Hypogonadotropic Hypogonadism 19 With Or Without Anosmia

A number sign (#) is used with this entry because hypogonadotropic hypogonadism-19 with or without anosmia (HH19) can be caused by heterozygous mutation in the DUSP6 gene (602748) on chromosome 12q22, sometimes in association with mutations in other genes, e.g., FGFR1 (136350) and SPRY4 (607984).

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 a cohort of 386 unrelated individuals with congenital hypogonadotropic hypogonadism, 199 of whom were anosmic and 187 normosmic, many of whom were known to harbor mutations in previously identified HH-associated genes, Miraoui et al. (2013) analyzed 7 genes involved in the FGF8 (600483)-FGFR1 (136350) network and identified 5 HH probands with heterozygous missense mutations in the DUSP6 gene (602748.0001-602748.0004). In 3 of the patients, the DUSP6 mutation was accompanied by a heterozygous missense mutation in another HH-associated gene, including FGFR1 (136350.0028; see HH2, 147950) and SPRY4 (607984.0001 and 607984.0003; see HH17, 615266). Additional features present in the 5 probands with DUSP6 mutations included abnormal dentition in 2, low bone mass in 2, and hearing loss in 1. Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.