ORPHA: 432, 478; DO: 0090085;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9q34.3 | Hypogonadotropic hypogonadism 9 with or without anosmia | 614838 | Autosomal dominant | 3 | NSMF | 608137 |
A number sign (#) is used with this entry because autosomal dominant hypogonadotropic hypogonadism-9 with or without anosmia (HH9) is caused by heterozygous mutation in the NELF gene (NSMF; 608137) on chromosome 9q34, sometimes in association with mutation in other genes, e.g., FGFR1 (136350) and HS6ST1 (604846).
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.
In 1 of 65 patients with IHH, Miura et al. (2004) identified a thr480-to-ala mutation in the NELF gene (T480A; 608137.0001). The mutation was not found in 100 normal control individuals, suggesting that it may be associated with IHH.
In a family in which the proband had severe Kallmann syndrome, his father had a history of delayed puberty and congenital anosmia, his mother had clinodactyly and Duane ocular retraction syndrome, his sister had midline defects with a bifid nose and high-arched palate, and his brother had clinodactyly alone, Pitteloud et al. (2007) identified heterozygosity for a missense mutation in the FGFR1 gene (L342S; 136350.0017) in the proband, his father, and his sister. Heterozygosity for an additional mutation, an 8-bp deletion in the NELF gene (608137.0002), was identified in the proband, his mother, and his brother. The mother and both sibs of the proband had normal puberty and a normal sense of smell by formal testing. Pitteloud et al. (2007) concluded that mutations in 2 different genes can synergize to produce a more severe phenotype in families with hypogonadotropic hypogonadism than either alone, and that this digenic model may account for some of the phenotypic heterogeneity seen in GnRH deficiency.
In a 44-year-old man with anosmic hypogonadotropic hypogonadism and in his unaffected brother, Tornberg et al. (2011) identified heterozygosity for a missense mutation in the HS6ST1 gene (604846.0001). Because of the reduced penetrance displayed in the family and phenotypic variability seen among other HH patients carrying the same HS6ST1 mutation, the authors analyzed 8 additional known HH-associated genes and detected the T480A NELF missense mutation in the affected brother. Tornberg et al. (2011) concluded that HH is an oligogenic disorder in which a limited number of genes contribute pathogenic alleles to the genetic network responsible for neuroendocrine control of human reproduction.
Miura, K., Acierno, J. S., Jr., Seminara, S. B. Characterization of the human nasal embryonic LHRH factor gene, NELF, and a mutation screening among 65 patients with idiopathic hypogonadotropic hypogonadism (IHH). J. Hum. Genet. 49: 265-268, 2004. [PubMed: 15362570] [Full Text: https://doi.org/10.1007/s10038-004-0137-4]
Pitteloud, N., Quinton, R., Pearce, S., Raivio, T., Acierno, J., Dwyer, A., Plummer, L., Hughes, V., Seminara, S., Cheng, Y.-Z., Li, W.-P., Maccoll, G., Eliseenkova, A. V., Olsen, S. K., Ibrahimi, O. A., Hayes, F. J., Boepple, P., Hall, J. E., Bouloux, P., Mohammadi, M., Crowley, W., Jr. Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J. Clin. Invest. 117: 457-463, 2007. [PubMed: 17235395] [Full Text: https://doi.org/10.1172/JCI29884]
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]