Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes

Abstract

Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been identified in Crouzon syndrome, an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis). A mutation in FGFR1 has been established in several families with Pfeiffer syndrome, where craniosynostosis is associated with specific digital abnormalities. We now report point mutations in FGFR2 in seven sporadic Pfeiffer syndrome patients. Six of the seven Pfeiffer syndrome patients share two missense mutations, which have also been reported in Crouzon syndrome. The Crouzon and Pfeiffer phenotypes usually breed true within families and the finding of identical mutations in unrelated individuals giving different phenotypes is a highly unexpected observation.

Mutation analysis of Crouzon syndrome in Taiwanese patients

“…1) of the FGFR2 gene was detected (10,13) in exon IIIc of the gene. This mutation will lead to phenylalanine to serine at amino acid 354 of the FGFR2 gene.…”

“…To date, most of the patients diagnosed with Crouzon syndrome have been shown to carry mutations of the FGFR2 gene (10,15). However, mutations remain to be identified in 50-73% of patients.…”

“…Point mutations at positions 289, 301, 314, 341, 343, 351, and 354 will lead to a structure change and loss of ligand binding activity of the IgIII domain (18). It is clear that the same mutation may lead to phenotypic heterogeneity, and a mutation such as Cys342Arg in FGFR2 can result in Crouzon and Pfeiffer syndromes (5,10). This molecular analysis of the FGFR gene not only provides useful information to help clinicians confirm a diagnosis and perform prenatal diagnoses, it will also have a great impact on the clinical classification of craniosynostosis syndrome.…”

“…Recent studies have demonstrated that mutations in three of the four known FGFR genes are responsible for a variety of craniosynostosis syndromes, including Crouzon (4-6), Apert (7,8), Pfeiffer (9,10), and Jackson-Weiss (3,9,11) syndromes. Crouzon syndrome shows a broader spectrum of mutations in the FGFR2 gene, and occasionally patients with Crouzon syndrome share identical mutations (Cys278Phe, Cys342Arg, and Cys342Tyr) with patients with Pfeiffer and Jackson-Weiss syndromes, respectively (3,8,10,11). The majority of mutations in FGFR2 are missense substitutions clustered around the third extracellular immunoglobulin-like domain, encoded by exons IIIa and IIIc.…”

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

“…Other dominantly inherited human skeletal disorders are also associated with mutations in FGF receptors. Different mutations in FGFR2 are responsible for the malformations observed in patients with Crouzon and Jackson-Weiss syndromes (Jabs et al, 1994), and mutations in FGFR1 were identified as the cause of Pfeiffer's syndrome (Muenke et al, 1994), although FGFR2 mutations have also been described in sporadic Pfeiffer Syndrome patients (Rutland et al, 1995). In all three syndromes, premature closure of the skull sutures results in craniosynostosis, which in the latter two syndromes is accompanied by limb defects.…”