Date Published: May 15, 2011
Publisher: Wiley Subscription Services, Inc., A Wiley Company
Author(s): Matthew L Warman, Valerie Cormier-Daire, Christine Hall, Deborah Krakow, Ralph Lachman, Martine LeMerrer, Geert Mortier, Stefan Mundlos, Gen Nishimura, David L Rimoin, Stephen Robertson, Ravi Savarirayan, David Sillence, Juergen Spranger, Sheila Unger, Bernhard Zabel, Andrea Superti-Furga.
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.
In the 1960s, accumulating evidence that genetic skeletal disorders were clinically and genetically heterogeneous prompted a group of international experts to prepare a document to reach an agreement on the nomenclature of what was then called “constitutional (or intrinsic) disorders of bone” [1970, 1971a,b,c,d; McKusick and Scott, 1971]. The “Nomenclature” was meant to bring together experts in radiology, clinical genetics, and pediatrics to agree on the denomination and classification of skeletal disorders, syndromes and metabolic diseases that were being newly described. Revisions have been prepared in 1977, 1983, 1992, and 1997 [1978, 1979, 1983, 1998, Rimoin, 1979; Spranger, 1992; Lachman, 1998]. Following the establishment of the International Skeletal Dysplasia Society (ISDS) in 1999, and to cope with the increasing complexity of information, revisions of the Nosology have been delegated to an expert group nominated ad hoc within the ISDS to ensure an adequate representation of clinical, radiological and molecular expertise (2001 and 2006 revisions) [Hall, 2002; Superti-Furga and Unger, 2007].
The Nosology Group of the International Skeletal Dysplasia Society met in August 2009. A consensus was reached for changes to be made to the grouping of disorders and about the inclusion of individual disorders. The drafts were circulated after the meeting and an effort was made to monitor recent publications up to November 2010. The criteria used for inclusion of individual disorders were unchanged from the previous revision. They were:
Four hundred fifty-six different conditions were included and placed in 40 groups defined by molecular, biochemical and/or radiographic criteria. Of these conditions, 316 (2006 revision: 215) were associated with one or more of 226 (2006 revision: 140) different genes. The results are presented in Table I. Within a group, disorders with known molecular basis have been listed preceding those with lesser degree of evidence; however, variants of the same disorder have been kept together.