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

Abstract

Crouzon Syndrome (CS), Pfeiffer syndrome (PS) and the phenotypically related Jackson-Weiss (JW) variant are three craniosynostotic conditions caused by heterozygous mutations in Fibroblast Growth Factor Receptor (FGFR) genes. Screening a large cohort of 84 patients with clinical features of CS, PS or JW by direct sequencing of genomic DNA, enabled FGFR1, 2 or 3 mutation detection in 79 cases. Mutations preferentially occurred in exons 8 and 10 of FGFR2 encoding the third Ig loop of the receptor. Among the 74 FGFR2 mutations that we identified, four were novel including three missense substitutions causing CS and a 2 bp deletion creating a premature stop codon and producing JW phenotype. Five FGFR2 mutations were found in one of the two tyrosine kinase subdomains and one in the Ig I loop. Interestingly, two FGFR2 mutations creating cysteine residues (W290C and Y340C) caused severe forms of PS while conversion of the same residues into another amino-acid (W290G/R, Y340H) resulted in Crouzon phenotype exclusively. Our data provide conclusive evidence that the mutational spectrum of FGFR2 mutations in CS and PS is wider than originally thought. Genotype-phenotype analyses based on our cohort and previous studies further indicate that in spite of some overlap, PS and CS are preferentially accounted for by two distinct sets of FGFR2 mutations. A limited number of recurrent amino-acid changes (W290C, Y340C, C342R and S351C) is commonly associated with the most severe Pfeiffer phenotypes of poor prognosis.

Craniosynostosis

“…FGFR2 mutations in Pfeiffer syndrome overlap those in Crouzon syndrome (Figure 2a), but the majority of severe cases are caused by a small subset of substitutions encoding Trp290Cys, Tyr340Cys, Cys342Arg or Ser351Cys. 17 Crouzon syndrome is usually the mildest of the FGFR2-associated disorders and the clinical diagnosis is suggested by the combination of crouzonoid facies (Figure 1n) and absence of major abnormalities of the hands and feet. Although bicoronal synostosis is most common, Crouzon syndrome can present with late-onset pansynostosis.…”

Effects of FGFR Signaling on Cell Proliferation and Differentiation of Apert Dental Cells

“…FGF-FGFR binding initiates receptor dimerization and phosphorylation of intrinsic tyrosine residues, leading to activation of several signal transduction pathways including phospholipase Cγ (PLCγ), mitogen-activated protein kinase (MAPK) and protein kinase C (PKC), which are important for signaling in osteoblast differentiation and bone formation [Du et al, 2012]. Mutations in FGFR2, located on human chromosome 10q26, result in several congenital syndromes with bony defects, including Crouzon (OMIM 123500), Jackson-Weiss (OMIM 123150), BeareStevenson (OMIM 123790), Pfeiffer (OMIM 101600) and Apert (OMIM 101200) [Lomri et al, 1998;Lajeunie et al, 1999Lajeunie et al, , 2006Schulz et al, 2007].…”

Mutational patterns in oncogenes and tumour suppressors

“…Tyrosine receptor kinases can also be activated by dimerization of the extracellular domains resulting in ligand-independent activation of the receptor. This is observed in FGFR2 by mutations R203C and W290C in the immunoglobulin-like (Ig-like) domains [41,42].…”