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| {{Infobox Disease | | __NOTOC__ |
| | Name = Dyskeratosis congenita
| | {{Dyskeratosis congenita}} |
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| | '''For patient information, click [[Dyskeratosis congenita (patient information)|here]].''' |
| | Caption =
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| | DiseasesDB = 30105
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| | ICD10 = {{ICD10|Q|82|8|q|80}}
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| | ICD9 = {{ICD9|757.39}} | |
| | ICDO =
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| | OMIM = 305000
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| | MedlinePlus =
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| | eMedicineSubj = derm
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| | eMedicineTopic = 111
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| | MeshID = D019871
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| {{CMG}} {{AE}} {{RT}} | | {{CMG}} {{AE}} {{RT}} |
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| | {{SK}} Cole-Rauschkolb-Toomey syndrome; DKCX; X-linked dyskeratosis congenita; Zinsser-Cole-Engman syndrome; Zinsser-Engman-Cole syndrome |
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| | ==[[Dyskeratosis congenita overview|Overview]]== |
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| | ==[[Dyskeratosis congenita historical perspective|Historical Perspective]]== |
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| | ==[[Dyskeratosis congenita classification|Classification]]== |
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| | ==[[Dyskeratosis congenita pathophysiology|Pathophysiology]]== |
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| | ==[[Dyskeratosis congenita causes| Causes]]== |
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| | ==[[Dyskeratosis congenita differential diagnosis|Differentiating Dyskeratosis Congenita from other Diseases]]== |
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| | ==[[Dyskeratosis congenita epidemiology and demographics|Epidemiology and Demographics]]== |
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| | ==[[Dyskeratosis congenita risk factors|Risk Factors]]== |
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| | ==[[Dyskeratosis congenita screening|Screening]]== |
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| | ==[[Dyskeratosis congenita natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| | ==Diagnosis== |
| | [[Dyskeratosis congenita history and symptoms|History and Symptoms]] | [[Dyskeratosis congenita physical examination|Physical Examination]] | [[Dyskeratosis congenita laboratory findings|Laboratory Findings]] | [[Dyskeratosis congenita electrocardiogram|Electrocardiogram]] | [[Dyskeratosis congenita x ray|X Ray]] | [[Dyskeratosis congenita CT|CT]] | [[Dyskeratosis congenita MRI|MRI]] | [[Dyskeratosis congenita echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Dyskeratosis congenita other imaging findings|Other Imaging Findings]] | [[Dyskeratosis congenita other diagnostic studies|Other Diagnostic Studies]] |
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| | ==Treatment== |
| | [[Dyskeratosis congenita medical therapy|Medical Therapy]] | [[Dyskeratosis congenita surgery|Surgery]] | [[Dyskeratosis congenita primary prevention|Primary Prevention]] | [[Dyskeratosis congenita secondary prevention|Secondary Prevention]] | [[Dyskeratosis congenita cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Dyskeratosis congenita future or investigational therapies|Future or Invesetigational Therapies]] |
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| | ==Case Studies== |
| | [[Dyskeratosis congenita case study one|Case #1]] |
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| | ==External Links== |
| | * [http://www.marrowfailure.cancer.gov/index.html Dyskeratosis Congenita research study of Inherited Bone Marrow Failure Syndromes (IBMFS) ] |
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| ==Overview==
| | {{Congenital malformations and deformations of integument}} |
| '''Dyskeratosis congenita''' (DKC), also called '''Zinsser-Cole-Engman syndrome''',<ref name=omim>{{OMIM|305000}}</ref><ref name="Andrews">James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Saunders. ISBN 0-7216-2921-0.</ref>{{rp|570}} is a rare progressive [[congenital disorder]] that in some ways resembles premature aging (similar to [[progeria]]). The disease mainly affects the [[integumentary system]], the organ system that protects the body from damage, with a major consequence being anomalies of the [[bone marrow]].
| | {{X-linked disorders}} |
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| ==Pathophysiology==
| | [[Category:Disease]] |
| Though the exact pathology of the disease is not yet fully understood, most evidence points to dyskeratosis congenita being primarily a disorder of poor [[telomere]] maintenance.<ref name="pmid11574891">{{cite journal |author=Vulliamy T, Marrone A, Goldman F, "et al." |title=The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. |journal=Nature |volume=413 |issue=6854 |pages=432–435 |year=2001 |month=September |pmid=11574891|url=http://www.nature.com/nature/journal/v413/n6854/full/413432a0.html| doi= 10.1038/35096585}}</ref> Specifically, the disease is related to one or more mutations which directly or indirectly affect the [[vertebrate]] [[telomerase]] RNA component (TERC).
| | [[Category:Rare diseases]] |
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| Telomerase is a [[reverse transcriptase]] which maintains a specific repeat sequence of [[DNA]], the telomere, during development. Telomeres are placed by telomerase on both ends of linear chromosomes as a way to protect linear DNA from general forms of chemical damage and to correct for the chromosomal [[Telomere#Telomere_shortening|end-shortening]] that occurs during normal [[DNA replication]].<ref name="pmid8811183">{{cite journal |author=Greider, CW. |title=Telomere length regulation. |journal=Annu. Rev. Biochem. |volume=65 |pages=337–365 |year=1996|month=May|pmid=8811183|url=http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.bi.65.070196.002005?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dncbi.nlm.nih.gov |doi=10.1146/annurev.bi.65.070196.002005?url_ver=Z39.88-2003}}</ref> This end-shortening is the result of the eukaryotic [[DNA polymerase]]s having no mechanism for synthesizing the final [[nucleotide]]s present on the end of the "lagging strand" of double stranded DNA. DNA polymerase can only synthesize new DNA from an old DNA strand in the 5'->3' direction. Given that DNA has two strands that are complementary, one strand must be 5'->3' while the other is 3'->5'. This inability to synthesize in the 3'->5' directionality is compensated with the use of [[Okazaki fragment]]s, short pieces of DNA that are synthesized 5'->3' from the 3'->5' as the replication fork moves. As DNA polymerase requires [[Primer (molecular biology)|RNA primers]] for DNA binding in order to commence replication, each Okazaki fragment is thus preceded by an RNA primer on the strand being synthesized. When the end of the chromosome is reached, the final RNA primer is placed upon this nucleotide region, and it is inevitably removed. Unfortunately once the primer is removed, DNA polymerase is unable to synthesize the remaining bases.<ref name="pmid8811183" /><ref name="watson">{{cite book |author=Wason, James; et al. |title=Molecular Biology of the Gene. 5th ed |journal=Annu. Rev. Biochem. |publisher=San Francisco: Pearson Education, Inc|year=2004}}</ref>
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| Sufferers of DKC have been shown to have a reduction in TERC levels invariably affecting the normal function of telomerase which maintains these telomeres.<ref name="pmid11574891" /><ref name="pmid17507419">{{cite journal |author=Walne AJ, Vulliamy T, Marrone A, "et al." |title=Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. |journal=Hum Mol Genet. |volume=16 |issue=13 |pages=1619–29 |year=2007 |month=July |pmid=17507419 |url=http://hmg.oxfordjournals.org/cgi/content/full/16/13/1619 |pmc=2882227 |doi=10.1093/hmg/ddm111}}</ref><ref name="pmid9590285">{{cite journal |author=Heiss NS, Knight SW, Vulliamy TJ, "et al." |title=X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. |journal=Nat. Genet.|volume=19 |issue=1 |pages=32–38 |year=1998 |month=May|pmid=9590285|url=http://www.nature.com/ng/journal/v19/n1/abs/ng0598-32.html| doi= 10.1038/ng0598-32}}</ref> With TERC levels down, telomere maintenance during development suffers accordingly. In humans, telomerase is inactive in most cell types after early development (except in extreme cases such as cancer).<ref name="pmid17015423">{{cite journal |author=Wong J, Collins K |title=Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita. |journal=Genes Dev. |volume=20 |pages=2848–2858 |year=2006 |month=October|pmid=17015423 |url=http://genesdev.cshlp.org/content/20/20/2848.long |doi=10.1101/gad.1476206 |issue=20 |pmc=1619937}}</ref> Thus, if telomerase is not able to efficiently affect the DNA in the beginning of life, chromosomal instability becomes a grave possibility in individuals much earlier than would be expected.{{fact|date=July 2012}}
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| A study shows that proliferative defects in DC skin [[keratinocytes]] are corrected by expression of the [[telomerase reverse transcriptase]], TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase [[RNA]] component, TERC. Experimental Dermatology 2010; 19: 279–288<ref>Gourronc, F. A., Robertson, M. M., Herrig, A. K., Lansdorp, P. M., Goldman, F. D. and Klingelhutz, A. J. (2010), [http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0625.2009.00916.x/abstract Proliferative defects in dyskeratosis congenita skin keratinocytes are corrected by expression of the telomerase reverse transcriptase, TERT, or by activation of endogenous telomerase through expression of papillomavirus E6/E7 or the telomerase RNA component, TERC]. Experimental Dermatology, 19: 279–288. {{doi|10.1111/j.1600-0625.2009.00916.x}}</ref>
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