Hypogonadotropic Hypogonadism 20 With Or Without Anosmia

A number sign (#) is used with this entry because hypogonadotropic hypogonadism-20 with or without anosmia (HH20) can be caused by heterozygous mutation in the FGF17 gene (603725) on chromosome 8p21, sometimes in association with mutations in other genes, e.g., FGFR1 (136350), HS6ST1 (604846), and FLRT3 (604808).

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 (CHH), 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 3 HH probands with heterozygous missense mutations in the FGF17 gene (603725.0001-603725.0003). One of the 3 probands belonged to a large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate, previously reported by White et al. (1983) and in which Tornberg et al. (2011) had identified mutations in both the FGFR1 (136350.0025) and HS6ST1 (604846.0002) genes. In that proband, Miraoui et al. (2013) also identified heterozygosity and homozygosity for 2 missense mutations in another FGF-network gene, FLRT3 (604808.0001 and 604808.0002, respectively; see HH21, 615271). Of the 3 probands with FGF17 mutations, 2 were anosmic and 1 was normosmic; additional features included low bone mass in 2 of the patients. 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.