Hypogonadotropic Hypogonadism 18 With Or Without Anosmia

A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-18 with or without anosmia (HH18) is caused by heterozygous or homozygous mutation in the IL17RD gene (606807) on chromosome 3p14, sometimes in association with mutation in other genes, e.g., FGFR1 (136350) and KISS1R (604161).

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 6 HH probands who were heterozygous and 2 who were homozygous for missense mutations in the IL17RD gene (see, e.g., 606807.0001-606807.0005). Two of the patients with a heterozygous IL17RD mutation also carried a heterozygous missense mutation in another HH-associated gene, FGFR1 (see 136350.0026) and KISS1R (see 604161.0007), respectively. All of the patients were anosmic, and 7 had absent puberty whereas 1 had partial puberty. Six of the 8 probands had congenital hearing loss, which was unilateral in 5 of them. The authors noted that hearing loss did not cosegregate with the IL17RD mutation in some pedigrees, indicating that although IL17RD mutations are strongly associated with anosmic HH and hearing loss, 1 allelic defect was likely not sufficient and that additional affected alleles in the same and/or other genes must be present to create the phenotype of Kallmann syndrome and hearing loss. 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.