ORPHA: 432, 478; DO: 0090071;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q24 | Hypogonadotropic hypogonadism 11 with or without anosmia | 614840 | Autosomal recessive | 3 | TACR3 | 162332 |
A number sign (#) is used with this entry because hypogonadotropic hypogonadism-11 with or without anosmia (HH11) can be caused by homozygous mutation in the TACR3 gene (162332) on chromosome 4q24.
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.
Topaloglu et al. (2009) performed genomewide SNP analysis in 9 unrelated consanguineous Turkish and Kurdish families with normosmic IHH and identified a region of homozygosity on chromosome 4q that segregated with disease in 1 Turkish and 2 Kurdish families. Analysis of the candidate gene TACR3 revealed homozygosity for 2 missense mutations (162332.0001 and 162332.0002). The mutations were found in heterozygosity in all unaffected parents, and were not found in 100 ethnically matched Turkish or Kurdish controls.
Gianetti et al. (2010) analyzed the TACR3 gene in 345 probands with normosmic IHH and identified 13 distinct variants in 19 of the probands (see, e.g., 162332.0003 and 162332.0004), most of whom were known to be negative for mutation in 7 or 8 other HH-associated genes. In some patients, a mutation was detected on only 1 allele of TACR3. Of 16 males carrying TACR3 variants for whom physical evidence was available, 15 (94%) had microphallus identified either neonatally or later in life. In addition, 10 (83%) of 12 patients who were assessed longitudinally after discontinuation of sex steroid therapy exhibited evidence of spontaneous partial or complete recovery of their reproductive axis, including increases in LH pulsatility, testosterone, testicular volume, presence of withdrawal bleeding, spontaneous menstrual cycles, and/or spontaneous pregnancy. Gianetti et al. (2010) noted that the high prevalence of reversal suggested that the role of the NKB system in GNRH (152760) secretion may be less critical in adult life than during late gestation and the early neonatal period.
Gianetti, E., Tusset, C., Noel, S. D., Au, M. G., Dwyer, A. A., Hughes, V. A., Abreu, A. P., Carroll, J., Trarbach, E., Silveira, L. F. G., Costa, E. M. F., de Mendonca, B. B., and 14 others. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J. Clin. Endocr. Metab. 95: 2857-2867, 2010. [PubMed: 20332248] [Full Text: https://doi.org/10.1210/jc.2009-2320]
Raivio, T., Falardeau, J., Dwyer, A., Quinton, R., Hayes, F. J., Hughes, V. A., Cole, L. W., Pearce, S. H., Lee, H., Boepple, P., Crowley, W. F., Jr., Pitteloud, N. Reversal of idiopathic hypogonadotropic hypogonadism. New Eng. J. Med. 357: 863-873, 2007. [PubMed: 17761590] [Full Text: https://doi.org/10.1056/NEJMoa066494]
Topaloglu, A. K., Reimann, F., Guclu, M., Yalin, A. S., Kotan, L. D., Porter, K. M., Serin, A., Mungan, N. O., Cook, J. R., Ozbek, M. N., Imamoglu, S., Akalin, N. S., Yuksel, B., O'Rahilly, S., Semple, R. K. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nature Genet. 41: 354-358, 2009. [PubMed: 19079066] [Full Text: https://doi.org/10.1038/ng.306]