Hypogonadotropic Hypogonadism due to Novel FGFR1 Mutations

Abstract

Objective: The underlying genetic etiology of hypogonadotropic hypogonadism (HH) is heterogeneous. Fibroblast growth factor signaling is pivotal in the ontogeny of gonadotropin-releasing hormone neurons. Loss-of-function mutations in FGFR1 gene cause variable HH phenotypes encompassing pubertal delay to idiopathic HH (IHH) or Kallmann syndrome (KS). As FGFR1 mutations are common, recognizing mutations and associated phenotypes may enhance clinical management.

Methods: Using a candidate gene approach, we screened 52 IHH/KS patients.

Results: We identified three novel (IVS3-1G>C and p.W2X, p.R209C) FGFR1 gene mutations. Despite predictive null protein function, patients from the novel mutation families had normosmic IHH without non-reproductive phenotype.

Conclusion: These findings further emphasize the great variability of FGFR1 mutation phenotypes in IHH/KS.

Keywords: FGFR1 mutations; Hypogonadotropic hypogonadism; Kallmann syndrome reduced penetrance..

Figure 1. Segregation of the FGFR1 mutations in families with affected individuals. (A) Pedigrees and descriptions in each family are shown. Filled symbols show patients with normosmic idiopathic hypogonadotropic hypogonadism/Kallmann syndrome; open symbols show clinically unaffected individuals. Squares indicate male family members, circles indicate female family members, the double line indicates consanguinity, and arrows point to probands. Genotypes are shown below each tested family members. (B) DNA sequence analysis of patients. The positions of the mutations are marked. The top lines show the homozygous wild-type genotype, and the bottom lines show heterozygous genotype