FGFR2 MUTATION IN CLINICALLY NONCLASSIFIABLE AUTOSOMAL-DOMINANT CRANIOSYNOSTOSIS WITH PRONOUNCED PHENOTYPIC VARIATION

We describe a mutation in the FGFR2 gene in affected members of a larg e family with inherited autosomal dominant craniosynostosis. The mutat ion is a G1044A transition at codon 344 of exon B of the gene and resu lts in abnormal splicing of the FGFR2 transcript. The phenotypic effec t of the mutation varies greatly. It ranges from minor anomalies such as slight hypertelorism and maxillary hypoplasia to severe manifestati ons such as brachycephaly and dolichocephaly. The severe cases require d surgery because of increased intracranial pressure. The patients can not be assigned clinically to one of the known craniosynostotic syndro mes with mutations in FGFRS2 e.g., Crouzon, Pfeiffer, or Jackson-Weiss . This study demonstrates that FGFR2 mutations can result in a spectru m of craniofacial abnormalities even within one family. The known epon ymic syndromes of Crouzon, Pfeiffer, or Jackson-Weiss only describe ph enotypic extremes of this spectrum. Therefore, the clinical classifica tion should be abandoned and replaced by a molecular one such as ''FGF R-associated craniosynostosis syndromes.'' (C) 1996 Wiley-Liss, Inc.