Molecular genetics of isolated hypogonadotropic hypogonadism and Kallmann syndrome

Isolated hypogonadotropic hypogonadism (IHH) is characterized by complete or partial failure of pubertal development due to impaired secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In the molecular pathogenesis of IHH, the gonadotropin-releasing hormone receptor (GnRH-R) and associated proteins have evolved as a central element. GnRH-R germline mutations were among the first genetic alterations identified in patients with IHH. These mutations are associated with impaired GnRH binding, ligand-induced signal transduction, or both, leading to various degrees of LH and FSH deficiency. As GnRH-R mutations explain several but not all cases of IHH, the search for new candidate genes continued in informative families. In 2003, mutations of the KiSS-1-derived peptide receptor GPR54 were identified in patients with IHH, opening a new pathway in the physiologic regulation of puberty and reproduction. GPR54 is putatively involved in the control of GnRH secretion. IHH associated with impaired olfactory function (Kallmann syndrome) may be caused by mutations of the X-chromosomal KAL1 (encoding anosmin) or the fibroblast growth factor receptor 1 genes (FGFR1), both leading to agenesis of olfactory and GnRH-secreting neurons. In addition to their clinical and diagnostic value, the identification of genetic and functional alterations in IHH helps to unravel the complex regulation of the gonadotropic axis.