Alternative titles; symbols
SNOMEDCT: 717256009; ORPHA: 90368; DO: 0110699;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.33 | Hypotrichosis 2 | 146520 | Autosomal dominant | 3 | CDSN | 602593 |
A number sign (#) is used with this entry because of evidence that hypotrichosis-2 (HYPT2) is caused by heterozygous mutation in the CDSN gene (602593) on chromosome 6p21.
Hypotrichosis simplex can affect all body hair or be limited to the scalp. Usually patients with the scalp-limited form of hypotrichosis present with normal hair at birth; they experience a progressive, gradual loss of scalp hair beginning at the middle of the first decade and leading to almost complete loss of scalp hair by the third decade. A few sparse, fine, short hairs remain in some individuals. Body hair, beard, eyebrows, axillary hair, teeth, and nails develop normally. Light and electron microscopy of hairs from early hypotrichosis simplex revealed no structural changes, whereas hairs from patients with advanced hypotrichosis showed focal areas of defective cuticular structure. Men and women are equally affected (summary by Betz et al., 2000).
For a discussion of genetic heterogeneity of nonsyndromic hypotrichosis, see 605389.
Hypotrichosis simplex of the scalp was first described by Toribio and Quinones (1974). They observed a large Spanish kindred with affected members in 8 generations. Affected children were normal at birth and in the first years of life. Between ages 5 and 12 years, retardation of hair growth was observed. Between ages 20 and 25 years, all affected persons, male and female, reached a terminal stage in which only a few sparse, fine, short hairs persisted on the scalp. There were no associated abnormalities of beard, eyebrows, axillary hair, teeth, or nails. In all earlier reported families, the disorder does not seem to have been limited to the scalp or present at birth. Hess and Uno (1991) described affected cases in 6 generations of a Caucasian family with 1 instance of male-to-male transmission. Hairs of the scalp were generally sparse and short of vellus type from childhood and thinned progressively with age. The family resembled those of Toribio and Quinones (1974) and Kohn and Metzker (1987) except that the 2 latter families showed normal scalp hair growth until the middle of the first decade, with severe hair loss by adolescence and complete loss by the third decade. In the family reported by Hess and Uno (1991), scalp hypotrichosis was fully manifest at birth, although it progressed. The same disorder may have been present in the 4-generation family reported by Ibsen et al. (1991). Onset of hypotrichosis was at age 6 to 17 years with almost total scalp alopecia by age 14 to 21 years. No associated ectodermal defects were found.
By a genomewide linkage analysis in 2 Danish families, Betz et al. (2000) localized the locus for hypotrichosis simplex of the scalp, which they symbolized HSS, to chromosome 6p21.3. The mapping was confirmed in the Spanish family originally described by Toribio and Quinones (1974), with a total lod score of 11.97 for marker D6S1701. The combined haplotype data identified the critical interval of 14.9 cM between markers D6S276 and D6S1607.
The transmission pattern of HYPT2 in the families reported by Levy-Nissenbaum et al. (2003) was consistent with autosomal dominant inheritance.
The CDSN gene (602593), located in the linkage interval on 6p21.3, encodes a protein of 529 amino acids called corneodesmosin that is exclusively expressed in cornified squamous epithelia. Levy-Nissenbaum et al. (2003) found heterozygous nonsense mutations in CDSN in 3 previously reported families with hypotrichosis: Q215X (602593.0001) in Israeli (Kohn and Metzker, 1987) and Spanish (Betz et al., 2000) families and Q200X (602593.0002) in a Danish family (Betz et al., 2000). Haplotype analysis in the Israeli and Spanish families showed that the mutation arose on a different genetic background in each.
Betz, R. C., Lee, Y.-A., Bygum, A., Brandrup, F., Bernal, A. I., Toribio, J., Alvarez, J. I., Kukuk, G. M., Ibsen, H. H. W., Rasmussen, H. B., Wienker, T. F., Reis, A., Propping, P., Kruse, R., Cichon, S., Nothen, M. M. A gene for hypotrichosis simplex of the scalp maps to chromosome 6p21.3. Am. J. Hum. Genet. 66: 1979-1983, 2000. [PubMed: 10793007] [Full Text: https://doi.org/10.1086/302934]
Hess, R. O., Uno, H. Hereditary hypotrichosis of the scalp. Am. J. Med. Genet. 39: 125-129, 1991. [PubMed: 2063912] [Full Text: https://doi.org/10.1002/ajmg.1320390202]
Ibsen, H. H. W., Clemmensen, O. J., Brandrup, F. Familial hypotrichosis of the scalp: autosomal dominant inheritance in four generations. Acta Derm. Venerol. 71: 349-351, 1991. [PubMed: 1681656]
Kohn, G., Metzker, A. Hereditary hypotrichosis simplex of the scalp. Clin. Genet. 32: 120-124, 1987. [PubMed: 3652491] [Full Text: https://doi.org/10.1111/j.1399-0004.1987.tb03338.x]
Levy-Nissenbaum, E., Betz, R. C., Frydman, M., Simon, M., Lahat, H., Bakhan, T., Goldman, B., Bygum, A., Pierick, M., Hillmer, A. M., Jonca, N., Toribio, J., Kruse, R., Dewald, G., Cichon, S., Kubisch, C., Guerrin, M., Serre, G., Nothen, M. M., Pras, E. Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nature Genet. 34: 151-153, 2003. [PubMed: 12754508] [Full Text: https://doi.org/10.1038/ng1163]
Toribio, J., Quinones, P. A. Hereditary hypotrichosis simplex of the scalp--evidence for autosomal dominant inheritance. Brit. J. Derm. 91: 687-696, 1974. [PubMed: 4141628] [Full Text: https://doi.org/10.1111/j.1365-2133.1974.tb12455.x]