Background: Congenital hypogonadotropic hypogonadism (CHH) is characterized by absent puberty and infertility due to a lack of GnRH secretion/action. In addition, patients exhibit variable non-reproductive phenotypes such as anosmia, cleft palate, synkinesia, and others. As many as 10% of CHH patients harbor mutations in FGFR1; this group is enriched for skeletal anomalies. We report here a novel CHH-associated skeletal phenotype, split hand/foot malformation (SHFM), defined as absent development of the central ray.
Methods: CHH patients exhibiting SHFM were identified from four international CHH cohorts. Probands and available family members underwent extensive phenotyping and were screened for mutations in FGFR1. The functional impact of identified mutations was assessed by homology modelling, crystallography-based structural predictions, and/or in vitro assays.
Results: We identified eight CHH probands exhibiting SHFM. Seven of these probands (88%) harbored FGFR1 mutations, including one homozygous (p.V429E) and six heterozygous mutations (p.G348R, p.G485R, p.Q594X, p.E670A, p.V688L, p.L712P). They all exhibited severe GnRH deficiency with absent puberty; cryptorchidism and/or micropenis were present in 5/7. Incomplete penetrance and variable expressivity of phenotypes (olfactory/reproductive/SHFM) were observed among mutation carriers in each family. All mutations were predicted to be loss-of-function by homology and structural modelling. The V429E mutation maps to the FRS2 binding domain of FGFR1; functional studies demonstrated that it decreases recruitment and association of FRS2Θ to FGFR1, thereby resulting in reduced MAPK signalling.
Conclusion: SHFM is a novel CHH-associated phenotype. Mice with limb mesenchyme-specific knock-out of Fgfr1 exhibit absent central ray development, thus phenocopying SHFM. FGFR1 should be prioritized for sequencing in CHH patients with SHFM, because the likelihood of finding a mutation increases from 10% (general CHH population) to 88% (CHH+SHFM).