Novel KISS1 Gene Mutation Leading to Male Hypogonadotropic Hypogonadism

Abstract The human KISS1 gene encodes the hypothalamic Kisspeptin, which is released in a pulsatile manner and binds the KISS1 receptor, that is located on gonadotropin releasing hormone neurons. This interaction ensures pulsatile gonadotropin releasing hormone secretion leading to induction of the hypothalamic-pituitary-gonadal axis and by this controls puberty onset. Disruption of this process is associated with hypogonadotropic hypogonadism. We identified a novel heterozygous KISS1 variant c.-7C>T in two brothers diagnosed with hypogonadotropic hypogonadism. The mutation affects the Kozak consensus sequence of the KISS1 gene and potentially interferes with KISS1 gene expression. Consequently, this affects the hypothalamic-pituitary-gonadal axis resulting in hypogonadotropic hypogonadism. In both patients, complete development of primary and secondary male sex characteristics and stabilization of serum sex steroid hormone levels was achieved by testosterone therapy. Additionally, human chorionic gonadotropin and follicle stimulating hormone combination therapy in the older brother (patient 1) induced spermatogenesis and enabled fatherhood. Apart from this, we identified the heterozygous CHD7 variant c.2690G>A in the younger brother (patient 2). However, the contribution of this variant to the pathogenesis of hypogonadotropic hypogonadism remains elusive.