Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome

Abstract

Pfeiffer syndrome is a skeletal disorder characterized by craniosynostosis associated with foot and hand anomalies. Mutations in the genes encoding fibroblast growth factor receptors 1 and 2 (FGFR1 and FGFR2) have recently been implicated in the aetiology of such a syndrome, as well as of other craniosynostotic conditions. We now report a novel missense mutation, a G to C transversion at position 1049 (exon IIIa) of FGFR2, detected in a patient with severe Pfeiffer clinical features. The mutation results in the substitution of a cysteine for tryptophan-290 in the third immunoglobulin-like domain and affects both spliceoforms of FGFR2. Mutations causing replacement of tryptophan-290 have also been reported previously in Crouzon syndrome, a similar but clinically distinct craniosynostotic disorder. This finding confirms the involvement of mutations of FGFR2 exon IIIa in Pfeiffer syndrome, and emphasizes both the extensive heterogeneity of the FGFR2 mutations that result in the Pfeiffer phenotype and the perturbations caused by unpaired cysteine residues in receptor dimerization and transduction of the FGFs signal.

Clinical expression in Pfeiffer syndrome type 2 and 3: Surveillance in Japan

“…[Robin et al, 2011]. Four types of FGFR2 mutations were detected in our study, all of which were identified previously [Rutland et al, 1995;Tartaglia et al, 1997;Gripp et al, 1998;Itoh et al, 2006]. In our series, FGFR2 mutations showed the same subtypes as reported by Cohen and the same phenotypic severity as reported previously for patients with identical mutations [Rutland et al, 1995;Tartaglia et al, 1997;Gripp et al, 1998;Itoh et al, 2006].…”

Further evidence of association between mutations in FGFR2 and syndromic craniosynostosis with sacrococcygeal eversion

“…Pfeiffer syndrome (PS; OMIM #101600) is an autosomal dominant disorder characterized by craniosynostosis, midface hypoplasia, broad thumbs, brachydactyly, broad great toes, and variable cutaneous syndactyly (Tartaglia et al, 1997;Kress et al, 2000;Teebi et al, 2002;Cohen, 2004). The premature fusion of one or more cranial sutures leads to an abnormal skull shape (Tartaglia et al, 1997).…”

“…The premature fusion of one or more cranial sutures leads to an abnormal skull shape (Tartaglia et al, 1997). There is considerable clinical heterogeneity and 3 subtypes of PS, with clinical overlap and with different prognostic trends (Cohen, 1993(Cohen, , 2004.…”

“…PS type 1 is genetically heterogeneous. Most cases are caused by several different mutations in exons 8 or 10 of the fibroblast growth factor receptor 2 (FGFR2) and a common mutation, P252R, at the gene encoding the fibroblast growth factor receptor 1 (FGFR1), is found in a few cases of PS type 1 (Tartaglia et al, 1997;Passos-Bueno et al, 1999;Kan et al, 2002;Wilkie, 2005). There have been very few reports on molecular characterization of PS cases types 2 and 3, possibly due to the rarity of the cases, and it is still not known if these severe phenotypes are caused by common mutations or if there is genetic heterogeneity.…”

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

“…11,12 Surprisingly, the same FGFR2 mutation can give rise to CS, PS or JW phenotype. 6,13 Until 2002, FGFR2 mutations had been identified almost exclusively in the extracellular domain of the receptor mainly in exons 8 (IIIa) and 10 (IIIc) encoding the third immunoglobulin-like (Ig III) loop and appeared to account for only 50% of CS and PS cases. 14 In 2002, novel mutations in other regions of the receptor including the IgII loop and the tyrosine kinase subdomains TK1 and TK2 have been reported.…”