ORPHA: 432, 478; DO: 0090092;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p12.3 | Hypogonadotropic hypogonadism 3 with or without anosmia | 244200 | Autosomal dominant | 3 | PROKR2 | 607123 |
A number sign (#) is used with this entry because hypogonadotropic hypogonadism-3 with or without anosmia (HH3) is caused by heterozygous mutation in the G protein-coupled prokineticin receptor-2 gene (PROKR2; 607123) on chromosome 20p12, sometimes in association with mutation in another gene, e.g., KAL1 (300836).
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.
Cole et al. (2008) confirmed autosomal dominant inheritance of HH3.
In a study of 192 patients with Kallmann syndrome, Dode et al. (2006) identified 10 and 4 different point mutations in the PROKR2 gene (e.g., 607123.0001-607123.0005) and in one of its ligands, prokineticin-2 (PROK2; 607002), respectively. One of the patients was heterozygous for a PROKR2 mutation (607123.0001) and a missense mutation in KAL1 (300836.0012), indicating possible digenic inheritance of the disorder.
In a cohort of 324 IHH patients, 170 of whom were anosmic and 154 normosmic, Cole et al. (2008) analyzed the PROKR2 and PROK2 genes and identified 10 and 5 different point mutations, respectively. All 10 mutations in PROKR2 were heterozygous (see, e.g., 607123.0001 and 607123.0006-607123.0009); 1 of the probands (see 607123.0007) also carried a heterozygous mutation in PROK2 (607002.0005). Of the 11 probands with a mutation in PROKR2, 7 had Kallmann syndrome and 4 had normosmic IHH. Two of the probands underwent partial puberty, 1 of whom experienced reversal of his hypogonadism later in life after discontinuation of sex steroid therapy (see 607123.0009). 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 PROKR2 can cause both Kallmann syndrome and normosmic IHH.
Possible Association with Functional Hypothalamic Amenorrhea in Carrier Females
Caronia et al. (2011) studied 55 women with functional hypothalamic amenorrhea, who had all completed puberty spontaneously and had a history of secondary amenorrhea for 6 months or more, with low or normal gonadotropin levels and low serum estradiol levels. All had 1 or more predisposing factors, including excessive exercise, loss of more than 15% of body weight, and/or a subclinical eating disorder, and all had normal results on neuroimaging. The authors screened 7 HH-associated genes in the 55 affected women and identified 7 patients from 6 families who carried heterozygous mutations, including 1 in KAL1, 2 in FGFR1, 2 in PROKR2, and 1 in the GNRHR gene. Since these women with mutations resumed regular menses after discontinuing hormone-replacement therapy, Caronia et al. (2011) concluded that the genetic component of hypothalamic amenorrhea predisposes patients to, but is not sufficient to cause, GnRH deficiency.
Dode et al. (2006) noted that Kallmann syndrome patients with mutations in PROKR2 or PROK2 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.
Caronia, L. M., Martin, C., Welt, C. K., Sykiotis, G. P., Quinton, R., Thambundit, A., Avbelj, M., Dhruvakumar, S., Plummer, L., Hughes, V. A., Seminara, S. B., Boepple, P. A., Sidis, Y., Crowley, W. F., Jr., Martin, K. A., Hall, J. E., Pitteloud, N. A genetic basis for functional hypothalamic amenorrhea. New Eng. J. Med. 364: 215-225, 2011. [PubMed: 21247312] [Full Text: https://doi.org/10.1056/NEJMoa0911064]
Cole, L. W., Sidis, Y., Zhang, C., Quinton, R., Plummer, L., Pignatelli, D., Hughes, V. A., Dwyer, A. A., Raivio, T., Hayes, F. J., Seminara, S. B., Huot, C., Alos, N., Speiser, P., Takeshita, A., Van Vliet, G., Pearce, S., Crowley, W. F., Jr., Zhou, Q.-Y., Pitteloud, N. Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency: molecular genetics and clinical spectrum. J. Clin. Endocr. Metab. 93: 3551-3559, 2008. [PubMed: 18559922] [Full Text: https://doi.org/10.1210/jc.2007-2654]
Dode, C., Teixeira, L., Levilliers, J., Fouveaut, C., Bouchard, P., Kottler, M.-L., Lespinasse, J., Lienhardt-Roussie, A., Mathieu, M., Moerman, A., Morgan, G., Murat, A., Toublanc, J.-E., Wolczynski, S., Delpech, M., Petit, C., Young, J., Hardelin, J.-P. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2: e175, 2006. Note: Electronic Article. [PubMed: 17054399] [Full Text: https://doi.org/10.1371/journal.pgen.0020175]
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]