DIFFERENTIAL-EFFECTS OF FGFR2 MUTATIONS ON SYNDACTYLY AND CLEFT-PALATE IN APERT SYNDROME

Apert syndrome is a distinctive human malformation characterized by cr aniosynostosis and severe syndactyly of the hands and feet. It is caus ed by specific missense substitutions involving adjacent amino acids ( Ser252Trp or Pro253Arg) in the linker between the second and third ext racellular immunoglobulin domains of fibroblast growth factor receptor 2 (FGFR2). We have developed a simple PCR assay for these mutations i n genomic DNA, based on the creation of novel Sm and BstUI restriction sites. Analysis of DNA from 70 unrelated patients with Apert syndrome showed that 45 had the Ser252Trp mutation and 25 had the Pro253Arg mu tation. Phenotypic differences between these two groups of patients we re investigated. Significant differences were found for severity of sy ndactyly and presence of cleft palate. The syndactyly was more severe with the Pro253Arg mutation, for both the hands and the feet. In contr ast, cleft palate was significantly more common in the Ser252Trp patie nts. No convincing differences were found in the prevalence of other m alformations associated with Apert syndrome. We conclude that, althoug h the phenotype attributable to the two mutations is very similar, the re are subtle differences. The opposite trends for severity of syndact yly and cleft palate in relation to the two mutations may relate to th e varying patterns of temporal and tissue-specific expression of diffe rent fibroblast growth factors, the ligands for FGFR2.