FGFR2 – Pfeiffer syndrome type 2

FGFR2‐related Pfeiffer syndrome type 2 is an autosomal dominant craniosynostosis characterized by cloverleaf skull, severe proptosis and radioulnar synostosis (HP:0002676; HP:0000520; HP:0002974). Affected infants present broad thumbs and great toes, midface hypoplasia and variable overlap with Antley‐Bixler syndrome features.

Genetic testing reveals heterozygous missense mutations at the Trp290 hotspot in FGFR2, notably c.870G>T (p.Trp290Cys), in 5 unrelated probands ([PMID:9475591]; [PMID:27683237]). These variants segregate in an autosomal dominant pattern with full penetrance and no additional affected relatives reported.

All reported PS type 2 cases involve the c.870G>T (p.Trp290Cys) change, which introduces an unpaired cysteine in the third immunoglobulin‐like domain. This locus appears to be a mutational hotspot, with 5 missense alleles identified, and no loss‐of‐function or splice variants described.

Functional studies demonstrate that introduction of an unpaired cysteine residue in FGFR2 extracellular domains induces aberrant intermolecular disulfide bond formation, ligand‐independent receptor dimerization and elevated tyrosine kinase activity ([PMID:8755573]; [PMID:8798788]). These gain‐of‐function effects recapitulate mesoderm induction in Xenopus assays and mirror the craniosynostosis phenotype.

Integration of genetic and experimental data supports a gain‐of‐function mechanism for FGFR2 Trp290Cys in Pfeiffer syndrome type 2. The consistent genotype–phenotype correlation, combined with in vitro receptor activation, underpins a moderate level of clinical validity and warrants targeted molecular testing in neonates presenting with cloverleaf skull and limb synostoses.

Key Take‐home: Screening for FGFR2 Trp290Cys variants enables precise diagnosis of Pfeiffer syndrome type 2 and informs prognosis and genetic counseling.

References

• American journal of medical genetics • 1998 • Novel mutation in the FGFR2 gene at the same codon as the Crouzon syndrome mutations in a severe Pfeiffer syndrome type 2 case. PMID:9475591
• American journal of medical genetics. Part A • 2017 • Mutation analysis of FGFR1-3 in 11 Japanese patients with syndromic craniosynostoses. PMID:27683237
• Proceedings of the National Academy of Sciences of the United States of America • 1996 • Constitutive receptor activation by Crouzon syndrome mutations in fibroblast growth factor receptor (FGFR)2 and FGFR2/Neu chimeras. PMID:8755573
• The Journal of biological chemistry • 1996 • Ligand-independent activation of fibroblast growth factor receptors by point mutations in the extracellular, transmembrane, and kinase domains. PMID:8798788

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