Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations

Abstract

PurposeCongenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising CHH and SHFM.MethodsWe identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions, and/or functional assays.ResultsWe identified 8 probands with CHH with (n=3, Kallmann Syndrome) or without anosmia (n=5) and SHFM, 7 of whom (88%) harbor FGFR1 mutations: one individual is homozygous for p.V429E; six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, and p.L712P. All mutations were predicted to be loss-of-function by in silico analysis. Probands with FGFR1 mutations have severe GnRH deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was only observed in the patient with the homozygous p.V429E mutation; V429 maps to the FRS2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of FRS2α to FG FR 1 , thereby resulting in reduced MAPK signaling.ConclusionFGFR1 should be prioritized for genetic testing in patients with CHH and SHFM, because the likelihood of a mutation increases from 10% in the general CHH population to 88%.

Genetic testing facilitates prepubertal diagnosis of congenital hypogonadotropic hypogonadism

“…Genetic testing is of particular utility in cases of neonatal suspicion in order to strengthen the diagnostic of CHH as well as to provide genetic counseling to the family. Previous reports described genetic testing in familial cases using Sanger sequencing . Here, we report genetic diagnosis of sporadic CHH in a prepubertal child using exome sequencing.…”

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway

“…). The clinical manifestations of FGFR1 alterations are very heterogeneous since loss‐of‐function mutations in FGFR1 have been linked to Kallman syndrome [Dode et al., ; Albuisson et al., ; Villanueva and de Roux, ], hypogonadotropic hypogonadism with or without anosmia [Costa‐Barbosa et al., ; Vizeneux et al., ; Villanueva et al., ], and Hartsfield syndrome [Simonis et al., ; Hong et al., ]. Gain‐of‐function mutations in FGFR1 have also been identified in about 5% of Pfeiffer syndrome with or without craniosynostosis [Chokdeemboon et al., ].…”

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

“…58,156 Indeed, combining CHH with specific associated phenotypes can increase the probability of finding causal mutations by targeted gene sequencing ( Figure 4). 21,28,104,157 CHH accompanied by other syndromic features such as congenital ichthyosis 158 or spherocytosis 159 is suggestive of a contiguous gene syndrome for which a karyotype or comparative genomic hybridization array analysis might be useful for identifying underlying chromosomal abnormalities. [159][160][161] Genetic counselling A legitimate question often raised by patients with CHH relates to the risk of passing on the disease to their offspring.…”