Dyskeratosis congenita

from Wikipedia, the free encyclopedia
Classification according to ICD-10
Q82.8 Other specified congenital skin malformations
ICD-10 online (WHO version 2019)

The dyskeratosis congenita (DC, DKC, Zinsser-Cole-Engman syndrome ) is a more relevant organ systems inherited disease that typically on skin and mucous membranes with symptoms abnormal skin pigmentation , nail dystrophy and leukoplakia shows.

Dyskeratosis congenita is clinically and genetically very heterogeneous . The symptoms usually appear in childhood, but the age at the onset of the disease varies greatly. Other anomalies were reported: dental anomalies , anomalies on the gastrointestinal tract , the urogenital system , premature graying , Hypotrichose , immune deficiencies , neurological disorders, ophthalmic disorders, lung nstörungen, skeletal disorders. Myelosuppression , a tendency to develop malignancies, and fatal respiratory complications are the leading causes of early mortality .

distribution

The exact prevalence of congenital dyskeratosis is unknown; it is estimated to be around 1 in 1 million.

root cause

The DC is genetically very heterogeneous . A distinction is made between X-linked recessive , autosomal dominant and autosomal recessive forms.

Two genes mutated in subtypes of DC ( DKC1 and TERC ) code for parts of the telomerase complex. A disturbed function of the telomerase is assumed to be the main cause of DC. The identification of DKC1 mutations in patients with Hoyeraal-Hreidarsson syndrome and of TERC mutations in some patients with aplastic anemia (AA) and myelodysplasia have expanded the spectrum of disorders associated with DC.

Other genes affected are TERT and TINF2 , which also code for proteins of the telomerase complex. Disturbances from TERC , TERT , DKC1 and TINF2 account for about half of all cases of DC. In a small proportion of patients, disorders in other genes that code for proteins of the telomerase complex ( CTC1 , NHP2 , NOP10 , RTEL1 , WRAP53 ) have been identified. In many patients, no disorder can be identified in any of these genes, but a relationship with telomerase is likely.

The gene and gene mutation database Online Mendelian Inheritance in Man (OMIM) distinguishes between the following variants (as of 2014):

abbreviation Inheritance Synonym (s) affected gene Gene locus First describer Link to OMIM
DKCX X-linked Zinsser-Cole-Engman syndrome DKC1 X q28 Milgrom et al. 1964 305000
DKCA1 autosomal dominant Scoggins type TERC 3 q26.2 Scoggins et al. 1971 127550
DKCA2 autosomal dominant - TERT 5 p15.33 Armanios et al. 2005 613989
DKCA3 autosomal dominant - TINF2 14 q12 Savage et al. 2008 613990
DKCA4 autosomal dominant - RTEL1 20 q13.33 Ballew et al. 2013 615190
DKCB1 autosomal recessive - NOLA3 15 q14 Sorrow et al. 1963 224230
DKCB2 autosomal recessive - NOLA2 5 q35.3 Vulliamy et al. 2008 613987
DKCB3 autosomal recessive - WRAP53 17 p13.3 Zhong et al. 2011 613988
DKCB4 autosomal recessive - TERT 5 p15.33 Basel-Vanagaite et al. 2008 613989
DKCB5 autosomal recessive - RTEL1 20 q13.33 Lamm et al. 2009 615190

Clinical manifestations

The clinical picture of congenital dyskeratosis can vary widely. In the smallest forms, there are only minor external abnormalities with normal bone marrow function . In more severely affected individuals, there are numerous physical changes and possibly threatening symptoms such as bone marrow depression , cancer or pulmonary fibrosis even in early childhood .

Three symptoms are characteristic: poorly growing and abnormally shaped fingernails and toenails ( nail dystrophy ), changes in the color of the skin ( skin pigmentation ), especially on the neck and chest, and whitish spots on the oral mucosa ( leukoplakia ).

Various manifestations of DC can be life threatening. These include in particular disorders of the bone marrow function such as bone marrow depression , aplastic anemia , myelodysplastic syndrome and leukemia . Other cancers are also common, including head and neck cancer , anal carcinoma and malignant tumors of the genital organs . The development of pulmonary fibrosis is also one of the potentially fatal complications of DC.

Other anomalies that have been reported include dental abnormalities , abnormalities in the gastrointestinal tract (e.g. liver disease), urogenital system ( urethral stricture with subsequent urinary tract infections ), premature graying ( canities praematura ), hair loss ( hypotrichosis ), immune defects , neurological Disorders, ophthalmological disorders (narrowing or occlusion of the tear ducts ), lung malformations , skeletal disorders ( osteoporosis , femoral head necrosis , aseptic bone necrosis of the humerus head ).

Most people with congenital dyskeratosis have normal intelligence and normal development of motor skills such as standing or walking. In severely affected individuals, however, developmental retardation can occur. In the severe form of Hoyeraal-Hreidaarsson syndrome, there is an unusually small and underdeveloped cerebellum with corresponding motor defects. The severe form of Revesz syndrome involves disorders of the retina of the eye.

treatment

The relationships between dyskeratosis congenita, aplastic anemia, and telomerase defect suggest that DC and AA patients, for whom conventional therapy is ineffective, could benefit from correction of the telomerase defect. A stem cell transplant with less intensive accompanying therapy ( conditioning ) may be the only cure for patients with bone marrow depression.

prevention

If a DKC1 or TERC mutation has been identified in a family, prenatal diagnosis is possible.

Web links

Individual evidence

  1. ↑ Related Genes to dyskeratosis congenita at Genetics Home Reference (ghr.nlm.nih.gov); Retrieved April 8, 2014.
  2. ↑ H. MILGROM, HL STOLL, JT CRISSEY: DYSKERATOSIS CONGENITA. A CASE WITH NEW FEATURES. In: Archives of Dermatology . Volume 89, March 1964, pp. 345-349, ISSN  0003-987X . PMID 14096348 .
  3. ↑ RB Scoggins, KJ Prescott, GH Asher, WK Blaylock, RW Bright: Dyskeratosis congenita with Fanconi-type anemia: investigations of immunologic and other defects. (Abstract) In: Clin. Res. 1971; 19, p. 409.
  4. ↑ M. Armanios, JL Chen, YP Chang, RA Brodsky, A. Hawkins, CA Griffin, JR Eshleman, AR Cohen, A. Chakravarti, A. Hamosh, CW Greider: Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. In: Proceedings of the National Academy of Sciences . Volume 102, Number 44, November 2005, pp. 15960-15964, ISSN  0027-8424 . doi: 10.1073 / pnas.0508124102 . PMID 16247010 . PMC 1276104 (free full text).
  5. ↑ SA Savage, N. Giri, GM Baerlocher, N. Orr, PM Lansdorp, BP Alter: TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. In: American Journal of Human Genetics . Volume 82, Number 2, February 2008, pp. 501-509, ISSN  1537-6605 . doi: 10.1016 / j.ajhg.2007.10.004 . PMID 18252230 . PMC 2427222 (free full text).
  6. ↑ BJ Ballew, M. Yeager, K. Jacobs, N. Giri, J. Boland, L. Burdett, BP Alter, SA Savage: Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. In: Human genetics. Volume 132, Number 4, April 2013, pp. 473-480, ISSN  1432-1203 . doi: 10.1007 / s00439-013-1265-8 . PMID 23329068 . PMC 3600110 (free full text).
  7. ↑ JM SORROW, JM HITCH: DYSKERATOSIS CONGENITA. FIRST REPORT OF ITS OCCURRENCE IN A FEMALE AND A REVIEW OF THE LITERATURE. In: Archives of dermatology. Volume 88, September 1963, pp. 340-347, ISSN  0003-987X . PMID 14043629 .
  8. ^ T. Vulliamy, R. Beswick, M. Kirwan, A. Marrone, M. Digweed, A. Walne, I. Dokal: Mutations in the telomerase component NHP2 cause the premature aging syndrome dyskeratosis congenita. In: Proceedings of the National Academy of Sciences . Volume 105, Number 23, June 2008, pp. 8073-8078, ISSN  1091-6490 . doi: 10.1073 / pnas.0800042105 . PMID 18523010 . PMC 2430361 (free full text).
  9. ↑ F. Zhong, SA Savage, M. Shkreli, N. Giri, L. Jessop, T. Myers, R. Chen, BP Alter, SE Artandi: Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. In: Genes & development. Volume 25, Number 1, January 2011, pp. 11-16, ISSN  1549-5477 . doi: 10.1101 / gad.2006411 . PMID 21205863 . PMC 3012932 (free full text).
  10. ↑ L. Basel-Vanagaite, I. Dokal, H. Tamary, A. Avigdor, BZ Garty, A. Volkov, T. Vulliamy: Expanding the clinical phenotype of autosomal dominant dyskeratosis congenita caused by TERT mutations. In: Haematologica. Volume 93, Number 6, June 2008, pp. 943-944, ISSN  1592-8721 . doi: 10.3324 / haematol.12317 . PMID 18460650 .
  11. ↑ N. Lamm, E. Ordan, R. Shponkin, C. Richler, M. Aker, Y. Tzfati: Diminished telomeric 3 'overhangs are associated with telomere dysfunction in Hoyeraal-Hreidarsson syndrome. In: PloS one. Volume 4, number 5, 2009, p. E5666, ISSN  1932-6203 . doi: 10.1371 / journal.pone.0005666 . PMID 19461895 . PMC 2680952 (free full text).