FGFR2 – Pfeiffer Syndrome Type 1

Pfeiffer syndrome type 1 is an autosomal dominant craniosynostosis disorder characterized by premature fusion of cranial sutures, broad thumbs, and variable syndactyly of hands and feet. Pathogenic variants in the fibroblast growth factor receptor 2 gene (FGFR2) disrupt receptor regulation in cranial osteogenesis, leading to the Pfeiffer phenotype and necessitating multidisciplinary management.

Genetic Evidence

FGFR2-related Pfeiffer syndrome exhibits autosomal dominant inheritance with both de novo and familial cases. A cohort of 78 unrelated probands was screened for FGFR2 mutations, identifying 40 individuals harboring heterozygous variants in exons IIIa/IIIc (PMID:10394936). Variants include missense substitutions such as c.758C>G (p.Ser253Trp) (PMID:40620881) and c.870G>C (p.Trp290Cys), which alter the IgIII domain and promote unpaired cysteine–mediated receptor dimerization.

Segregation and Variant Spectrum

Most pathogenic FGFR2 alleles in Pfeiffer syndrome arise de novo, though familial segregation has been documented in multiple kindreds. Reported variant classes are predominately missense substitutions within the IgIII linker or domain, with recurrent hotspot residues at Ser252, Pro253, and Trp290.

Functional Evidence

Functional assays demonstrate ligand-independent FGFR2 activation. Point mutations corresponding to Pfeiffer syndrome variants induce constitutive tyrosine kinase activity and receptor dimerization in Xenopus oocytes, driving mesoderm induction without ligand (PMID:8798788). Structural modeling predicts that unpaired cysteines in the IgIII domain facilitate aberrant intermolecular disulfide bonding, consistent with constitutive receptor signaling.

Mechanism and Clinical Implications

Gain-of-function FGFR2 mutations promote ectopic receptor activation in cranial sutures, leading to premature osteogenic differentiation and skull dysmorphology. Molecular confirmation of FGFR2 mutations guides genetic counseling, surgical planning, and anticipatory monitoring for airway and auditory complications.

Key Take-home: FGFR2 mutation analysis is critical for definitive diagnosis and tailored management of Pfeiffer syndrome type 1.

References

• Clinical medicine insights. Case reports • 2025 • Pfeiffer Syndrome (Acrocephalosyndactyly) With Significant Syndactyly and Brachydactyly: A Case Report. PMID:40620881
• Human genetics • 1999 • Analysis of the mutational spectrum of the FGFR2 gene in Pfeiffer syndrome. PMID:10394936
• The Journal of biological chemistry • 1996 • Ligand-independent activation of fibroblast growth factor receptors by point mutations in the extracellular, transmembrane, and kinase domains. PMID:8798788

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