FGFR1 – Pfeiffer Syndrome

Pfeiffer syndrome is an autosomal dominant craniosynostosis syndrome characterized by premature fusion of cranial sutures, brachycephaly, midface retrusion, broad and medially deviated thumbs and great toes, and variable limb anomalies (HP:0001363, HP:0000248, HP:0011800). While FGFR2 mutations account for the majority of cases, gain-of-function variants in FGFR1 (HGNC:3688) have been implicated in type I Pfeiffer syndrome (MONDO:0007043).

Genetic evidence for FGFR1 involvement includes the recurrent c.755C>G (p.Pro252Arg) substitution identified in multiple unrelated kindreds. A three-generation family with five affected members demonstrated cosegregation of heterozygous c.755C>G (p.Pro252Arg) and variable expressivity across generations, from mild digital anomalies to classic brachycephaly and syndactyly (PMID:25251565). Four additional familial cases have been reported with the identical Pro252Arg change, emphasizing recurrence in FGFR1 (PMID:14564217). Earlier linkage studies mapped a subset of Pfeiffer syndrome families to FGFR1 at 8p11–p12, confirming genetic heterogeneity with FGFR2 (PMID:7795583).

Inheritance is autosomal dominant, with at least four additional affected relatives demonstrating segregation of the FGFR1 p.Pro252Arg allele in one large pedigree. No loss-of-function variants have been reported, and the variant spectrum in FGFR1 is narrow, with c.755C>G (p.Pro252Arg) accounting for nearly all FGFR1-related cases.

Functional assays support a gain-of-function mechanism. Murine knock-in of the orthologous Pro250Arg mutation leads to premature suture fusion, increased osteoblast proliferation, and upregulation of Cbfa1 in calvarial sutures, recapitulating human craniosynostosis (PMID:10942429). Structural and binding studies reveal that Pro252Arg enhances ligand affinity and hydrogen bonding with FGF2 and FGF9, further increasing downstream FGFR1 signaling (PMID:14613973).

No conflicting reports or benign population variants at this allele have been described, and animal models and biochemical data consistently demonstrate pathogenicity. The combined genetic segregation, recurrent variant identification across unrelated families, and concordant functional data meet criteria for a Definitive gene-disease association.

Key take-home: The FGFR1 c.755C>G (p.Pro252Arg) mutation is a fully penetrant, gain-of-function variant causing autosomal dominant Pfeiffer syndrome with variable expressivity, supporting its use in molecular diagnosis and genetic counseling.

References

• American journal of medical genetics. Part A • 2014 • Variable expressivity of pfeiffer syndrome in a family with FGFR1 p.Pro252Arg mutation. PMID:25251565
• Clinical dysmorphology • 2003 • The appearance of the feet in Pfeiffer syndrome caused by FGFR1 P252R mutation. PMID:14564217
• Human molecular genetics • 1995 • Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. PMID:7795583
• Human molecular genetics • 2000 • A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. PMID:10942429
• Human molecular genetics • 2004 • Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity. PMID:14613973

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