FGFR3 – Hypochondroplasia

Hypochondroplasia (HCH) is an autosomal dominant skeletal dysplasia characterized by disproportionate short stature, lumbar lordosis, and macrocephaly. Germline gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene underlie HCH, with the majority of cases harboring the recurrent c.1620C>A (p.Asn540Lys) variant in the proximal tyrosine kinase domain. This association has been validated across multiple unrelated cohorts with robust segregation and functional evidence.

Genetic evidence for FGFR3 in HCH includes >242 molecularly confirmed probands, of whom >95% carry the N540K substitution (c.1620C>A) ([PMID:7670477]). Segregation analyses in at least four multigenerational families demonstrate co-segregation of heterozygous FGFR3 variants with HCH phenotypes, with 16 affected relatives identified ([PMID:7670477]). Additional cohort studies reinforce genetic heterogeneity, with N540K detected in 21 of 29 index cases and other missense mutations (e.g., c.1619A>C (p.Asn540Thr)) accounting for sporadic or familial presentations ([PMID:8880574],[PMID:8589686]).

The variant spectrum in HCH is dominated by missense substitutions in FGFR3: c.1620C>A (p.Asn540Lys) and c.1620C>G (p.Asn540Lys) in TK1; rarer alterations include c.1612A>G (p.Ile538Val) and extracellular domain changes such as c.805A>T (p.Ser269Cys). Deep-intronic or structural variants have not been implicated. Recurrent founder effects are not reported.

Functional studies demonstrate that N540K and related mutations confer constitutive FGFR3 activation. Graded activation assays show that HCH-associated substitutions (Asn540Lys/Thr) induce moderate receptor autophosphorylation compared to stronger activation by TD and ACH mutations ([PMID:8640234]). Knock-in mouse models expressing the Lys644Glu (murine equivalent of Asn540Lys) recapitulate growth plate abnormalities, activate STAT1/5 pathways, and up-regulate cell cycle inhibitors (p16, p18, p19), directly linking FGFR3 activation to impaired chondrocyte proliferation ([PMID:9887329]).

Clinically, HCH presents with mild rhizomelic shortening, lumbar hyperlordosis, macrocephaly, and variable neurological involvement including temporal lobe dysgenesis and epilepsy in Asn540Lys carriers. Radiographic hallmarks include decreased interpedicular distances and metaphyseal flaring. Growth hormone therapy yields modest height gains but does not normalize disproportion ([PMID:36442838]).

Overall, FGFR3 meets criteria for a definitive gene–disease relationship with HCH. The autosomal dominant inheritance, recurrent hotspot mutations in >200 probands, consistent segregation in families, and concordant in vitro/in vivo functional evidence support clinical genetic testing for FGFR3 variants in suspected HCH cases. Key Take-home: Testing for FGFR3 exon 11 hotspot mutations, particularly c.1620C>A (p.Asn540Lys), is essential for accurate diagnosis, genetic counseling, and management of hypochondroplasia.

References

• Nature Genetics • 1995 • A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia PMID:7670477
• Journal of Medical Genetics • 1996 • Clinical and genetic heterogeneity of hypochondroplasia PMID:8880574
• Human Molecular Genetics • 1995 • A common FGFR3 gene mutation in hypochondroplasia PMID:8589686
• Nature Genetics • 1996 • Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia PMID:8640234
• Human Molecular Genetics • 1999 • A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors PMID:9887329

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