FGFR2 mutations in patients with Pfeiffer syndrome type III. K. Hedrich, H. Thiele, A. Rühl, I. Hansmann, U. Hehr. Humangenetik, Martin-Luther-Universität, Halle, Germany.

   Craniosynostosis, the premature fusion of one or several cranial sutures, is with a prevalence of appr. 1 in 3,000 one of the most common craniofacial anomalies at birth. Recently, mutations in three of the four human fibroblast growth factor receptor genes (FGFRs) have been shown to account for appr. 15-20% of all cases with craniosynostosis. Here we report the results of a screening for FGFR mutations in 5 familial cases and 10 sporadic patients with craniosynostosis, referred to our department for genetic counseling. Two of the patients were identified as Pfeiffer syndrome Type III. In addition to bilateral coronal craniosynostosis with short anterior cranial base and ocular proptosis, both patients presented with developmental delay, hydrocephalus internus, hearing deficit and short stature. In both patients previously reported mutations affecting exon IgIIIc of FGFR2 were identified. The first patient died at the age of 34 months following repeated craniosurgery, the clinical course was complicated by dyspnoe resulting from choanal stenosis and stenosis of the bronchi. She was found to carry the common FGFR2 mutation Cys342Arg within exon IgIIIc, which had previously been reported in more than 20 patients with CS, PS or JWS. The second patient presented with localized tracheostenosis and multiple orthopedic problems including hip dysplasia, severe scoliosis and limited extension of the elbows. Mutation analysis confirmed an A(-2)G substitution at the acceptor splice site of exon IgIIIc. Comparison of the clinical features of both patients with the previously reported cases further underlines the wide phenotypic spectrum of identical FGFR2 nucleotide substitutions, most notably in exon IgIIIc, and supports the idea of additional genetic and/or environmental factors modifying the extend of the initial mutation effect.