ORPHA: 432, 478; DO: 0090075;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q14.3 | {Hypogonadotropic hypogonadism 15 with or without anosmia} | 614880 | Autosomal dominant | 3 | HS6ST1 | 604846 |
A number sign (#) is used with this entry because of evidence that susceptibility to hypogonadotropic hypogonadism-15 with or without anosmia (HH15) can be conferred by variation in the HS6ST1 gene (604846) on chromosome 2q14, sometimes in association with mutations in other genes, e.g., FGFR1 (136350) and NELF (608137).
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 the genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see 147950.
Tornberg et al. (2011) sequenced the coding exons and flanking splice sites of the candidate gene HS6ST1 (604846) in genomic DNA from 338 GnRH (GNRH1; 152760)-deficient patients, 271 males and 67 females, including 105 familial cases. They identified 5 heterozygous missense mutations in the HS6ST1 gene in 7 probands, 5 with anosmia and 2 with normosmia (604846.0001-604846.0005). All of the HS6ST1 variants affected highly conserved residues, exhibited reduced activity compared to wildtype, and were not found in 500 controls or the SNP database. A wide spectrum of severity and timing of onset of GnRH deficiency was observed in the patients, and clinical variability was evident both within and across families carrying the same genetic variant. One patient exhibited reversal of GnRH deficiency, with normal adult serum testosterone level and normal sperm count after discontinuation of replacement therapy; 14 years later, repeat neuroendocrine evaluation confirmed a sustained reversal of his GnRH deficiency. To test whether other genetic factors were contributing to the observed variability, Tornberg et al. (2011) analyzed 8 additional HH-associated genes and identified heterozygous variants in the FGFR1 gene (136350.0025) and in the NELF gene (608137.0001) in 2 of the HH families, respectively. Noting that HS6ST1-associated HH segregates as a complex trait with inheritance patterns that likely result from oligogenic interactions, the authors concluded that the identified HS6ST1 missense mutations might not be sufficient to cause disease, and suggested that HS6ST1 represents an important gene contributing pathogenic alleles to the genetic network responsible for the neuroendocrine control of human reproduction.
In a large consanguineous 10-generation French Canadian family with anosmic HH and cleft palate in which Tornberg et al. (2011) had identified mutations in both the HS6ST1 (604846.0002) and FGFR1 (136350.0025) genes, Miraoui et al. (2013) analyzed 7 genes involved in the FGF8 (600483)-FGFR1 (136350) network and identified additional mutations in 2 more genes, FGF17 (603725.0001) and FLRT3 (604808.0001 and 604808.0002). Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.
Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am. J. Hum. Genet. 92: 725-743, 2013. [PubMed: 23643382] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.008]
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]
Tornberg, J., Sykiotis, G. P., Keefe, K., Plummer, L., Hoang, X., Hall, J. E., Quinton, R., Seminara, S. B., Hughes, V., Van Vliet, G., Van Uum, S., Crowley, W. F., Habuchi, H., Kimata, K., Pitteloud, N., Bulow, H. E. Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc. Nat. Acad. Sci. 108: 11524-11529, 2011. [PubMed: 21700882] [Full Text: https://doi.org/10.1073/pnas.1102284108]