FGFR2 – Apert syndrome

Apert syndrome is a classic autosomal dominant craniosynostosis syndrome characterized by coronal suture fusion, midfacial hypoplasia, severe syndactyly of hands and feet, turricephaly, brachycephaly, hypertelorism, proptosis, and other variable anomalies. The disorder results from germline gain-of-function mutations in the fibroblast growth factor receptor 2 gene (FGFR2), leading to aberrant FGF signaling in cranial and limb development.

1 Clinical Validity

The FGFR2–Apert syndrome association is classified as Definitive based on identification of the same two missense mutations, Ser252Trp and Pro253Arg, in over 160 unrelated individuals across multiple ethnicities with consistent de novo occurrence and paternal-origin bias, coupled with extensive functional concordance (PMID:9002682; PMID:8673103).

2 Genetic Evidence

Inheritance is autosomal dominant with most cases arising de novo in the paternal germline. Multi-center surveys report 36 unrelated patients harboring either c.755C>G (p.Ser252Trp) in 71% or c.758C>G (p.Pro253Arg) in 26% of cases (PMID:7668257; PMID:9002682). Segregation is documented in familial transmission (mother and son) for c.758C>G (p.Pro253Arg) (PMID:9664610). Rare structural variants including a 1.93 kb IIIb/IIIc exon deletion and Alu insertions further expand the spectrum of pathogenic FGFR2 rearrangements (PMID:21943124).

3 Functional Evidence

Biochemical and structural assays demonstrate that both Ser252Trp and Pro253Arg substitutions increase FGFR2 ligand affinity and broaden ligand specificity, permitting ectopic activation by multiple FGFs at physiological concentrations (PMID:11121055). Crystal structures reveal additional contacts at the FGF2-FGFR2 interface unique to each mutation (PMID:11390973). In vivo models confirm ligand-independent receptor activation drives aberrant osteogenic and chondrogenic differentiation consistent with the human phenotype (PMID:12112473).

4 Genotype–Phenotype Correlation

Comparative studies show Pro253Arg is associated with more severe syndactyly, whereas Ser252Trp carriers have a higher incidence of cleft palate and greater risk of obstructive sleep apnea and midface hypoplasia (PMID:8651276; PMID:37582295). These subtle differences inform surgical planning and prognosis.

5 Conclusion and Clinical Utility

The causative FGFR2 mutations in Apert syndrome have been exhaustively validated genetically and functionally, supporting reliable molecular diagnosis via targeted sequencing or prenatal testing. Early identification enables multidisciplinary management—including neurosurgical, craniofacial, and genetic counseling interventions—with clear genotype-driven prognostic guidance.

Key Take-home: FGFR2 gain-of-function mutations Ser252Trp and Pro253Arg are definitively causative of Apert syndrome, enabling precise molecular diagnosis and personalized clinical management.

References

• Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. 1997 • PMID:9002682
• Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome. 1996 • PMID:8651276
• Structural basis for fibroblast growth factor receptor 2 activation in Apert syndrome. 2001 • PMID:11390973
• Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome. 2000 • PMID:11121055
• Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. 1995 • PMID:7668257
• Exclusive paternal origin of new mutations in Apert syndrome. 1996 • PMID:8673103

Evidence Based Scoring (AI generated)