Case Report: Homozygous KISS1R mutation associated with congenital hypogonadotropic hypogonadism in two siblings: pulsatile GnRH therapy restores pituitary architecture and induces pubertal development.

Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder characterized by deficient production, secretion, or action of gonadotropin-releasing hormone (GnRH), the central regulator of the reproductive axis. We report two siblings from a consanguineous family with CHH caused by a homozygous nonsense mutation (c.182C > A; p. Ser 61Ter) in exon 1 of KISS1R gene. The 15-years-old male proband presented with absent puberty, micropenis, and gynecomastia. Endocrine evaluation revealed low gonadotropin levels and brain magnetic resonance imaging (MRI) showed pituitary hypoplasia. His 12-years-old sister exhibited puberty delays, with absent breast development and pubic hair. The male patient received 1 year of pulsatile GnRH therapy, resulting in significant clinical improvements, including markedly increased testicular volume (from 0.9 to 5.6 mL), penile growth, and the resolution of gynecomastia. Notably, follow-up imaging demonstrated morphological recovery of the pituitary gland, with an increase in height from 3.5 to 4.5 mm, accompanied by the successful induction of spermatogenesis. This excellent response to GnRH underscores its efficacy in restoring fertility, particularly when initiated in early adolescence, and highlights the value of genetic diagnosis in consanguineous families.