Hypogonadotropic Hypogonadism 14 With Or Without Anosmia

A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-14 with or without anosmia (HH14) can be caused by heterozygous mutation in the WDR11 gene (606417) on chromosome 10q26.

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.

Cytogenetics

In a 16-year-old boy with Kallmann syndrome, Schinzel et al. (1995) found a tiny chromosome fragment attached to the long arm of chromosome 1, without a visible reciprocal translocation chromosome. Through reverse chromosome painting, they defined an unbalanced der(1),t(1;10)(q44;q26) translocation. This was the third case of Kallmann syndrome with a de novo rearrangement between 2 autosomes. They suggested that the distal long arm of chromosome 1 may contain a candidate gene.

Mapping

Bhagavath et al. (2006) karyotyped 76 HH patients and identified a sporadic male patient with complete hypogonadotropic hypogonadism (no evidence of any puberty) and hyposmia who had a balanced chromosome translocation, reported as 46,XY, t(10;12)(q26.3;q13.1). After excluding copy number variation as the cause of the phenotype, Kim et al. (2010) mapped the translocation breakpoints using fluorescence in situ hybridization (FISH) followed by array painting using a customized oligonucleotide array, resulting in restatement of the karyotype to 46,XY, t(10;12)(q26.12;q13.11). PCR analysis narrowed the breakpoints further and ultimately localized the breakpoint on chromosome 12 between nucleotides 46,038,271 and 46,038,272 and the breakpoint on chromosome 10 between nucleotides 122,053,649 and 122,053,650 (NCBI36). Given previous reports of chromosome 10q26 in association with HH phenotypes (e.g., Schinzel et al., 1995), Kim et al. (2010) hypothesized that 10q was more likely than 12q to harbor the causative gene.

Molecular Genetics

Kim et al. (2010) screened 123 normosmic and hyposmic/anosmic HH patients for mutations in 3 candidate genes on chromosome 10q26, but identified no causative mutations. Sequencing a fourth candidate gene, WDR11 (606417), in 201 normosmic or hyposmic/anosmic HH patients, they identified 5 different heterozygous missense mutations in 6 unrelated probands, including 5 normosmic patients (see, e.g., 606417.0001 and 606417.0002) and 1 anosmic patient (606417.0003). DNA from the parents was unavailable, but the mutations were not found in more than 400 controls.