Normosmic congenital hypogonadotropic hypogonadism

Normosmic congenital hypogonadotropic hypogonadism (nCHH), also known as idiopathic hypogonadotropic hypogonadism (IHH) with normal sense of smell, is a rare genetic disorder characterized by absent or incomplete puberty due to deficient production or action of gonadotropin-releasing hormone (GnRH). Unlike Kallmann syndrome, which shares the same gonadotropin deficiency but includes anosmia (absent sense of smell), individuals with nCHH have a normal or near-normal sense of smell. The condition results from impaired GnRH secretion or signaling at the hypothalamic-pituitary level, leading to low levels of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone), and consequently low sex steroid production by the gonads. The disorder primarily affects the reproductive and endocrine systems. In males, key features include micropenis and cryptorchidism (undescended testes) at birth, failure to undergo puberty with absent or minimal development of secondary sexual characteristics, small testes, decreased libido, and infertility. In females, the condition manifests as primary amenorrhea (absence of menstruation), absent or incomplete breast development, and infertility. Some patients may present with partial forms showing some degree of pubertal development. Associated features can occasionally include synkinesia (mirror movements), renal anomalies, or dental agenesis, depending on the underlying genetic cause. Numerous genes have been implicated in nCHH, including GNRHR, KISS1R (GPR54), TAC3, TACR3, GNRH1, KISS1, FGFR1, PROKR2, and others. The condition can follow autosomal recessive, autosomal dominant, X-linked, or oligogenic inheritance patterns depending on the causative gene. Treatment involves hormone replacement therapy to induce and maintain secondary sexual characteristics — typically testosterone in males and estrogen-progesterone combinations in females. When fertility is desired, pulsatile GnRH therapy or gonadotropin injections (LH/FSH) can be used to stimulate gonadal function and enable conception. With appropriate treatment, patients can achieve normal sexual development and fertility in many cases. Rarely, spontaneous reversal of hypogonadism has been reported.

Common questions about Normosmic congenital hypogonadotropic hypogonadism