Hypogonadotropic Hypogonadism 10 With Or Without Anosmia

A number sign (#) is used with this entry because hypogonadotropic hypogonadism-10 with or without anosmia (HH10) is caused by homozygous mutation in the TAC3 gene (162330) on chromosome 12q13.

Description

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, see 147950.

Clinical Features

Gianetti et al. (2010) reported a female proband with normosmic IHH from a large multiply consanguineous Asian family. She had 3 affected sisters, including 1 who was anosmic, and an unaffected sister. There was evidence for neuroendocrine recovery after discontinuation of sex steroid therapy in the affected individuals: the proband conceived a child without fertility medications but suffered an early pregnancy loss, whereas 1 of her affected sisters conceived spontaneously and carried the pregnancy to term. The third affected sister had regular menstrual cycles but had not conceived, and the unaffected sister had a positive withdrawal bleed to a progesterone challenge but did not cycle spontaneously.

Molecular Genetics

In a Turkish IHH family with a region of homozygosity on chromosome 12q, Topaloglu et al. (2009) analyzed the biologically plausible candidate gene TAC3 and identified homozygosity for a missense mutation in the 2 affected sisters (162330.0001). The mutation was found in heterozygosity in the unaffected parents and was not found in 100 ethnically matched Turkish or Kurdish controls.

Gianetti et al. (2010) analyzed the TAC3 gene in 345 probands with normosmic IHH and identified homozygosity for a 1-bp deletion (162330.0002) in a female proband from a large multiply consanguineous Asian family who was negative for mutation in 7 other HH-associated genes. She had 3 affected sisters, including 1 who was anosmic, who were also homozygous for the deletion; an unaffected sister was a heterozygous carrier of the mutation.