CLINICAL AND MOLECULAR STUDIES OF ACHONDROPLASIS

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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 phenotype of affected individuals, and 3) molecular genetic studies designed to identify mutations in other FGFR3 disorders. Clinical studies have continued to collect information on neurologic and respiratory complications of achondroplasia in children less than 4 years of age. To date, a total of 130 cases have been ascertained. Data analysis is ongoing. Molecular genetic studies in our lab have determined that the mutated allele in sporadic cases of achondroplasia is predominantly inherited from the paternal chromosome. Advanced paternal age may play a role in the high mutation rate observed at this site. Studies of DNA from the 10-15% of patients without the typical hypochondroplasia mutation have failed to find additional FGFR3 mutations. These findings support previous speculation that there may be genetic heterogeneity in hypochondroplasia. We have shown, in collaboration with Dr. Max Muenke, that a new craniosynostosis syndrome can result from a specific FGFR3 mutation, also found in isolated craniosynostosis of the coronal sutures and that a newly identified skeletal dysplasia, with profound growth retardation, mental retardation and acanthosis nigricans, also results from a specific FGFR3 mutation. In collaboration with Dr. Jeffrey Baron of NICHD we have identified a possible FGFR3 mutation/polymorphism associated with generalized short stature. Additional studies are underway to clarify these findings.