Genetics of hypogonadotropic hypogonadism

Background: Idiopathic hypogonadotropic hypogonadism (HH) results from a defect in the normal pulsatile secretion pattern of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Clinically it can be categorized as one of two types: HH associated with anosmia, known as Kallmann syndrome, and isolated HH. The anatomical explanation for Kallmann syndrome stems from incomplete or total failure of GnRH-secreting neurons to migrate from the olfactory epithelium to their final destination in the mediobasal hypothalamus. Several genes are involved in the migration of the GnRH neurons. Conclusions: Mutations of the KAL1 gene, encoding for anosmin 1, and of the FGFR1 (or KAL2) gene, encoding for fibroblast growth factor receptor 1, can be found in familial cases of Kallmann syndrome. KAL1 mutations are responsible for X-linked recessive inheritance, and FGFR1 mutations are the autosomal dominant form. Moreover, mutations of the gonadotropin-releasing hormone receptor gene and G-protein-coupled receptor 54 gene are found in over 50% of familial cases of isolated HH with autosomal recessive inheritance.