CLINICAL AND MOLECULAR STUDIES OF ACHONDROPLASIA

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This study has three specific aims: 1) the identification and characterization of causes of morbidity and mortality in achondroplasia, 2) molecular genetic studies designed to identify correlations between mutations which cause achondroplasia and related disorders and the phenotypes of affected individuals, and elucidate their pathogenesis, and 3) molecular genetic studies designed to identify mutations in other FGFR3 disorders. A newly identified skeletal dysplasia, with Severe Achondroplasia, Developmental Delay and Acanthosis Nigricans (SADDAN), has been found to result from a specific FGFR3 mutation, K650M. To date, the mutation has been found in 3 patients with this phenotype. Efforts are underway to further define the clinical phenotype and elucidate the pathogenesis of the disorder caused by the K650M mutation. Collaborative studies with Dr. Jeffrey Baron of NICHD have identified an FGFR3 alteration associated with generalized short stature. This alteration, which has been found in 5 patients to date, is predicted to alter a known splice site. The pathogenesis of short stature resulting, at least in part, from this alteration is under investigation. In collaboration with Dr. Chuxia Deng of NIDDK, mouse models for thantophoric dysplasia type II and the SADDAN phenotype have been created.