FGFR3 – Muenke syndrome

Muenke syndrome (MS) is an autosomal-dominant craniosynostosis disorder defined by a single recurrent FGFR3 variant. The birth prevalence is ~1 in 10,000 live births, accounting for 8–10% of coronal synostosis cases. Core features include uni- or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, downslanted palpebral fissures, and variable hearing loss and developmental delay ([PMID:20592905]).

Genetic studies have identified a heterozygous c.749C>G (p.Pro250Arg) missense change in FGFR3 as the defining lesion. In an international natural history study of 106 patients from 71 families, 33 cases (64.7%) showed familial inheritance and 51 were de novo, with complete co-segregation in tested relatives ([PMID:26740388]). Segregation in multi-generation kindreds and recurrence in diverse populations confirm autosomal-dominant transmission with variable expressivity.

The variant spectrum for MS is narrowly focused: nearly all affected individuals harbor c.749C>G (p.Pro250Arg). No other recurrent FGFR3 variants have been linked to MS. Functional assays of this mutation demonstrate ligand-independent activation of FGFR3, increased mitogenic signaling through MAPK and STAT pathways, and altered chondrocyte proliferation, consistent with premature suture fusion ([PMID:15241680]).

Mechanistically, Pro250Arg lies in the IgII–IgIII linker, enhancing FGFR3 dimerization and downstream kinase activity. Cellular and mouse models overexpressing activated FGFR3 recapitulate craniosynostosis and bone growth phenotypes. Rescue experiments remain limited but support a gain-of-function pathogenic model.

Despite high penetrance for suture synostosis, expressivity is broad: some carriers present only with hydrocephalus or palatal clefting without craniosynostosis ([PMID:27568649]), and identical twins can exhibit discordant severity ([PMID:19449410]). This variable penetrance has led to occasional delayed or missed diagnoses.

Integration of genetic and functional data establishes a definitive FGFR3–Muenke syndrome association. Molecular testing for c.749C>G (p.Pro250Arg) is essential for diagnosis in any coronal synostosis, family screening, and genetic counseling. Key Take-home: FGFR3 c.749C>G (p.Pro250Arg) testing should be performed in all suspected MS cases due to its diagnostic and prognostic utility.

References

• American journal of medical genetics. Part A • 2016 • Muenke syndrome: An international multicenter natural history study. PMID:26740388
• Human genetics • 2004 • Paternal origin of FGFR3 mutations in Muenke-type craniosynostosis. PMID:15241680
• American journal of medical genetics. Part A • 2009 • Significant phenotypic variability of Muenke syndrome in identical twins. PMID:19449410
• Journal of Korean medical science • 2010 • A Korean family with the Muenke syndrome. PMID:20592905

Evidence Based Scoring (AI generated)