View source for Dyskeratosis congenita

{{Infobox Disease
| Name = Dyskeratosis congenita
| Image = 
| Caption = 
| DiseasesDB = 30105
| ICD10 = {{ICD10|Q|82|8|q|80}}
| ICD9 = {{ICD9|757.39}}
| ICDO = 
| OMIM = 305000
| MedlinePlus = 
| eMedicineSubj = derm
| eMedicineTopic = 
| MeshID = D019871
}}
{{CMG}} ;{{AE}} {{RT}}

'''''Synonyms and keywords''''': Zinsser-Cole-Engman syndrome

==Overview==
'''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]].

==Pathophysiology==
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).

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>

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.

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>

===Genetics===
Of the components of the telomerase RNA component (TERC), one of key importance is the [[SnoRNA#H.2FACA_box|box H/ACA]] domain.  This H/ACA domain is responsible for maturation and stability of TERC and therefore of telomerase as a whole.  The [[mammal]]ian H/ACA [[ribonucleoprotein]] contains four [[protein]] subunits: dyskerin, Gar1, Nop10, and Nhp2. [[Mutation]]s in Nop10,<ref name="pmid17507419" /> Nhp2<ref name="pmid18523010">{{cite journal |author=Vulliamy T, Beswick R, Kirwan M, "et al." |title=Mutations in the telomerase component Nhp2 cause the premature ageing syndrome dyskeratosis congenita. |journal=Proc Natl Acad Sci USA|volume=105 |year=2008 |month=June|pmid=18523010|url=http://www.pnas.org/content/105/23/8073.long |doi=10.1073/pnas.0800042105 |issue=23 |pages=8073–8 |pmc=2430361 }}</ref> and dyskerin1<ref name="pmid9590285" /> have all been shown to lead to DKC-like symptoms.

====Autosomal recessive form====
The true [[phenotype]] of DKC individuals may depend upon which protein has incurred a mutation.  One documented autosomal recessive mutation<ref name="pmid17507419" /> in a family that carries DKC has been found in Nop10. Specifically, the mutation is a change of base from cytosine to thymine in a highly conserved region of the Nop10 sequence.  This mutation, on [[Chromosome 15 (human)|chromosome 15]], results in an [[amino acid]] change from [[arginine]] to [[tryptophan]]. [[Dominance (genetics)#Recessive trait|Homozygous recessive]] individuals show the symptoms of dyskeratosis congenita in full.  As compared to age-matched normal individuals, those suffering from DKC have telomeres of a much shorter length. Furthermore, heterozygotes, those who have one normal [[allele]] and one coding for the disease, also show relatively shortened telomeres.  The cause of this was determined to be a reduction in TERC levels in those with the Nop10 mutation. With TERC levels down, telomere maintenance, especially in development, would be presumed to suffer accordingly. This would lead to the telomere shortening described.<ref name="pmid17507419" />

Nhp2 mutations are similar in characterization to Nop10. These mutations are also autosomal recessive with three specific [[single-nucleotide polymorphism]]s being recognized which result in dyskeratosis congenita.  Also like Nop10, individuals with these Nhp2 mutations have a reduction in the amount of telomerase RNA component (TERC) present in the cell. Again it can be presumed that a reduction in TERC results in aberrant telomere maintenance and thus shortened telomeres.  Those homozygous recessive for mutations in Nhp2 do show shorter telomeres when compared with age-matched normal individuals.<ref name="pmid18523010" />

====X-linked form====
The best characterized form of dyskeratosis congenita is a result of one or more mutations in the long arm of the [[X chromosome]] in the gene DKC1.<ref name="pmid11574891" /><ref name="pmid9590285" />  This results in the X-linked recessive form of the disease wherein the major protein affected is dyskerin. Of the five mutations described by Heiss and colleagues in ''Nature Genetics'',<ref name="pmid9590285" /> four were single nucleotide polymorphisms all resulting in the change of highly [[Conserved sequence|conserved amino acids]].  One case was an in-frame deletion resulting in the loss of a [[leucine]] [[amino acid|residue]], also conserved in mammals.  In three of the cases, the specific amino acids affected ([[phenylalanine]], [[proline]], [[glycine]]) are found in the same [[locus (genetics)|locus]] in humans as they are in yeast (''[[S. Cerevisiae]]'') and the [[brown rat]] (''R. Norvegicus'').<ref name="pmid9590285" />  This establishes the sequence conservation and importance of dyskerin within the eukaryotes.  The relevant nature of dyskerin throughout most species is to catalyze the [[RNA transcription|post-transcriptional]] [[pseudouridine|pseudouridylation]] of specific [[uridine]]s found in non-coding RNAs, such as [[ribosomal RNA]] (rRNA). Cbf5, the yeast analog of human dyskerin, is indeed known to be associated with the processing and maturation of rRNA.<ref name="pmid11574891" />  In humans this role can be attributed to dyskerin.<ref name="pmid9590285" />  Thus, the X-linked form of this disease may result in specific issues related to dysfunctional rRNA and perhaps a graver phenotype.  Within the vertebrates, as opposed to single celled eukaryotes, dyskerin is a key component of the telomerase RNA component (TERC) in the form of the H/ACA motif.<ref name="pmid17015423" />  This X-linked variety, like the Nop10 and Nhp2 mutations, demonstrates shortened telomeres as a result of lower TERC concentrations.

====Autosomal dominant form====
The evidence supporting the importance of the H/ACA domain in human telomerase is abundant.  At least one study<ref name="pmid19095616">{{cite journal |author=Trahan C, Dragon F |title=Dyskeratosis congenita mutations in the H/ACA domain of human telomerase RNA affect its assembly into a pre-RNP. |journal=RNA |volume=15 |issue=2 |pages=235–43 |year=2009 |month=February|pmid=19095616|url=http://rnajournal.cshlp.org/content/15/2/235.long |doi=10.1261/rna.1354009 |pmc=2648702}}</ref> has shown that these mutations affect telomerase activity by negatively affecting pre-RNP assembly and maturation of human telomerase RNA. Nonetheless, mutations which directly affect the telomerase RNA components would presumably exist and should also cause premature aging or DKC-like symptoms.  Indeed, three families with mutations in the human TERC gene have been studied with intriguing results.<ref name="pmid11574891" />  In two of these families, two family-specific single nucleotide polymorphisms were present while in the other there persisted a large-scale deletion (821 base pairs of DNA) on [[Chromosome 3 (human)|chromosome 3]] which includes 74 bases coding for a section of the H/ACA domain.  These three different mutations result in a mild form of dyskeratosis congenita which uniquely follows an autosomal dominant pattern of inheritance.  Premature graying, early dental loss, predisposition to skin cancer, as well as shortening of telomere length continue to be characteristic of this disease.

==Epidemiology and Demographics==
'''Age''': The mucocutaneous features of DKC typically develop between ages 5 and 15 years.  The median age of onset of the peripheral cytopenia is 10 years.

'''Gender''': The male-to-female ratio is approximately 3:1.

==Natural history, Complications and Prognosis==
Prognosis of the disease is poor with a mean survival of 30 years.  Prognosis is worse for X-linked and autosomal recessive forms compared to autosomal dominant form.

Complications include:
* [[Conjunctivitis]], [[blepharitides]], lacrimal duct stenosis, and [[pterygium]]
* [[Mandibular hypoplasia]], [[osteoporosis]], [[avascular necrosis]], and [[scoliosis]].
* [[Cirrhosis]]
* Bone marrow failure - infections, bleeding
* Pulmonary fibrosis
* [[Dysphagia]], [[dysuria]], [[phimosis]], and [[epiphora]] - due to constriction and stenosis can occur at the sites of [[leukoplakia]]
* Increased risk of malignancy - increased prevalence of malignant mucosal neoplasms, particularly squamous cell carcinoma of the mouth, nasopharynx, esophagus, rectum, vagina, or cervix.  These often occur within sites of leukoplakia.  The prevalence of squamous cell carcinoma of the skin is also increased. 
* [[Death]] - due to infections, bleeding

==Diagnosis==
===Symptoms===
Patients with DKC complain of 
* Cutaneous pigmentation - hyper or hypo-pigmentation
* Premature graying of hair
* [[Dystrophy]] of the [[nail (anatomy)|nail]]s - ridging and longitudinal splitting
* [[Leukoplakia]] of the oral mucosa (patches on the tongue and inside the mouth)
* Continuous/excess lacrimation (due to [[atresia]] of the [[lacrimal duct]]s)
* Decreased libido (due to [[testicular atrophy]] in the male carriers).

===Physical Examination===
The triad of reticulated [[hyperpigmentation]] of the skin, [[nail dystrophy]], and [[leukoplakia]] characterizes DKC.  The syndrome is clinically heterogeneous; in addition to the diagnostic mucocutaneous features and [[bone marrow]] failure, affected individuals can have a variety of other clinical features.

'''Skin''':
* Abnormal skin pigmentation - tan-to-gray hyperpigmented or hypopigmented macules and patches in a mottled or reticulated pattern.  Reticulated pigmentation occurs in approximately 90% of patients. 
* Poikilodermatous changes with [[atrophy]] and [[telangiectasia]] are common.
* Alopecia of the scalp, eyebrows, and eyelashes
* Premature graying of the hair
* [[Hyperhidrosis]]
* [[Hyperkeratosis]] of the palms and soles
* [[Adermatoglyphia]] (loss of dermal ridges on fingers and toes).

The cutaneous presentation may clinically and histologically resemble graft versus host disease.  The typical distribution involves the sun-exposed areas, including the upper trunk, neck, and face.

'''Extremities''':
* [[Nail dystrophy]] (ridging and longitudinal splitting) - seen in approximately 90% of patients, with fingernail involvement often preceding toenail involvement.
* Absent nails - in advanced disease.

'''Mucosal findings''':
* Mucosal leukoplakia - occurs in approximately 80% of patients and typically involves the buccal mucosa, tongue, and oropharynx. 
Patients also may have an increased prevalence and severity of periodontal disease.
Other mucosal sites may be involved (e.g., esophagus, urethral meatus, glans penis, lacrimal duct, conjunctiva, vagina, anus). 

'''Respiratory''':
* Rales are heard in those having [[pulmonary fibrosis]].

'''Neurologic''': 
* Low ID
* Patients may have learning difficulties and mental retardation.

'''Eye''': 
* Excessive tearing
* [[Red eyes]]

'''Abdomen''': 
* [[Esophageal webs]]
* [[Hepatosplenomegaly]]

'''Genitourinary system findings:''': 
* [[Hypospastic testes]] (small testis), 
* [[Hypospadias]]
* [[Ureteral stenosis]]

'''Female carriers''': 

Female carries of DKC may have subtle clinical features.  One study showed that 3 of 20 female carriers had clinical features that included a single dystrophic nail, a patch of hypopigmentation, or mild leukoplakia.

===Lab tests===
* Complete blood counts and differential counts
* Stool tests for occult blood
* [[Pulmonary function tests]]

===X-ray===
* X-ray head shows calcification of [[basal ganglia]]
* Chest x-ray for [[pulmonary fibrosis]]

==Treatment==
Recent research has used [[Induced pluripotent stem cell|Induced pluripotent stem cells]] to study the disease mechanisms in humans, and discovered that the repgrogramming of somatic cells restores telomere elongation in dyskeratosis congenita cells despite the genetic lesions that affect telomerase.  The reprogrammed DC cells were able to overcome a critical limitation in [[Telomerase RNA component|TERC]] (Telomerase RNA component) levels and restored function (telomere maintenance and self-renewal).  Therapeutically, methods aimed at increasing TERC expression could prove beneficial in DC patients. <ref name="pmid20164838">{{cite journal | author = Agarwal ''et al'' | title = : Telomere elongation in induced pluripotent stem cells from dyskeratosis congenita patients | journal = Nature | volume = 464 | issue = | pages = 292-296 | year = 2010 | month = | pmid = 20164838 | doi = 10.1038/nature08792 }}</ref>



== References ==
{{reflist|2}}

==External links==
*[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=dkc GeneReviews/NCBI/NIH/UW entry on Dyskeratosis Congenita]
* [http://www.marrowfailure.cancer.gov/index.html Dyskeratosis Congenita research study of Inherited Bone Marrow Failure Syndromes (IBMFS) ]

{{Congenital malformations and deformations of integument}}
{{X-linked disorders}}


[[Category:Disease]]
[[Category:Rare diseases]]



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