FGFR2 – Antley-Bixler Syndrome

Fibroblast growth factor receptor 2 (FGFR2) mutations underlie a dominant form of Antley-Bixler syndrome (ABS), a complex craniosynostosis disorder characterized by radiohumeral synostosis, midface hypoplasia, proptosis, choanal atresia, and occasional genital anomalies. Initial case reports described a de novo C1064G (p.Ser351Cys) substitution in the IgIII domain in a patient with skull and elbow synostosis (PMID:9605588). Subsequent cohort analysis identified heterozygous FGFR2 variants in 7 of 16 unrelated ABS patients, including NM_022970.4(FGFR2):c.826T>G (p.Phe276Val), supporting a recurrent mutational hotspot in exons encoding the extracellular domain (PMID:10633130).

Inheritance is autosomal dominant, with most cases arising as sporadic de novo events. Familial segregation is limited; no multigenerational kindreds have been reported, and no additional affected relatives were documented in the key studies. Variant spectrum is dominated by missense substitutions that introduce or disrupt cysteine residues, leading to aberrant intermolecular disulfide bonding in the IgIII domain.

Genetic evidence meets strong ClinGen criteria: at least 8 unrelated probands harboring pathogenic FGFR2 variants and consistent de novo occurrence. The principal variant NM_022970.4(FGFR2):c.826T>G (p.Phe276Val) exemplifies the mutation class linking FGFR2 to ABS.

Functional assays demonstrate a gain-of-function mechanism: extracellular mutations that introduce unpaired cysteines promote ligand-independent receptor dimerization and elevate tyrosine kinase activity (PMID:8798788; PMID:8755573). Such constitutive activation recapitulates craniosynostotic phenotypes in cell and animal models.

In neural crest cell assays, expression of mutant FGFR2 (C278F) induced chondrogenesis and early osteogenic markers Sox9, Col2a1, and osteopontin without exogenous FGF, mirroring premature suture fusion in ABS (PMID:12112473). Rescue and isoform-specific studies underscore the role of the IgIII cysteine loop in receptor regulation.

Collectively, genetic and experimental data strongly validate FGFR2 gain-of-function as the pathogenic mechanism in Antley-Bixler syndrome. Clinical screening of FGFR2 exons IIIa/IIIc is recommended for early diagnosis, risk assessment, and potential precision therapeutics targeting aberrant FGFR2 signaling.

Key Take-home: FGFR2 missense mutations causing constitutive receptor activation are a clinically actionable cause of Antley-Bixler syndrome, supporting molecular diagnosis and informing therapeutic development.

References

• American journal of medical genetics • 1998 • FGFR2 mutation associated with clinical manifestations consistent with Antley-Bixler syndrome. PMID:9605588
• Journal of medical genetics • 2000 • Evidence for digenic inheritance in some cases of Antley-Bixler syndrome? PMID:10633130
• 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
• Developmental dynamics • 2002 • Induction of chondrogenesis in neural crest cells by mutant fibroblast growth factor receptors. PMID:12112473

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