ORPHA: 1775; DO: 0070015;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q14 | ?Dyskeratosis congenita, autosomal recessive 1 | 224230 | Autosomal recessive | 3 | NOP10 | 606471 |
A number sign (#) is used with this entry because of evidence that autosomal recessive dyskeratosis congenita-1 (DKCB1) is caused by homozygous mutation in the NOP10 gene (606471) on chromosome 15q14. One such family has been reported.
Dyskeratosis congenita is a bone marrow failure syndrome classically characterized by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa. Progressive bone marrow failure occurs in over 80% of cases and is the main cause of early mortality. The phenotype is highly variable, and affected individuals may have multiple additional features, including pulmonary fibrosis, liver cirrhosis, premature hair loss and/or graying, osteoporosis, atresia of the lacrimal ducts, and learning difficulties. Predisposition to malignancy is an important feature. The disorder is caused by defects in the maintenance of telomeres (summary by Kirwan and Dokal, 2008).
For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).
Early Descriptions of Autosomal Recessive Dyskeratosis Congenita
Addison and Rice (1965) described a male with DKC who had seemingly typical skin and mucosal changes, as well as pancytopenia. His sister had poikiloderma and oral leukoplakia, progressing to squamous carcinoma fatal at age 24 years. Sorrow and Hitch (1963) described a female patient with DKC who had fatal cervical and vaginal squamous carcinoma.
Juneja et al. (1987) described an autosomal recessive form of DKC in a brother and sister. The girl, aged 7 years, had pancytopenia. Her fingers and toes were described as dystrophic. She died of generalized infection with Pseudomonas aeruginosa after operation for appendicitis. Her 11-year-old brother had mild thrombocytopenia with abnormally small platelets. T-cell abnormalities were also described.
Drachtman and Alter (1992) found that the clinical phenotype of dyskeratosis congenita varied according to mode of inheritance. They categorized all sporadic male cases and families with multiple male cases as X-linked recessive (DCKX; 305000). Autosomal recessive cases included all sporadic female cases, cases in which both male and female sibs of only 1 generation were affected, and those cases with known parental consanguinity. Families with affected male and female members in consecutive generations were classified as autosomal dominant (127550). X-linked recessive and autosomal recessive cases had a high incidence of nail dystrophy, cutaneous manifestations and leukoplakia, as well as a similar median age (approximately 15 years) at diagnosis and a similar prognosis. Autosomal dominant cases had a milder variant of the syndrome, the median age at diagnosis being 28 years and the median survival longer than 50 years. It is possible that some sporadic female cases categorized as having an autosomal recessive form are, in fact, X-linked recessive carriers.
Elliott et al. (1999) described a 16-year-old woman of Syrian-Arab descent with dyskeratosis congenita, microcephaly, and a purple discoloration of the tongue. The latter findings had been reported in another female patient with DKC (Pai et al., 1989) and may be distinctive features of the autosomal recessive form of the disorder. The findings of an affected brother and parental consanguinity supported the hypothesis of autosomal recessive inheritance. The patient also showed sparse scalp hair and eyelashes, prominent periorbital telangiectasia, bilateral lacrimal duct obstruction, and hypoplastic/dysplastic nails.
Patients with Confirmed NOP10 Gene Mutations
Walne et al. (2007) reported a consanguineous family from Saudi Arabia in which 3 individuals had DKC, diagnosed at ages 16, 20, and 15 years, respectively. All had reticular skin pigmentation over the neck and upper extremities, dystrophic nails, and abnormal dentition. All also had thickening of the skin over the palms and soles. Hypocellular bone marrow with peripheral pancytopenia was only observed in 1 patient, and none had leukoplakia. Cellular studies showed significant telomere shortening and reduced levels of TERC (602322). The heterozygous parents were unaffected, but also had telomere lengths that were statistically lower than normal.
Evidence for autosomal recessive inheritance of dyskeratosis congenita comes from the finding of parental consanguinity in affected families and affected sibs (Costello and Buncke, 1956; Fudenberg et al., 1979; Juneja et al., 1987). Pai et al. (1989) described a sporadic female case and reviewed other reported cases in females, indicating autosomal inheritance.
By homozygosity mapping in 16 consanguineous families with dyskeratosis congenita, Walne et al. (2007) found evidence of heterogeneity. By linkage analysis in one Saudi family, they found a maximum lod score of 2.7 for linkage to chromosome 15q14.
In all 3 affected members of a consanguineous Saudi family with autosomal recessive dyskeratosis congenita linked to chromosome 15, Walne et al. (2007) identified homozygosity for a causative mutation in the NOP10 gene (R34W; 606471.0001). Those affected had significant telomere shortening and reduced telomerase RNA component (TERC; 602322) levels.
Autosomal dominant and X-linked recessive DKC are caused by mutations in genes that are components of H/ACA snoRNP complexes including telomerase. Walne et al. (2007) noted that their finding of mutations in the NOP10 gene in autosomal recessive DKC strengthens the model that defective telomere maintenance is the primary pathology in DKC.
Addison, M., Rice, M. S. The association of dyskeratosis congenita and Fanconi's anaemia. Med. J. Aust. 1: 797-799, 1965. [PubMed: 14312691] [Full Text: https://doi.org/10.5694/j.1326-5377.1965.tb72218.x]
Costello, M. J., Buncke, C. M. Dyskeratosis congenita. AMA Arch. Derm. 73: 123-132, 1956. [PubMed: 13282498] [Full Text: https://doi.org/10.1001/archderm.1956.01550020023004]
Drachtman, R. A., Alter, B. P. Dyskeratosis congenita: clinical and genetic heterogeneity: report of a new case and review of the literature. Am. J. Pediat. Hemat. Oncol. 14: 297-304, 1992. [PubMed: 1456394]
Elliott, A. M., Graham, G. E., Bernstein, M., Mazer, B., Teebi, A. S. Dyskeratosis congenita: an autosomal recessive variant. Am. J. Med. Genet. 83: 178-182, 1999. [PubMed: 10096592] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990319)83:3<178::aid-ajmg6>3.0.co;2-3]
Fudenberg, H. H., Goust, J. M., Vesole, D. H., Salinas, C. F. Active and suppressor T cells: diminution in a patient with dyskeratosis congenita and in first-degree relatives. Gerontology 25: 231-237, 1979. [PubMed: 313356] [Full Text: https://doi.org/10.1159/000212345]
Juneja, H. S., Elder, F. F. B., Gardner, F. H. Abnormality of platelet size and T-lymphocyte proliferation in an autosomal recessive form of dyskeratosis congenita. Europ. J. Haemat. 39: 306-310, 1987. [PubMed: 3500870] [Full Text: https://doi.org/10.1111/j.1600-0609.1987.tb00774.x]
Kirwan, M., Dokal, I. Dyskeratosis congenita: a genetic disorder of many faces. Clin. Genet. 73: 103-112, 2008. [PubMed: 18005359] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00923.x]
Pai, G. S., Morgan, S., Whetsell, C. Etiologic heterogeneity in dyskeratosis congenita. Am. J. Med. Genet. 32: 63-66, 1989. [PubMed: 2705484] [Full Text: https://doi.org/10.1002/ajmg.1320320114]
Sorrow, J. M., Jr., Hitch, J. M. Dyskeratosis congenita: first report of its occurrence in a female and a review of the literature. Arch. Derm. 88: 340-347, 1963. [PubMed: 14043629] [Full Text: https://doi.org/10.1001/archderm.1963.01590210098015]
Walne, A. J., Vulliamy, T., Marrone, A., Beswick, R., Kirwan, M., Masunari, Y., Al Qurashi, F., Aljurf, M., Dokal, I. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum. Molec. Genet. 16: 1619-1629, 2007. [PubMed: 17507419] [Full Text: https://doi.org/10.1093/hmg/ddm111]