Nonstop mutation in the Kisspeptin 1 receptor (KISS1R) gene causes normosmic congenital hypogonadotropic hypogonadism

Purpose Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder mostly characterized by gonadotropins release and/or action deficiencies. Both isolated (idiopathic hypogonadotropic hypogonadism) and syndromic (Kallmann) forms are identified depending on the olfactory ability. Clinical and genetic heterogeneities of CHH have been widely explored, thus improving our understanding of the disease’s pathophysiology. This work aims to (1) provide a detailed clinical and hormonal description of normosmic CHH patients and (2) identify the mutation linked to the studied phenotype. Participants and methods We investigated three affected patients with normosmic CHH, belonging to a consanguineous Tunisian family. Patients underwent an insulin-induced hypoglycemia test. We performed whole exome sequencing to identify the causal mutation. Results At first diagnosis, a total gonadotropic deficiency was identified in all patients. The insulin-induced hypoglycemia test has also revealed a reduced cortisol secretion and complete growth hormone deficiency. At 20.8 years, one female exhibited a spontaneous recovery of the hypothalamic–pituitary–adrenal axis function, unlike her affected siblings who still depend on corticosteroid replacement therapy. Herein, we identified a novel homozygous nonstop mutation (c.1195T>C) in KISS1R gene in all affected subjects. This mutation led to the substitution of the physiologic stop codon by an arginine (p.X399R). Conclusions Our study highlights the importance of the KISS1R signaling, in gonadotropin-releasing hormone neurons, in the control of reproductive function. Additionally, our data suggests a complex central and peripheral metabolic control of puberty, through the hypothalamic KISS1R signaling. We suggest a mutual link between the hypothalamic–pituitary–gonadal, –adrenal, and –somatotropic axes.