NOVEL FGFR2 MUTATIONS IN CROUZON AND JACKSON-WEISS SYNDROMES SHOW ALLELIC HETEROGENEITY AND PHENOTYPIC VARIABILITY

Mutations have been reported for several craniosynostotic disorders in exon IIIa (exon U or 7) or IIIc (exon B or 9) of the fibroblast growt h factor receptor 2 gene (FGFR2), Among the conditions with FGFR2 muta tions are two autosomal dominant syndromes, Crouzon and Jackson-Weiss. In this study, 24 Crouzon and one Jackson-Weiss syndrome patients wer e screened for mutations in the two exons by direct sequencing, and mu tations were detected in 28% (7/25) of all cases, Five different mutat ions were found including two novel (W290G, C342W) and two previously reported, recurrent mutations for Crouzon syndrome (A344A, S354C), and one new mutation for Jackson-Weiss syndrome (C342R), The W290G mutati on was found in exon IIIa which is common to both alternatively splice d forms of FGFR2, BEK (expressed predominantly in primordial bones) an d KGFR (expressed preferentially in epithelia), Atypical Crouzon syndr ome features of epithelial-derived anal and/or external ear anomalies were present in the two affected family members with the mutation, Thi s phenotype possibly reflects the expression of both mutant BEK and KG FR, In addition, the Jackson-Weiss syndrome mutation, C342R, in exon I IIc was observed previously in other craniosynostotic syndromes, Crouz on and Pfeiffer. These results underscore the allelic heterogeneity of these conditions and the complexity of the phenotypic consequences of FGFR2 mutations.