JACKSON-WEISS-SYNDROME - IDENTIFICATION OF 2 NOVEL FGFR2 MISSENSE MUTATIONS SHARED WITH CROUZON AND PFEIFFER CRANIOSYNOSTOTIC DISORDERS

Jackson-Weiss syndrome is a rare skeletal disorder characterized by cr aniosynostosis associated with foot malformations. This condition is i nherited as an autosomal dominant trait with complete penetrance and w ide phenotypic heterogeneity. Mutations in the fibroblast growth facto r receptor 2 (FGFR2) gene have been recently identified as causes of t his syndrome and of at least four other craniosynostotic disorders, na mely che Apert, Beare-Stevenson cutis gyrata, Crouzon and Pfeiffer syn dromes. We report two novel FGFR2 missense mutations associated with p henotypes consistent with Jackson-Weiss syndrome. Both nucleotide chan ges predict a serine for cysteine-342 substitution in the second half of the third immunoglobulin-like domain. The replacement of Cys-342 wi th arginine has previously been reported in one of the three Jackson-W eiss cases investigated. Interestingly, both Cys342Ser and Cys342Arg s ubstitutions have been found to be associated with the Crouzon and Pfe iffer phenotypes; a phenotypic heterogeneity, Crouzon vs Jackson-Weiss clinical features, has been also observed for Gln289Pro and Ala344Gly amino-acid changes. This finding indicates the genetic homogeneity of the ''heterogeneous'' Jackson-Weiss phenotype and a common molecular basis for these apparently ''clinically distinct'' craniosynostotic di sorders.