Hypogonadotropic Hypogonadism 4 With Or Without Anosmia

A number sign (#) is used with this entry because autosomal dominant hypogonadotropic hypogonadism-4 with or without anosmia (HH4) is caused by heterozygous mutation in the prokineticin-2 gene (PROK2; 607002) on chromosome 3p13, sometimes in association with mutation in another gene, e.g., PROKR2 (607123).

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 autosomal hypogonadotropic hypogonadism with or without anosmia, see 147950.

Molecular Genetics

In a study of 192 patients with Kallmann syndrome, Dode et al. (2006) identified 4 and 10 different point mutations in the PROK2 gene (e.g., 607002.0001-607002.0002) and in its receptor, PROKR2 (607123), respectively. All of the mutations in the PROK2 gene occurred in heterozygous state.

Dode et al. (2006) noted that Kallmann syndrome patients with mutations in PROK2 or PROKR2 had variable degrees of olfactory and reproductive dysfunction and did not seem to have any of the occasional clinical anomalies that had been reported in previously characterized genetic forms of the disease, i.e., bimanual synkinesis, renal agenesis, dental agenesis, and cleft lip or palate.

In 2 brothers with Kallmann syndrome and their sister who had normosmic idiopathic hypogonadotropic hypogonadism, Pitteloud et al. (2007) identified homozygosity for a 1-bp deletion in the PROK2 gene (607002.0003). An unaffected brother was heterozygous for the mutation; the truncated protein was found to lack bioactivity in vitro.

Leroy et al. (2008) identified respective homozygous mutations in the PROK2 gene (607002.0003-607002.0004) in 2 of 320 patients with Kallmann syndrome, suggesting that it is a rare cause of the disorder. Leroy et al. (2008) concluded that only biallelic PROK2 mutations result in Kallmann syndrome, and that patients with heterozygous mutations have another pathogenic mutation in a Kallmann-related gene.

In a cohort of 324 IHH patients, 170 of whom were anosmic and 154 normosmic, Cole et al. (2008) analyzed the PROK2 and PROKR2 genes and identified 5 and 10 different point mutations, respectively. The 5 mutations in PROK2 were heterozygous in 4 probands (see, e.g., 607002.0004-607002.0006) and homozygous in 1 (607002.0003); 1 of the heterozygous probands (see 607002.0005) also carried a heterozygous mutation in PROKR2 (V115M; 607123.0007). Four of the probands with a mutation in PROK2 had Kallmann syndrome and 1 reported a normal sense of smell. The mutation-positive probands were screened for mutations in other HH-associated genes, including KAL1 (300836), FGFR1 (136350), KISS1R (604161), NELF (608137), and GNRHR (138850), but no additional mutations were detected. All mutant alleles appeared to decrease intracellular calcium mobilization; some also exhibited decreased MAPK signaling and decreased receptor expression. Cole et al. (2008) concluded that loss-of-function mutations in PROK2 can cause both Kallmann syndrome and normosmic IHH.

Animal Model

Pitteloud et al. (2007) generated Prok2 -/- mice which, in addition to olfactory bulb defects, exhibited disrupted GnRH neuron migration, resulting in a dramatic decrease in the GnRH neuron population in the hypothalamus as well as hypogonadotropic hypogonadism. Heterozygous mice did not show an abnormal phenotype.