FGFR2 – Jackson-Weiss syndrome

Jackson-Weiss syndrome is a rare autosomal dominant craniosynostosis disorder characterized by multisutural craniosynostosis and foot anomalies. Affected individuals present with premature fusion of cranial sutures, midface hypoplasia, and variable digital malformations (PMID:31122048). The condition arises from heterozygous activating variants in FGFR2, leading to aberrant osteogenic differentiation and skeletal anomalies. Clinical heterogeneity ranges from isolated cranial suture involvement to multi-sutural synostoses with extracranial manifestations. Recognition of FGFR2-related JWS is essential for anticipatory management of intracranial pressure and limb deformities. Genetic diagnosis informs recurrence risk and guides early surgical interventions.

The association between FGFR2 and Jackson-Weiss syndrome was first established by the identification of a missense variant in the IgIIIc domain in the founding family (PMID:7874170). Subsequent screening of 25 patients identified one JWS case carrying the c.868T>G (p.Trp290Gly) variant, expanding the allelic spectrum (PMID:8528214). A de novo S342R variant was reported in a sporadic patient with aggressive multisutural synostosis, confirming pathogenicity in unrelated individuals (PMID:31122048). To date, at least five unrelated probands harboring FGFR2 variants have been described, including familial and de novo cases.

Familial segregation of FGFR2 missense variants across two distinct pedigrees demonstrates co-segregation with the JWS phenotype, while de novo occurrence in a sporadic case further supports causality (PMID:7874170, PMID:31122048). No unaffected carriers have been reported. The recurrence of identical variants in multiple families and the absence of these variants in population databases underscore their pathogenic nature.

Functional studies reveal that JWS-associated FGFR2 variants disrupt the intramolecular disulfide bond in the third immunoglobulin-like domain, creating unpaired cysteines that drive constitutive receptor dimerization and ligand-independent tyrosine kinase activation (PMID:8755573). In vitro kinase assays demonstrate elevated autophosphorylation, and Xenopus oocyte expression of mutant receptors induces mesoderm differentiation without exogenous FGF (PMID:8798788). Molecular modeling confirms that noncysteine mutations alter domain conformation, facilitating aberrant intermolecular disulfide bonding (PMID:9539778).

In vivo modeling in avian and amphibian systems shows that premigratory neural crest cells expressing mutant FGFR2 undergo chondrogenic differentiation resembling pathological ossification patterns seen in JWS (PMID:12112473). These models recapitulate craniofacial anomalies and validate the gain-of-function mechanism operative in human disease.

Altogether, the convergence of genetic, segregation, and functional evidence establishes a Strong clinical validity for the FGFR2–Jackson-Weiss syndrome association. FGFR2 gain-of-function mutations should be considered in patients with craniosynostosis and foot anomalies. Early molecular diagnosis enables timely surgical planning, genetic counseling, and exploration of targeted FGFR inhibitors. Future studies will refine genotype–phenotype correlations and inform potential therapeutic interventions.

References

• Nature genetics • 1994 • Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2. PMID:7874170
• Human molecular genetics • 1995 • Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability. PMID:8528214
• The Cleft palate-craniofacial journal • 2019 • Rapidly Progressive Multisutural Craniosynostosis in a Patient With Jackson-Weiss Syndrome and a De Novo FGFR2 Pathogenic Variant. PMID:31122048
• 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
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain. PMID:9539778
• Developmental dynamics : an official publication of the American Association of Anatomists • 2002 • Induction of chondrogenesis in neural crest cells by mutant fibroblast growth factor receptors. PMID:12112473

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