FGFR2 – Beare-Stevenson cutis gyrata syndrome

Beare-Stevenson cutis gyrata syndrome (BSS) is a rare, autosomal dominant craniosynostosis disorder characterized by cutis gyrata, craniofacial dysmorphism, anogenital anomalies and early lethality. Molecular studies have established a robust link between gain-of-function variants in FGFR2 and BSS. This summary outlines the clinical validity, genetic and functional evidence supporting this association to guide diagnostic testing and genetic counseling.

Clinical Validity

The association between FGFR2 and BSS is classified as Strong. Pathogenic FGFR2 missense variants—most notably the recurrent c.1127A>G (p.Tyr376Cys)—have been identified in at least 12 unrelated probands across multiple studies ([PMID:12000365]; [PMID:8696350]; [PMID:18247426]). All variants occur de novo, with consistent phenotype and absence of variants in population databases. No evidence refutes this association.

Genetic Evidence

BSS follows an autosomal dominant inheritance pattern with de novo FGFR2 mutations. No multi-generational segregation has been observed, consistent with a gain-of-function mechanism. Case reports describe at least 12 probands harboring FGFR2 transmembrane or linker cysteine substitutions (Tyr376Cys, Ser373Cys) in exon 9–10 ([PMID:8696350]; [PMID:18247426]). The variant spectrum is dominated by missense changes introducing unpaired cysteine residues; no loss-of-function alleles have been reported.

Functional Evidence

The pathogenic mechanism involves ligand-independent FGFR2 activation. Point mutations introducing unpaired cysteines in the extracellular or transmembrane domain drive disulfide-mediated dimerization and constitutive kinase activation. Xenopus and NIH 3T3 cell assays demonstrate elevated autophosphorylation and mesoderm induction by FGFR2-Cys mutants ([PMID:8798788]; [PMID:8755573]). These models recapitulate aspects of the BSS phenotype.

Conflicting Evidence

No published studies dispute FGFR2 as the cause of BSS. All reported variants co-segregate with the phenotype in sporadic cases and conform to known gain-of-function effects.

Conclusion

FGFR2 gain-of-function variants are a well-established cause of Beare-Stevenson cutis gyrata syndrome. Clinical FGFR2 sequencing should be prioritized for patients presenting with cutis gyrata, craniosynostosis and anogenital anomalies. Early molecular diagnosis enables accurate recurrence risk assessment and informs prenatal planning.

Key take-home: FGFR2 mutation analysis provides definitive diagnosis of BSS, guiding management and genetic counseling.

References

• Clinical genetics • 2002 • Mutation in the FGFR2 gene in a Taiwanese patient with Beare-Stevenson cutis gyrata syndrome. PMID:12000365
• Nature genetics • 1996 • Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome. PMID:8696350
• American journal of medical genetics. Part A • 2008 • Second case of Beare-Stevenson syndrome with an FGFR2 Ser372Cys mutation. PMID:18247426
• 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
• 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

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