Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder (incidence, 1/15.000‑1/50.000) characterized by delayed or absent puberty due to a deficient secretion of gonadotropin‑releasing hormone (GnRH). A KAL1 mutation is the most common genetic cause of CHH, which is typically associated with anosmia. By contrast, the less common kisspeptin‑1 receptor (KISS1R) mutation is more frequently observed in normosmic patients. This study aimed to investigate a 21‑year‑old male with normosmic CHH caused by a novel homozygous splice‑site mutation in the KISS1R gene (c.505+2T>G). The location of the identified variant (c.505+2T>G) near the exon‑intron junction suggests the possibility of receptor dysfunction. 2The clinical features included micropenis, reduced body hair, erectile dysfunction and small testes. The hormonal analysis confirmed low testosterone levels with inappropriately normal gonadotropin levels. The pituitary magnetic resonance imaging indicated normal results, and a GnRH stimulation test confirmed a hypothalamic origin of the deficiency. The patient responded well to human chorionic gonadotropin alpha monotherapy, indicating increased testosterone levels, spermatogenesis and testicular volume. During a 24‑week follow‑up, the patient maintained hormonal and clinical improvements, including the normalization of erectile function and increased body hair growth. To our knowledge, this KISS1R variant has not been previously investigated. Thus, the findings of the present study contribute novel insights into the genetic spectrum of CHH. Given the consanguinity in the family, this case also emphasizes the value of genetic counseling in familial forms of CHH.
