subscription Services, Inc., A Wiley Company (Hoboken )
                May 2011
                15 March 2011
                : 155
                : 5
                : 943-968
                [1 ]Orthopaedic Research Laboratories, Department of Orthopaedic Surgery, The Howard Hughes Medical Institute, Children's Hospital Boston, Massachusetts
                [2 ]Department of Genetics and INSERM U781, Paris Descartes University, Hôpital Necker Enfants Malades Paris, France
                [3 ]Institute of Child Health, University of London London, UK
                [4 ]Medical Genetics Institute, Steven Spielberg Building, Cedars-Sinai Medical Center Los Angeles, California
                [5 ]Departments of Orthopaedic Surgery and Human Genetics, UCLA Los Angeles, California
                [6 ]Department of Medical Genetics, University Hospital of Antwerp, University of Antwerp Edegem, Belgium
                [7 ]Institut für Medizinische Genetik, Charité Universitätsmedizin Berlin, Max-Planck-Institut für Molekulare Genetik Berlin, Germany
                [8 ]Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center Fuchu, Tokyo, Japan
                [9 ]Department of Paediatrics and Child Health, Dunedin School of Medicine, Otago University Dunedin, New Zealand
                [10 ]Murdoch Children's Research Institute, Royal Children's Hospital, Department of Paediatrics, University of Melbourne Victoria, Australia
                [11 ]Discipline of Genetic Medicine, The Children's Hospital at Westmead Clinical School, The University of Sydney Westmead, Australia
                [12 ]Centre for Pediatrics and Adolescent Medicine, Freiburg University Hospital, University of Freiburg Freiburg, Germany
                [13 ]Medical Genetics Service, University of Lausanne, CHUV—Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland
                [14 ]Department of Pediatrics, University of Lausanne, CHUV—Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland
                Author notes
                *Correspondence to: Andrea Superti-Furga, Centre Hospitalier Universitaire Vaudois (CHUV), Av. Decker, 2, 1011 Lausanne, Switzerland. E-mail: asuperti@ 123456unil.ch

                The 9th ISDS meeting and the Nosology workshop were held in Boston in July 2009 and supported by The Manton Center for Orphan Disease Research, Children's Hospital, Boston, Massachusetts; Children's Orthopaedic Surgery Foundation, Inc., Boston, Massachusetts; The Osteogenesis Imperfecta Foundation, Gaithersburg, Maryland; Biomarin, Novato, California; and Enobia Pharma, Montreal, Quebec, Canada. The 2010 Nosology tables are available online at the International Skeletal Dysplasia Society web site ( http://www.isds.ch).

                Copyright © 2011 Wiley-Liss, Inc.

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                Research Articles


                skeletal genetics, osteochondrodysplasias, nosology, dysostoses, molecular basis of disease


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