ORPHA: 432; DO: 0090073;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q32.1 | ?Hypogonadotropic hypogonadism 13 with or without anosmia | 614842 | Autosomal recessive | 3 | KISS1 | 603286 |
A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-13 with or without anosmia (HH13) is caused by homozygous mutation in the KISS1 gene (603286) on chromosome 1q32. One such family has been reported.
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. (2012) reported a consanguineous Kurdish family in which 4 sisters had normosmic hypogonadotropic hypogonadism. The proband presented at 14.9 years of age with absent breast development. She had a bone age of 13 years, and pelvic ultrasonography revealed hypoplastic uterus and ovaries lacking follicles. Bone mineral density testing indicated osteopenia with a Z-score of -2.1 at the femoral neck. A GnRH (152760) stimulation test revealed a blunted response, and LH profiling during sleep showed readings that were all below the lower limit of detection. Two older sisters, aged 30 years and 16 years, respectively, had similar presentations, and a 12-year-old sister had not developed any breast tissue and had a bone age of 10 years. All 4 affected sisters were otherwise healthy, with no dysmorphic features and a normal sense of smell by conventional testing. Their anterior pituitary function was normal apart from the failure to undergo puberty, and there was no evidence of structural lesions on MRI of olfactory bulbs and sulci, hypothalamus, and pituitary regions.
In a consanguineous Kurdish family in which 4 sisters had normosmic hypogonadotropic hypogonadism, Topaloglu et al. (2012) performed genomewide SNP analysis and identified 2 regions of homozygosity common to all affected individuals but not present in any unaffected family member. One of the regions was a 5.5-Mb segment on chromosome 1 that included the candidate gene KISS1 (603286); sequencing of KISS1 revealed homozygosity for a missense mutation (603286.0001) that segregated with the disease and was not found in 100 ethnically matched controls. Subsequent analysis of KISS1 in 12 additional families with normosmic hypogonadotropic hypogonadism and in 90 sporadic cases revealed no mutations.
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., Tello, J. A., Kotan, L. D., Ozbek, M. N., Yilmaz, M. B., Erdogan, S., Gurbuz, F., Temiz, F., Millar, R. P., Yuksel, B. Inactivating KISS1 mutation and hypogonadotropic hypogonadism. New Eng. J. Med. 366: 629-635, 2012. [PubMed: 22335740] [Full Text: https://doi.org/10.1056/NEJMoa1111184]