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..