Genetic causes of hypogonadotropic hypogonadism

Idiopathic hypogonadotropic hypogonadism (IHH), defined by a complete or partial impaired secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), 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: IHH associated with anosmia, known as Kallmann syndrome, and isolated IHH. 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. Recently several genes have been identified, which are involved in the migration of GnRH neurons. 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 genes expressed at the hypothalamic level and directly involved in the endocrine regulation of gametogenesis have been found to be causative for IHH. Loss-of function mutations of the GnRH-receptor do account for 50% of familial cases of IHH without anosmia. Similar to this mutations have been found in the G-protein-coupled receptor 54 gene (GPR54), a receptor which together with its natural ligand kisspetin (KiSS-1), turned out to be a novel, essential regulator of puberty and reproduction via the control of GnRH secretion or modulation of the pituitary response to GnRH stimulation. Genotype-phenotype correlations in IHH due to GnRH receptor and GPR54 mutations indicate thatsimilar mutations may lead to a variable phenotype and suggest the impact of the other, presumably pituitary factors on the clinical presentation of IHH.