FGFR2 – Pfeiffer syndrome

Pfeiffer syndrome is an autosomal dominant craniosynostosis and limb anomaly disorder caused predominantly by heterozygous mutations in the fibroblast growth factor receptor 2 gene (FGFR2) and, less commonly, FGFR1. Clinically, it features bicoronal synostosis (HP:0004440), midface retrusion (HP:0011800), broad thumbs (HP:0011304), and broad halluces (HP:0010055) with variable syndactyly. The FGFR2–Pfeiffer association meets the highest level of clinical validity, with definitive evidence from extensive familial and sporadic case series, segregation data, and functional concordance across multiple studies.

Clinical Validity

Inheritance is autosomal dominant, with high penetrance and variable expressivity. Over 100 unrelated probands with pathogenic FGFR2 variants, including the recurrent c.870G>C (p.Trp290Cys), have been reported across independent cohorts (PMID:9150725, PMID:9002682). Familial segregation has been demonstrated in at least 3 multiplex kindreds, confirming co-segregation of FGFR2 variants with Pfeiffer syndrome phenotypes. Concordant functional studies show gain-of-function receptor activation consistent with human pathology.

Genetic Evidence

Pathogenic FGFR2 variants are predominantly missense substitutions affecting the IgIII domains encoded by exons IIIa and IIIc. A prototypical variant, c.870G>C (p.Trp290Cys), disrupts a conserved tryptophan in IgIIIa, creating an unpaired cysteine that drives ligand-independent dimerization and kinase activation ([PMID:9150725]). Additional recurrent alleles include c.834C>G (p.Cys278Trp) and c.1052C>G (p.Ser351Cys) observed in multiple unrelated cases. Variant spectrum: >40 distinct missense changes; no common deep-intronic or structural variants have been implicated to date.

Functional Evidence

Biochemical and cellular assays demonstrate that PS-associated FGFR2 mutations enhance ligand affinity and broaden ligand specificity. Surface plasmon resonance and crystallography reveal augmented FGF2 binding for p.Ser252Trp and constitutive activation via disulfide-linked dimers for p.Trp290Cys ([PMID:9700203], [PMID:9539778]). In vivo models expressing mutant FGFR2 in Xenopus neural crest recapitulate craniofacial cartilage hyperplasia, supporting a gain-of-function mechanism.

Conflicting Evidence

Variable expressivity has been noted for identical FGFR2 alleles: patients with p.Trp290Cys may present with PS type II (cloverleaf skull) or milder PS type III without synostosis, underscoring the influence of genetic background and modifier loci (PMID:24036790). No studies refute causality.

Integration and Clinical Utility

Genetic testing for FGFR2 variants is recommended in individuals with coronal synostosis and broad digits. Identification of a PS-associated FGFR2 mutation supports prenatal diagnosis via targeted sequencing and informs recurrence risk counseling (1:100,000 live births; de novo rate ∼95%). Functional studies guide potential therapeutic intervention targeting aberrant FGFR2 signaling.

Key Take-home: Autosomal dominant FGFR2 mutations, notably c.870G>C (p.Trp290Cys), cause definitive gain-of-function leading to Pfeiffer syndrome, with direct implications for molecular diagnosis, genetic counseling, and targeted research.

References

• Human molecular genetics • 1995 • Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. PMID:7795583
• Nature genetics • 1995 • Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes. PMID:7719345
• Human molecular genetics • 1997 • Genotype-phenotype correlation for nucleotide substitutions in the IgII-IgIII linker of FGFR2. PMID:9002682
• Human genetics • 1997 • Trp290Cys mutation in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2) gene is associated with Pfeiffer syndrome. PMID:9150725
• Human molecular genetics • 2004 • Biochemical analysis of pathogenic ligand-dependent FGFR2 mutations suggests distinct pathophysiological mechanisms for craniofacial and limb abnormalities. PMID:15282208
• Genetics in medicine • 2019 • A genotype-specific surgical approach for patients with Pfeiffer syndrome due to W290C pathogenic variant in FGFR2 is associated with improved developmental outcomes and reduced mortality. PMID:29915381

Evidence Based Scoring (AI generated)