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ERROR: type should be string, got "https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUubWVkc2NhcGUuY29tL2FydGljbGUvMTExMDUxNi1vdmVydmlldw==\nDyskeratosis Congenita\nAuthor: David T Robles, MD, PhD, FAAD; Chief Editor: William D James, MD more...\nSections Dyskeratosis Congenita\nWorkup\nLaboratory Studies\nImaging Studies\nDermoscopic Findings\nHistologic Findings\nMedication Summary\nColony-stimulating factors\nDyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, was first described in 1906. It is a rare, progressive bone marrow failure syndrome characterized by the triad of reticulated skin hyperpigmentation, nail dystrophy, and oral leukoplakia. Evidence exists for telomerase dysfunction, ribosome deficiency, and protein synthesis dysfunction in this disorder. Early mortality is often associated with bone marrow failure, infections, fatal pulmonary complications, or malignancy. [1, 2]\nTo date, there are 14 genes that have been identified with DKC (ACD,DCK1, TERC, TERT, NOP10, NHP2, TINF2, USB1, TCAB1, CTC1, PARN,RTEL1, WRAP53, and C16orf57). [3, 4, 5] DKC is genetically heterogeneous, with X-linked recessive (Mendelian Inheritance in Man [MIM] 305000), autosomal dominant (MIM 127550), and autosomal recessive (MIM 224230) subtypes. DKC is related to telomerase dysfunction [6, 7] ; all genes associated with this syndrome (ie, DKC1, TERT, TERC, NOP10) encode proteins in the telomerase complex responsible for maintaining telomeres at the ends of chromosomes regarding shortening length, protection, and replication. [8]\nIn the X-linked recessive form, the gene defect lies in the DKC1 gene (located at Xq28), which encodes for the protein dyskerin. Dyskerin is composed of 514 amino acids and has a role in ribosomal RNA processing and telomere maintenance. [9, 10, 11] Modification of dyskerin by SUMOylation has been shown to stabilize the protein. In addition, a mutation in the DKC1 gene is also found on exon 15, revealing a duplication, which adds a lysine residue on a polylysine tract on the C-terminus. All in all, there have been over 50 mutations found in DKC1. [12, 13, 14]\nIn the autosomal dominant form, mutations in the RNA component of telomerase (TERC) or telomerase reverse transcriptase (TERT) are responsible for disease phenotype. [7, 15, 16]\nDefects in the NOP10 gene were found in association with autosomal recessive DKC. [17] NOP10 encodes small nucleolar ribonucleoproteins (snoRNP) associated with the telomerase complex. In persons with autosomal dominant DKC and in terc-/- knockout mice, genetic anticipation (ie, increasing severity and/or earlier disease presentation with each successive generation) has been reported. [18]\nA heterozygous mutation was found on the conserved telomere maintenance component 1 gene (CTC1). This implication is also associated with a pleiotropic syndrome, Coats plus. [19]\nHomozygous autosomal recessive mutations in RTEL1 lead to similar phenotypes that parallel with Hoyeraal-Hreidarsson (HH) syndrome. It is associated with short, heterogeneous telomeres. In the presence of functional DNA replication, RTEL1 mutations produce a large amount of extrachromosomal T-circles. Enzymes remove the T-circles and therefore shorten the telomere. RTEL1 has a role in managing DNA damage by increasing sensitivity; therefore, mutations on this gene cause both telomeric and nontelomeric causes of DKC. [20]\nPatients with DKC have reduced telomerase activity and abnormally short tracts of telomeric DNA compared with normal controls. [21, 22] Telomeres are repeat structures found at the ends of chromosomes that function to stabilize chromosomes. With each round of cell division, the length of telomeres is shortened and the enzyme telomerase compensates by maintaining telomere length in germline and stem cells. Because telomeres function to maintain chromosomal stability, telomerase has a critical role in preventing cellular senescence and cancer progression. Rapidly proliferating tissues with the greatest need for telomere maintenance (eg, bone marrow) are at greatest risk for failure. DKC1 has been found to be a direct target of the c-myc oncogene, strengthening the connection between DKC and malignancy. [23]\nAnalysis of 270 families in the DKC registry found that mutations in dyskerin (DKC1), TERT, and TERC only account for 64% of patients, with an additional 1% due to NOP10, suggesting that other genes associated with this syndrome are, as yet, unidentified. In addition to the mutations that directly effect telomere length, studies also indicate that a DKC diagnosis should not be based solely on the length of the telomere, but also the fact that there are defects in telomere replication and protection. [8] In addition, revertant mosaicism has been a new recurrent event in DKC. [24]\nStudies have also shown the significance of DNA methylation. A study in patients with DKC has shown changes in the CpG sites affiliated with the internal promoter region of the PR domain, specifically containing 8 (PRDM8) when compared with healthy control groups. [25]\nDKC is estimated to occur in 1 in 1 million people. More than 200 individuals have been reported in the literature.\nNo racial predilection has been reported. The DKC registry includes patients from all over the world, with families from at least 40 different countries currently in the registry.\nThe male-to-female ratio is approximately 3:1.\nPatients usually present during the first decade of life, with the skin hyperpigmentation and nail changes typically appearing first.\nDKC is a multisystem disorder that carries a poor prognosis (mean survival of 30 y), with most deaths related to infections, bleeding, and malignancy. In the DKC registry, approximately 70% of affected individuals died of bone marrow failure or its complications, and these deaths occurred at a median age of 16 years. Therapeutic interventions are mostly palliative, but BMT and SCT for aplastic anemia have been tried with variable success. Wide variation in clinical phenotype may occur in individuals, suggesting that other genetic or environmental factors may be contributory. The prognosis is worse for the X-linked and autosomal forms compared with the autosomal dominant form.\nHoyeraal-Hreidarsson (HH) syndrome is also associated with mutations in DKC1. Mutations in this gene have been described in patients with HH syndrome, which is characterized by intrauterine growth restriction, microcephaly, mental retardation, cerebellar malformation, and progressive bone marrow failure. Mucosal ulcerations have been found in a few patients, and some authorities hypothesize that HH syndrome may be a severe variant of DKC in which affected individuals die before the development of mucocutaneous findings. One study found that patients with HH syndrome have significantly shorter telomeres than those with the milder form of disease.\nIn addition, studies have also found that not only are shortened telomeres associated with HH syndrome, but more so are telomere dysfunction and telomere protection. [14] The severe neurologic deficits in this severe form point to an important role of the DKC1 gene in brain function.\nThe biology of telomere shortening is not only associated with DKC, but it has comorbid associations with neuropsychiatric conditions. A cohort study with 6 pediatric and 8 adult subjects showed that 83% of the children and 88% of the adult had a comorbid neuropsychiatric condition. These conditions include schizophrenia, anxiety, intellectual disability, attention-deficit/hyperactivity disorder, adjustment disorder, mood disorders, or pervasive developmental disorders. [26]\nMortality/morbidity\nIn an analysis of individuals with DKC, approximately 70% of patients died either directly from bone marrow failure or from its complications at a median age of 16 years. Eleven percent died from sudden pulmonary complications; a further 11% died of pulmonary disease in the bone marrow transplantation (BMT) setting. Seven percent died from malignancy (eg, Hodgkin disease, pancreatic carcinoma). Fatal opportunistic infections such as Pneumocystis carinii pneumonia and cytomegalovirus infection have been reported.\nClinical Presentation\nJyonouchi S, Forbes L, Ruchelli E, Sullivan KE. Dyskeratosis congenita: a combined immunodeficiency with broad clinical spectrum--a single-center pediatric experience. Pediatr Allergy Immunol. 2011 May. 22(3):313-9. [Medline].\nBallew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. 2013 Jun. 6(3):327-37. [Medline].\nIslam A, Rafiq S, Kirwan M, et al. Haematological recovery in dyskeratosis congenita patients treated with danazol. Br J Haematol. 2013 Sep. 162(6):854-6. [Medline].\nPagon RA, Adam MP, Ardinger HH, eds. GeneReviews. Seattle, Wash: University of Washington; 1993-2016.\nKilic SS, Cekic S. Juvenile Idiopathic Inflammatory Myopathy in a Patient With Dyskeratosis Congenita Due to C16orf57 Mutation. J Pediatr Hematol Oncol. 2016 Mar. 38 (2):e75-7. [Medline].\nBessler M, Du HY, Gu B, Mason PJ. Dysfunctional telomeres and dyskeratosis congenita. Haematologica. 2007 Aug. 92(8):1009-12. [Medline].\nGarcia CK, Wright WE, Shay JW. Human diseases of telomerase dysfunction: insights into tissue aging. Nucleic Acids Res. 2007. 35(22):7406-16. [Medline].\nTouzot F, Le Guen T, de Villartay JP, Revy P. Dyskeratosis congenita: short telomeres are not the rule. Science of Medicine. June 2012. 28(6-7):618-24.\nMason PJ, Wilson DB, Bessler M. Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance. Curr Mol Med. 2005 Mar. 5(2):159-70. [Medline].\nWalne AJ, Marrone A, Dokal I. Dyskeratosis congenita: a disorder of defective telomere maintenance?. Int J Hematol. 2005 Oct. 82(3):184-9. [Medline].\nZeng XL, Thumati NR, Fleisig HB, Hukezalie KR, Savage SA, Giri N, et al. The accumulation and not the specific activity of telomerase ribonucleoprotein determines telomere maintenance deficiency in X-linked dyskeratosis congenita. Hum Mol Genet. 2011 Nov 4. [Medline].\nAllenspach EJ, Bellodi C, Jeong D, et al. Common variable immunodeficiency as the initial presentation of dyskeratosis congenita. J Allergy Clin Immunol. 2013 Jul. 132(1):223-6. [Medline].\nBrault ME, Lauzon C, Autexier C. Dyskeratosis congenita mutations in dyskerin SUMOylation consensus sites lead to impaired telomerase RNA accumulation and telomere defects. Hum Mol Genet. 2013 Sep 1. 22(17):3498-507. [Medline].\nTouzot F, Gaillard L, Vasquez N, et al. Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita. J Allergy Clin Immunol. 2012 Feb. 129(2):473-82, 482.e1-3. [Medline].\nMarrone A, Sokhal P, Walne A, Beswick R, Kirwan M, Killick S, et al. Functional characterization of novel telomerase RNA (TERC) mutations in patients with diverse clinical and pathological presentations. Haematologica. 2007 Aug. 92(8):1013-20. [Medline].\nMarrone A, Walne A, Tamary H, Masunari Y, Kirwan M, Beswick R, et al. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood. 2007 Dec 15. 110(13):4198-205. [Medline].\nWalne AJ, Vulliamy T, Marrone A, Beswick R, Kirwan M, Masunari Y, et al. Genetic heterogeneity in autosomal recessive dyskeratosis congenita with one subtype due to mutations in the telomerase-associated protein NOP10. Hum Mol Genet. 2007 Jul 1. 16(13):1619-29. [Medline].\nRuggero D, Grisendi S, Piazza F, Rego E, Mari F, Rao PH. Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science. 2003 Jan 10. 299(5604):259-62. [Medline].\nKeller RB, Gagne KE, Usmani GN, Asdourian GK, Williams DA, Hofmann I, et al. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer. 2012 Aug. 59(2):311-4. [Medline]. [Full Text].\nBallew BJ, Joseph V, De S, et al. A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome. PLoS Genet. 2013 Aug. 9(8):e1003695. [Medline]. [Full Text].\nAlter BP, Rosenberg PS, Giri N, Baerlocher GM, Lansdorp PM, Savage SA. Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica. 2011 Nov 4. [Medline].\nGadalla SM, Katki HA, Shebl FM, Giri N, Alter BP, Savage SA. The Relationship between DNA Methylation and Telomere Length in Dyskeratosis Congenita. Aging Cell. 2011 Oct 8. [Medline].\nAlawi F, Lee MN. DKC1 is a direct and conserved transcriptional target of c-MYC. Biochem Biophys Res Commun. 2007 Nov 3. 362(4):893-8. [Medline].\nJongmans MC, Verwiel ET, Heijdra Y, et al. Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. Am J Hum Genet. 2012 Mar 9. 90(3):426-33. [Medline]. [Full Text].\nWeidner CI, Lin Q, Birkhofer C, Gerstenmaier U, Kaifie A, Kirschner M, et al. DNA methylation in PRDM8 is indicative for dyskeratosis congenita. Oncotarget. 2016 Mar 8. 7 (10):10765-72. [Medline].\nRackley S, Pao M, Seratti GF, et al. Neuropsychiatric conditions among patients with dyskeratosis congenita: a link with telomere biology?. Psychosomatics. 2012 May-Jun. 53(3):230-5. [Medline]. [Full Text].\nQureishi A, Lamyman A, Silva P, Cox G. Posterior pharyngeal wall squamous cell carcinoma arising in a patient with dyskeratosis congenita. J Laryngol Otol. 2012 Dec. 126(12):1299-301. [Medline].\nGleeson M, O'Marcaigh A, Cotter M, Brosnahan D, Vulliamy T, Smith OP. Retinal vasculopathy in autosomal dominant dyskeratosis congenita due to TINF2 mutation. Br J Haematol. 2012 Dec. 159(5):498. [Medline].\nZheng XY, Xu J, Li W, Li SS, Shi CP, Zhao ZY, et al. Frosted Branch Angiitis in Pediatric Dyskeratosis Congenita: A Case Report. Medicine (Baltimore). 2016 Mar. 95 (12):e3106. [Medline].\nOlson TS, Chan ES, Paessler ME, et al. Liver failure due to hepatic angiosarcoma in an adolescent with dyskeratosis congenita. J Pediatr Hematol Oncol. 2014 May. 36(4):312-5. [Medline]. [Full Text].\nCalado RT, Brudno J, Mehta P, Kovacs JJ, Wu C, Zago MA, et al. Constitutional telomerase mutations are genetic risk factors for cirrhosis. Hepatology. 2011 May. 53(5):1600-7. [Medline]. [Full Text].\nKutbay NO, Yurekli BS, Erdemir Z, Karaca E, Unal I, Yaman B, et al. A case of dyskeratosis congenita associated with hypothyroidism and hypogonadism. Hormones (Athens). 2016 Apr. 15 (2):297-9. [Medline].\nAlder JK, Parry EM, Yegnasubramanian S, et al. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. Hum Mutat. 2013 Nov. 34(11):1481-5. [Medline]. [Full Text].\nDokal I, Vulliamy T. Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev. 2003 Dec. 17(4):217-25. [Medline].\nField JJ, Mason PJ, An P, Kasai Y, McLellan M, Jaeger S. Low frequency of telomerase RNA mutations among children with aplastic anemia or myelodysplastic syndrome. J Pediatr Hematol Oncol. 2006 Jul. 28(7):450-3. [Medline].\nAlter BP, Baerlocher GM, Savage SA, Chanock SJ, Weksler BB, Willner JP, et al. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood. 2007 Sep 1. 110(5):1439-47. [Medline].\nDokal I, Vulliamy T, Mason P, Bessler M. Clinical utility gene card for: dyskeratosis congenita. Eur J Hum Genet. 2011 Nov. 19(11):[Medline]. [Full Text].\nGüngör Ş, Erdemir AV, Göncü EK, Gürel MS, Özekinci S. A case of dyskeratosis congenita with dermoscopic and reflectance confocal microscopic features. J Am Acad Dermatol. 2015 Jul. 73 (1):e11-3. [Medline].\nErduran E, Hacisalihoglu S, Ozoran Y. Treatment of dyskeratosis congenita with granulocyte-macrophage colony-stimulating factor and erythropoietin. J Pediatr Hematol Oncol. 2003 Apr. 25(4):333-5. [Medline].\nNelson AS, Marsh RA, Myers KC, Davies SM, Jodele S, O'Brien TA, et al. A Reduced-Intensity Conditioning Regimen for Patients with Dyskeratosis Congenita Undergoing Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2016 May. 22 (5):884-8. [Medline].\nGiri N, Pitel PA, Green D, Alter BP. Splenic peliosis and rupture in patients with dyskeratosis congenita on androgens and granulocyte colony-stimulating factor. Br J Haematol. 2007 Sep. 138(6):815-7. [Medline].\nGadalla SM, Sales-Bonfim C, Carreras J, Alter BP, Antin JH, Ayas M, et al. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Dyskeratosis Congenita. Biol Blood Marrow Transplant. 2013 Jun 8. [Medline].\nHartman RI, Hill-Kayser CE. Proton therapy and radiation sensitivity in dyskeratosis congenita. J Pediatr Hematol Oncol. 2014 Jan. 36(1):e51-3. [Medline].\nOstronoff F, Ostronoff M, Calixto R, Florêncio R, Domingues MC, Souto Maior AP, et al. Fludarabine, cyclophosphamide, and antithymocyte globulin for a patient with dyskeratosis congenita and severe bone marrow failure. Biol Blood Marrow Transplant. 2007 Mar. 13(3):366-8. [Medline].\nMachado-Pinilla R, Carrillo J, Manguan-Garcia C, et al. Defects in mTR stability and telomerase activity produced by the Dkc1 A353V mutation in dyskeratosis congenita are rescued by a peptide from the dyskerin TruB domain. Clin Transl Oncol. 2012 Oct. 14(10):755-63. [Medline]. [Full Text].\nSerravallo M, Jagdeo J, Glick SA, Siegel DM, Brody NI. Sirtuins in dermatology: applications for future research and therapeutics. Arch Dermatol Res. 2013 May. 305(4):269-82. [Medline].\nSinha S, Trivedi V, Krishna A, Rao N. Dyskeratosis congenita- management and review of complications: a case report. Oman Med J. 2013 Jul. 28(4):281-4. [Medline]. [Full Text].\nBohn OL, Whitten J, Spitzer B, et al. Posttransplant lymphoproliferative disorder complicating hematopoietic stem cell transplantation in a patient with dyskeratosis congenita. Int J Surg Pathol. 2013 Oct. 21(5):520-5. [Medline].\nIsoda T, Mitsuiki N, Ohkawa T, et al. Irreversible leukoencephalopathy after reduced-intensity stem cell transplantation in a dyskeratosis congenita patient with TINF2 mutation. J Pediatr Hematol Oncol. 2013 May. 35(4):e178-82. [Medline].\nPenmatsa C, Jampanapalli SR, Bezawada S, Birapu UK, Radharapu VK. Zinsser-Cole-Engman Syndrome: A Rare Case Report. J Clin Diagn Res. 2016 Jun. 10 (6):ZD07-9. [Medline].\nDavid T Robles, MD, PhD, FAAD Director, Dermatology Division, Chaparral Medical Group\nDavid T Robles, MD, PhD, FAAD is a member of the following medical societies: American Academy of Dermatology\nJacquiline Habashy, DO, MSc Resident Physician, Department of Dermatology, Western University of Health Sciences College of Osteopathic Medicine of the Pacific\nJacquiline Habashy, DO, MSc is a member of the following medical societies: American Osteopathic College of Dermatology\nEdward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine\nEdward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology\nRichard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA\nRichard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society\nVan Perry, MD Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio\nVan Perry, MD is a member of the following medical societies: American Academy of Dermatology\nWilliam D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine\nWilliam D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology\nDisclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.\nJean Paul Ortonne, MD Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France\nJean Paul Ortonne, MD is a member of the following medical societies: American Academy of Dermatology\nPhilip Fleckman, MD Professor, Department of Internal Medicine, Division of Dermatology, University of Washington\nPhilip Fleckman, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Phi Beta Kappa, Society for Investigative Dermatology, American Society for Cell Biology\nJonathan M Olson, MD Fellow, Division of Dermatology, University of Washington Medical Center\nJonathan M Olson, MD is a member of the following medical societies: American Medical Association\nencoded search term (Dyskeratosis Congenita) and Dyskeratosis Congenita\nPediatric Myelodysplastic Syndrome\nReperfusion Injury in Stroke\nPrimary Myelofibrosis\nWaldenstrom Macroglobulinemia\nNewsbeat - Stem Cell Research and Cloning\nFirst Worldwide Survey of Hematopoietic Stem Cell Transplantation\nAtopic Dermatitis: Five Promising Targeted Therapies\nTop News From ASH 2019: Slideshow\nAccording to Dermatologists\nCollagen: 'Fountain of Youth' or Edible Hoax?\nEvidence Growing That Eczema Itch More Than Skin Deep\nShingrix for Herpes Zoster: A Review\nSkin, Hair and Nail Supplements\nSunscreen Photoprotection and Vitamin D Status\nNews Stem-Cell Transplant Improves Outcomes of High-Risk Sickle-Cell Disease\nNews Investigated for Manslaughter, 'Disgraced' Surgeon Gets 16 Months\n2001 /viewarticle/909342 Journal Article\nJournal Article Stem Cell Therapies for Alzheimer's Disease: Is It Time?\nJournal Article Cell Therapy for Chronic Stroke"