FCFR2 EXON IIIA AND IIIE MUTATIONS IN CROUZON, JACKSON-WEISS, AND PFEIFFER SYNDROMES - EVIDENCE FOR MISSENSE CHANGES, INSERTIONS, AND A DELETION DUE TO ALTERNATIVE RNA SPLICING

Fibroblast growth factor receptor 2 (FGFR2) mutations have been associ ated with the craniosynostotic conditions Crouzon, Jackson-Weiss, and Pfeiffer syndromes. Previously, mutations were described in the exons IIIa and IIIc, which form the extracellular, third immunoglobulin-like domain (IgIII) and adjacent linker regions, both of which are normall y involved in ligand binding;. For all three conditions, mutations wer e found in exon IIIc. Only in Crouzon syndrome were mutations identifi ed in exon IIIa. In this study, 39 cases with one of these three condi tions were screened for exon IIIa or IIIc mutations. Eleven mutations are reported in 17 unrelated cases. Mutations in exon IIIa are identif ied for not only Crouzon but also Jackson-Weiss and Pfeiffer syndromes . Four mutations in either exon IIIa or exon IIIc reported only in Cro uzon syndrome are present also in one of the other two syndromes. Two insertions, one in exon IIIa in a Crouzon syndrome patient and the oth er in exon IIIc in a Pfeiffer syndrome patient, were observed. The lat ter mutation has the same alternative RNA splicing effect as a reporte d synonymous mutation for Crouzon syndrome. A missense mutation was de tected in one Pfeiffer syndrome family in which two members had cranio synostosis without limb anomalies. The inter- and intrafamilial variab ility in expression of FGFR2 mutations suggests that these three syndr omes, presumed to be clinically distinct, are instead representative o f a spectrum of related craniosynostotic and digital disorders.