ORPHA: 432, 478; DO: 0090084;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q12.2 | Hypogonadotropic hypogonadism 5 with or without anosmia | 612370 | Autosomal dominant | 3 | CHD7 | 608892 |
A number sign (#) is used with this entry because autosomal dominant hypogonadotropic hypogonadism-5 with or without anosmia (HH5) is caused by heterozygous mutation in the chromodomain helicase DNA-binding protein-7 gene (CHD7; 608892) on chromosome 8q12.
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.
Kim et al. (2008) analyzed the CHD7 gene in 197 patients with Kallmann syndrome or normosmic hypogonadotropic hypogonadism and identified 7 different heterozygous mutations in 7 sporadic patients, 3 with KS and 4 with IHH, respectively (see, e.g., 608892.0012-608892.0015). A splice site mutation (608892.0013) in a female KS patient with cleft lip and palate and hearing loss had previously been reported by Jongmans et al. (2008) in 2 brothers with 'relatively mild' CHARGE syndrome (214800), and a missense mutation (608892.0012) that was found in a male patient with IHH, cleft lip, and cryptorchidism had previously been reported by Delahaye et al. (2007) in a mother and 2 sons from a family with both typical and atypical CHARGE syndrome phenotypes. Kim et al. (2008) concluded that both normosmic IHH and Kallmann syndrome due to CHD7 mutations are mild allelic variants of CHARGE syndrome.
Cariboni et al. (2015) reported 2 brothers with Kallmann syndrome who were heterozygous for missense mutations in the CHD7 and SEMA3E genes (see 608166.0002).
Cariboni, A., Andre, V., Chauvet, S., Cassatella, D., Davidson, K., Caramello, A., Fantin, A., Bouloux, P., Mann, F., Ruhrberg, C. Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome. J. Clin. Invest. 125: 2413-2428, 2015. [PubMed: 25985275] [Full Text: https://doi.org/10.1172/JCI78448]
Delahaye, A., Sznajer, Y., Lyonnet, S., Elmaleh-Berges, M., Delpierre, I., Audollent, S., Wiener-Vacher, S., Mansbach, A. L., Amiel, J., Baumann, C., Bremond-Gignac, D., Attie-Bitach, T., Verloes, A., Sanlaville, D. Familial CHARGE syndrome because of CHD7 mutation: clinical intra- and interfamilial variability. Clin. Genet. 72: 112-121, 2007. [PubMed: 17661815] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00821.x]
Jongmans, M. C. J., Hoefsloot, L. H., van der Donk, K. P., Admiraal, R. J., Magee, A., van de Laar, I., Hendriks, Y., Verheij, J. B. G. M., Walpole, I., Brunner, H. G., van Ravenswaaij, C. M. A. Familial CHARGE syndrome and the CHD7 gene: a recurrent missense mutation, intrafamilial recurrence and variability. Am. J. Med. Genet. 146A: 43-50, 2008. [PubMed: 18074359] [Full Text: https://doi.org/10.1002/ajmg.a.31921]
Kim, H.-G., Kurth, I., Lan, F., Meliciani, I., Wenzel, W., Eom, S. H., Kang, G. B., Rosenberger, G., Tekin, M., Ozata, M., Bick, D. P., Sherins, R. J., Walker, S. L., Shi, Y., Gusella, J. F., Layman, L. C. Mutations in CHD7, encoding a chromatin-remodeling protein, cause idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. Am. J. Hum. Genet. 83: 511-519, 2008. [PubMed: 18834967] [Full Text: https://doi.org/10.1016/j.ajhg.2008.09.005]
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]