Rare FGFR1 c.1977+1G>A splice-site variant in hypogonadotropic hypogonadism-2 with anosmia

Abstract

Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a rare disorder caused by deficient gonadotropin-releasing hormone secretion or action and may present with anosmia when the olfactory system is affected. FGFR1 is one of the most frequently implicated genes and is associated with considerable phenotypic variability. Here, we report a 14-year-old female with anosmia, delayed pubertal development, low luteinizing hormone and follicle-stimulating hormone levels, myopia, scoliosis, pectus deformity, disproportionately long limbs and fingers, and absent ovaries. Family history revealed delayed puberty in her father and elder brother, suggesting variable intrafamilial expression. Genomic DNA isolated from peripheral blood was analyzed by whole-exome sequencing, and a heterozygous FGFR1 splice-site variant, NM_023110.3:c.1977+1G>A, was identified. This variant affects a canonical donor splice site and supports the molecular diagnosis of FGFR1-associated hypogonadotropic hypogonadism-2 with anosmia. The case expands the recognized clinical spectrum of FGFR1-related disease and underlines the value of genetic testing for diagnosis, counselling, and follow-up in patients with suspected congenital hypogonadotropic hypogonadism.