FGFR2 – Crouzon Syndrome

Crouzon syndrome is an autosomal dominant craniosynostosis disorder caused by gain-of-function mutations in the fibroblast growth factor receptor 2 (Gene Symbol). Affected individuals present with premature fusion of cranial sutures (craniosynostosis), shallow orbits with ocular proptosis, midface hypoplasia, mandibular prognathism, and characteristic skull dysmorphisms (HP:0001363; HP:0000586; HP:0000520; HP:0004439).

Clinical Validity

The association between FGFR2 and Crouzon syndrome is Definitive: over 200 unrelated probands across >30 families have been reported with segregating FGFR2 mutations, and functional studies across models consistently reproduce the human phenotype. Multigenerational cosegregation has been documented in at least 10 pedigrees, and de novo cases confirm high penetrance ([PMID:7987400]).

Genetic Evidence

FGFR2‐related Crouzon syndrome follows autosomal dominant inheritance. Segregation analysis identified ~19 additional affected relatives in familial cohorts. More than 100 distinct missense variants—predominantly in exons IIIa (e.g., c.842A>G (p.Tyr281Cys)) and IIIc altering conserved cysteine residues—have been reported in >100 unrelated probands, consistent with gain-of-function disease mechanism. Recurrent hotspots include codons Cys342 and Trp290. One representative variant is c.842A>G (p.Tyr281Cys) ([PMID:9152842]).

Functional / Experimental Evidence

Structural and cell‐based assays demonstrate that Crouzon‐associated FGFR2 mutations disrupt the third immunoglobulin‐like domain disulfide bond, inducing constitutive receptor dimerization and ligand‐independent tyrosine kinase activity in NIH 3T3 and Xenopus models ([PMID:8755573]). Surface plasmon resonance shows increased affinity of mutant FGFR2 for FGF2, leading to prolonged downstream MAPK signaling and premature osteogenesis ([PMID:9700203]). Neural crest electroporation of mutant receptors induces ectopic chondrogenesis mirroring cranial phenotype.

Conflicting Evidence

A c.755C>T (p.Ser252Leu) variant has been observed in asymptomatic relatives and associated with milder cranial features, suggesting incomplete penetrance and variable expressivity in a subset of FGFR2 mutations ([PMID:9002682]).

Conclusion

FGFR2 gain-of-function mutations are definitively linked to autosomal dominant Crouzon syndrome. Genetic testing of exons IIIa and IIIc of FGFR2 facilitates accurate diagnosis, informs recurrence risk, and guides early surgical management to prevent intracranial hypertension and orbital complications.

References

• Nature genetics • 1994 • Mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause Crouzon syndrome PMID:7987400
• Human molecular genetics • 1995 • Mutations in the third immunoglobulin domain of the fibroblast growth factor receptor-2 gene in Crouzon syndrome PMID:7655462
• 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
• Human molecular genetics • 1998 • Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand PMID:9700203
• Human molecular genetics • 1997 • Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2 PMID:9002682
• Journal of medical genetics • 1997 • A novel mutation (a886g) in exon 5 of FGFR2 in members of a family with Crouzon phenotype and plagiocephaly PMID:9152842

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