Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary ... Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).' For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see 147950.
In affected individuals from the large consanguineous Saudi family with autosomal recessive normosmic hypogonadotropic hypogonadism mapping to chromosome 19p13.3, originally reported by Bo-Abbas et al. (2003), Seminara et al. (2003) identified homozygosity for a missense mutation in the ... In affected individuals from the large consanguineous Saudi family with autosomal recessive normosmic hypogonadotropic hypogonadism mapping to chromosome 19p13.3, originally reported by Bo-Abbas et al. (2003), Seminara et al. (2003) identified homozygosity for a missense mutation in the GPR54 gene (L148S; 604161.0001), located within the critical linkage region. Analysis of 63 additional unrelated patients with normosmic idiopathic hypogonadotropic hypogonadism and 20 patients with anosmic hypogonadotropic hypogonadism revealed 1 normosmic HH patient with compound heterozygosity for mutations in GPR54 (604161.0002-604161.0003). In 5 affected sibs from a consanguineous family with normosmic hypogonadotropic hypogonadism mapping to chromosome 19p13, de Roux et al. (2003) sequenced 5 candidate genes and identified homozygosity for a 155-bp deletion within the GPR54 gene (604161.0004). In 5 patients with normosmic hypogonadotropic hypogonadism from 2 unrelated Arab-Muslim families from Syria and Israel, Tenenbaum-Rakover et al. (2007) identified homozygosity for a missense mutation in the GPR54 gene (L102P; 604161.0005). In a male patient with anosmic hypogonadotropic hypogonadism, Miraoui et al. (2013) identified 2 heterozygous missense mutations, 1 in the KISS1R gene (A194D; 604161.0007) and 1 in the IL17RD gene (A735P; 606807.0003). - Exclusion Studies Bo-Abbas et al. (2003) studied 4 families with autosomal recessive idiopathic hypogonadotropic hypogonadism, including a consanguineous pedigree from the Middle East. Defects within the genomic coding sequences of GNRH1 (152760) and GNRHR were excluded by temperature-gradient gel electrophoresis (TGGE), direct sequencing, and haplotypes created from simple sequence polymorphisms flanking the GNRH1 and GHRHR loci.