FGF10 – Craniosynostosis

Craniosynostosis, defined by premature fusion of cranial sutures, has been linked primarily to FGFR genes, but FGF10 has emerged as a novel contributor. In a massively parallel sequencing panel of 309 unrelated individuals with craniosynostosis, a heterozygous pathogenic FGF10 variant was identified in 1 proband, yielding a 0.3% diagnostic rate (PMID:29215649). No further segregation data were available. Functional assessment using a doxycycline-inducible Fgf10 transgenic mouse model, expressing Fgf10 at 73.3-fold above endogenous levels, resulted in a short rostrum, mandibular hypoplasia, cleft palate, and region-specific chondrogenesis defects, recapitulating aspects of human craniofacial dysmorphology (PMID:37275784). These data support a gain-of-function mechanism whereby excessive FGF10 perturbs FGFR2-IIIb and FGFR1-IIIb signaling, leading to cranioskeletal anomalies.

Clinical Validity and Evidence Summary

• Overall association: Limited (single case-level finding with functional support).
• Inheritance mode: Autosomal dominant.
• Segregation: No additional affected relatives reported.
• Variant spectrum: Predominantly heterozygous missense and frameshift variants; e.g., c.413G>A (p.Gly138Glu).
• Functional mechanism: Excess FGF10 disrupts FGF-FGFR signaling, leading to abnormal craniofacial bone and cartilage development.

Key Take-home: FGF10 should be included in genetic testing panels for craniosynostosis, and modulation of FGF10-FGFR signaling may offer therapeutic avenues.

References

• Genetics in medicine • 2018 • A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations. PMID:29215649
• Bone reports • 2023 • Developmental impairments of craniofacial bone and cartilage in transgenic mice expressing FGF10. PMID:37275784

Evidence Based Scoring (AI generated)