Hypogonadotropic hypogonadism has been described in several human genetic diseases. Congenital isolated hypogonadotropic hypogonadism is classified into two categories: one that is associated with anosmia (Kallmann syndrome) and one that is apparently isolated. Mutations and deletions of the KAL1 gene, which encodes for a protein involved in cell adhesion, have been observed in many cases of the X-linked form of Kallmann syndrome. Recently, loss-of-function mutations of fibroblast growth factor receptor-1 (FGFR1) were associated with an autosomal dominant form of Kallmann syndrome. Genotype-phenotype correlations confirm the large spectrum of the phenotype due to FGFR1 mutations. Cases of isolated hypogonadotropic hypogonadism were considered to be idiopathic until the description of mutations of the gonadotropin releasing hormone receptor, luteinizing hormone and follicle stimulating hormone genes. However, defects in these genes only account for a small percentage of familial cases, which suggests that other proteins may be involved in regulation of the gonadotropic axis. We recently described GPR54 as one of these proteins by genome mapping in a very informative family. In vivo studies and genotype-phenotype correlations indicate that gonadotropic axis regulation by GPR54 occurs mainly at the level of the hypothalamus.
(c) 2005 S. Karger AG, Basel.