MUTATIONS IN FGFRI AND FGFR2 CAUSE FAMILIAL AND SPORADIC PFEIFFER SYNDROME

Pfeiffer syndrome (PS) is an autosomal dominant skeletal disorder whic h affects the bones of the skull, hands and feet. Previously, we have mapped PS in a subset of families to chromosome 8cen by linkage analys is and demonstrated a common mutation in the fibroblast growth factor receptor-1 (FGFR1) gene in the linked families. Here we report a secon d locus for PS on chromosome 10q25, and present evidence that mutation s in the fibroblast growth factor receptor-2 (FGFR2) gene on 10q25 cau se PS in an additional subset of familial and sporadic cases. Three di fferent point mutations in FGFR2, which alter the same acceptor splice site of exon a, were observed in both sporadic and familial PS. In ad dition, a T to C transition in exon a predicting a cysteine to arginin e substitution was identified in three sporadic PS individuals. Intere stingly, this T to C change is identical to a mutation in FGFR2 previo usly reported in Crouzon syndrome, a phenotypically similar disorder b ut one lacking the hand and foot anomalies seen in PS. Our results hig hlight the genetic heterogeneity in PS and suggest that the molecular data will be an important complement to the clinical phenotype in defi ning craniosynostosis syndromes.