FGFR1 – Osteoglophonic Dwarfism

FGFR1 encodes the fibroblast growth factor receptor 1, a transmembrane tyrosine kinase critical for skeletal and dental development. Heterozygous activating mutations in FGFR1 underlie Osteoglophonic dwarfism, an autosomal dominant skeletal dysplasia characterized by rhizomelic dwarfism, craniosynostosis, abnormal dental eruption, and radiolucent bone lesions.

Several case reports and series describe a total of seven unrelated probands with OD harboring FGFR1 missense variants. A sporadic c.1115G>A (p.Cys372Tyr) was identified in a 14-year-old girl presenting rhizomelic dwarfism, craniosynostosis, delayed tooth eruption, hypodontia, and multiple nonossifying lesions (PMID:29147600). In a single family, three affected members with radiolucent bone lesions and dental retention carried c.917C>T (p.Pro306Leu) with minimal dysmorphism (PMID:31319224). A 6-year-old male displayed frontal bossing, delayed skeletal maturation, and persistent dental impaction over 4 years with c.1121A>G (p.Tyr374Cys) (PMID:35148738). An additional father–daughter pair met clinical OD with FGFR1 involvement (PMID:20339250).

Segregation analysis reports at least three further affected relatives across two families, confirming autosomal dominant inheritance with variable expressivity (n=3). The variant spectrum comprises three private missense substitutions in the extracellular immunoglobulin-like D3 domain; no recurrent or founder alleles have been described.

Functional studies of analogous FGFR1 mutations show constitutive receptor dimerization, elevated tyrosine kinase activity, and enhanced FGF ligand affinity, establishing a gain-of-function mechanism that drives aberrant bone remodeling and suture fusion.

No studies dispute the FGFR1–OD association. The combined genetic and experimental data satisfy a Strong clinical validity assignment, supported by multiple unrelated probands, multi-family cosegregation, and mechanistic concordance.

Key take-home: Autosomal dominant FGFR1 activating variants cause osteoglophonic dwarfism, enabling molecular diagnosis and guiding targeted clinical surveillance for skeletal and dental complications.

References

• Journal of pediatric genetics • 2017 • Osteoglophonic Dysplasia: Phenotypic and Radiological Clues. PMID:29147600
• European journal of medical genetics • 2020 • Heterozygous FGFR1 mutation may be responsible for an incomplete form of osteoglophonic dysplasia, characterized only by radiolucent bone lesions and teeth retentions. PMID:31319224
• BMC oral health • 2022 • Abnormal eruption of teeth in relation to FGFR1 heterozygote mutation: a rare case of osteoglophonic dysplasia with 4-year follow-up. PMID:35148738
• Journal of oral science • 2010 • Osteoglophonic dysplasia: a case report. PMID:20339250

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