Novel Fibroblast Growth Factor Receptor 1 Mutations in Patients with Congenital Hypogonadotropic Hypogonadism with and without Anosmia

CONTEXT: Kallmann syndrome is a clinically and genetically heterogeneous disorder. To date, loss-of-function mutations in the genes encoding anosmin-1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1) have been described in the X-linked and autosomal dominant forms of this syndrome, respectively. OBJECTIVE: The objective was to investigate genetic defects in the KAL1 and FGFR1 genes in patients with congenital isolated hypogonadotropic hypogonadism (IHH). PATIENTS: Eighty patients (71 males and nine females) with IHH were studied, of which 30 were familial. Forty-six of them had olfactory abnormalities. METHODS: The coding regions of both KAL1 and FGFR1 genes were amplified and automatically sequenced. The KAL1 mutations were investigated only in patients with olfactory abnormalities, whereas FGFR1 was studied in the entire group. RESULTS: Two novel KAL1 mutations, an intragenic deletion of exons 3-6 and a splicing mutation IVS7 + 1G>A, were identified in two of 46 patients with Kallmann syndrome. Eight novel heterozygous FGFR1 mutations (G48S, L245P, R250W, A343V, P366L, K618fsX654, P722S, and V795I) were identified in nine of 80 patients with IHH. Eight of them had olfactory abnormalities. Interestingly, the G48S mutation was identified in a normosmic IHH patient. Two unrelated females, who carried FGFR1 mutations, had anosmia and normal reproductive function. CONCLUSION: We identified novel mutations in KAL1 and FGFR1 genes in IHH patients. FGFR1 mutations were identified in 17% of the patients with olfactory abnormalities and in one of 34 normosmic IHH patients. In addition, isolated anosmia was identified in two unrelated females as a partial phenotypic manifestation of FGFR1 defects.