Genotypic and phenotypic spectra of FGFR1, FGF8, and FGF17 mutations in a Chinese cohort with idiopathic hypogonadotropic hypogonadism.

Objective: To analyze the prevalence of FGFR1, FGF8, and FGF17 mutations in a Chinese cohort with idiopathic hypogonadotropic hypogonadism (IHH) and to characterize the clinical presentations and therapeutic outcomes of IHH patients with FGFR1, FGF8, and FGF17 mutations.

Design: Retrospective cohort.

Setting: University hospital.

Patient(s): A total of 145 IHH probands (125 men and 20 women) were recruited for this study.

Interventions(s): Hormone assays.

Main Outcome Measure(s): Whole-exome sequencing, polymerase chain reaction-Sanger sequencing, in silico functional prediction.

Result(s): Six novel mutations (p.154_158del, p.E496Rfs*12, p.W190X, p.S134D, p.W10X, and c.1552 + 3insT) in FGFR1, two novel mutations (p.E176K and p.R184C) in FGF8, three novel mutations (p.48_52del, p.P120L, and p.K191R) in FGF17, and five reported mutations (p.W289X, p.G237S, p.V102I, p.R250Q, and p.T340M) in FGFR1 were identified in 18 IHH patients. The functional consequences of all mutations were analyzed in silico. In addition to hypogonadotropic hypogonadism, 44.4% (8/18) patients exhibited other clinical deformities, including dental agenesis (3/18, 16.7%), hearing loss (3/18, 16.7%), and hand malformation (2/18, 11.1%). hCG/hMG therapy was effective in promoting sexual development in IHH patients with FGFR1, FGF8, and FGF17 mutations.

Conclusion(s): We extended the mutational spectrum of FGFR1, FGF8, and FGF17 in IHH patients. The prevalence of FGFR1, FGF8, and FGF17 mutations in IHH was 12.4%. hCG/hMG therapy was effective to acquire fertility for patients with FGFR1, FGF8, and FGF17 mutations but has a risk of transmitting the mutations and IHH to the next generation.