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Dyskeratosis congenita and other short telomere syndromes

Timothy S Olson, MD, PhD
Section Editor
Donald H Mahoney, Jr, MD
Deputy Editor
Alan G Rosmarin, MD


Dyskeratosis congenita (DC) is an inherited disorder characterized by bone marrow failure, cancer predisposition, and additional somatic abnormalities. DC and related short telomere syndromes are caused by mutations that interfere with normal maintenance of telomeres, the regions at the ends of the chromosomes that protect nucleated cells from the loss or gain of genetic material.

This topic discusses the evaluation, diagnosis, and management of DC and related short telomere syndromes.

Other inherited bone marrow failure syndromes including Fanconi anemia (FA), Shwachman-Diamond syndrome (SDS), Diamond-Blackfan anemia (DBA), congenital amegakaryocytic thrombocytopenia (CAMT), and a general approach to the diagnostic evaluation of unexplained bone marrow failure are presented separately.

FA – (See "Clinical manifestations and diagnosis of Fanconi anemia" and "Management and prognosis of Fanconi anemia".)

SDS – (See "Shwachman-Diamond syndrome".)

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Literature review current through: Dec 2017. | This topic last updated: Nov 03, 2017.
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  1. Barbaro PM, Ziegler DS, Reddel RR. The wide-ranging clinical implications of the short telomere syndromes. Intern Med J 2016; 46:393.
  2. Makarov VL, Hirose Y, Langmore JP. Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell 1997; 88:657.
  3. Aubert G, Baerlocher GM, Vulto I, et al. Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes. PLoS Genet 2012; 8:e1002696.
  4. Alter BP, Baerlocher GM, Savage SA, et al. Very short telomere length by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood 2007; 110:1439.
  5. Lansdorp PM. Telomeres, stem cells, and hematology. Blood 2008; 111:1759.
  6. Allsopp RC, Morin GB, DePinho R, et al. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 2003; 102:517.
  7. Goldman FD, Aubert G, Klingelhutz AJ, et al. Characterization of primitive hematopoietic cells from patients with dyskeratosis congenita. Blood 2008; 111:4523.
  8. Bertuch AA. The molecular genetics of the telomere biology disorders. RNA Biol 2016; 13:696.
  9. Stanley SE, Gable DL, Wagner CL, et al. Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. Sci Transl Med 2016; 8:351ra107.
  10. Venteicher AS, Abreu EB, Meng Z, et al. A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science 2009; 323:644.
  11. Zhong F, Savage SA, Shkreli M, et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev 2011; 25:11.
  12. Nandakumar J, Bell CF, Weidenfeld I, et al. The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. Nature 2012; 492:285.
  13. Tummala H, Walne A, Collopy L, et al. Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. J Clin Invest 2015; 125:2151.
  14. Townsley DM, Dumitriu B, Liu D, et al. Danazol Treatment for Telomere Diseases. N Engl J Med 2016; 374:1922.
  15. Vulliamy T, Marrone A, Szydlo R, et al. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 2004; 36:447.
  16. Armanios M, Chen JL, Chang YP, et al. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A 2005; 102:15960.
  17. Dokal I. Dyskeratosis congenita. Hematology Am Soc Hematol Educ Program 2011; 2011:480.
  18. Nelson ND, Bertuch AA. Dyskeratosis congenita as a disorder of telomere maintenance. Mutat Res 2012; 730:43.
  19. Alter BP, Rosenberg PS, Giri N, et al. Telomere length is associated with disease severity and declines with age in dyskeratosis congenita. Haematologica 2012; 97:353.
  20. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Rev 2010; 24:101.
  21. Jones M, Bisht K, Savage SA, et al. The shelterin complex and hematopoiesis. J Clin Invest 2016; 126:1621.
  22. Ojha J, Codd V, Nelson CP, et al. Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia. Cancer Epidemiol Biomarkers Prev 2016; 25:1043.
  23. Ballew BJ, Yeager M, Jacobs K, et al. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum Genet 2013; 132:473.
  24. Simon AJ, Lev A, Zhang Y, et al. Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. J Exp Med 2016; 213:1429.
  25. Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 2007; 356:1317.
  26. Parry EM, Alder JK, Qi X, et al. Syndrome complex of bone marrow failure and pulmonary fibrosis predicts germline defects in telomerase. Blood 2011; 117:5607.
  27. Glousker G, Touzot F, Revy P, et al. Unraveling the pathogenesis of Hoyeraal-Hreidarsson syndrome, a complex telomere biology disorder. Br J Haematol 2015; 170:457.
  28. Vulliamy TJ, Marrone A, Knight SW, et al. Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood 2006; 107:2680.
  29. Savage SA, Stewart BJ, Weksler BB, et al. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis 2006; 37:134.
  30. Vulliamy T, Marrone A, Goldman F, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 2001; 413:432.
  31. Xin ZT, Beauchamp AD, Calado RT, et al. Functional characterization of natural telomerase mutations found in patients with hematologic disorders. Blood 2007; 109:524.
  32. Walne AJ, Vulliamy T, Beswick R, et al. TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood 2008; 112:3594.
  33. Savage SA, Giri N, Baerlocher GM, et al. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet 2008; 82:501.
  34. Guo Y, Kartawinata M, Li J, et al. Inherited bone marrow failure associated with germline mutation of ACD, the gene encoding telomere protein TPP1. Blood 2014; 124:2767.
  35. Kocak H, Ballew BJ, Bisht K, et al. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. Genes Dev 2014; 28:2090.
  36. Marrone A, Walne A, Tamary H, et al. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood 2007; 110:4198.
  37. Gramatges MM, Qi X, Sasa GS, et al. A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome. Blood 2013; 121:3586.
  38. Walne AJ, Vulliamy T, Marrone A, 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; 16:1619.
  39. Vulliamy T, Beswick R, Kirwan M, et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci U S A 2008; 105:8073.
  40. Heiss NS, Knight SW, Vulliamy TJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998; 19:32.
  41. Vulliamy TJ, Knight SW, Dokal I, Mason PJ. Skewed X-inactivation in carriers of X-linked dyskeratosis congenita. Blood 1997; 90:2213.
  42. Alder JK, Parry EM, Yegnasubramanian S, et al. Telomere phenotypes in females with heterozygous mutations in the dyskeratosis congenita 1 (DKC1) gene. Hum Mutat 2013; 34:1481.
  43. https://www.dcoutreach.org/ (Accessed on March 16, 2017).
  44. Gorgy AI, Jonassaint NL, Stanley SE, et al. Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders. Chest 2015; 148:1019.
  45. Kannengiesser C, Borie R, Ménard C, et al. Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis. Eur Respir J 2015; 46:474.
  46. Fedick AM, Shi L, Jalas C, et al. Carrier screening of RTEL1 mutations in the Ashkenazi Jewish population. Clin Genet 2015; 88:177.
  47. Kirwan M, Dokal I. Dyskeratosis congenita: a genetic disorder of many faces. Clin Genet 2008; 73:103.
  48. Dyskeratosis Congenita and Telomere Biology Disorders: Diagnosis and Management Guidelines, 1st edition, Savage SA, Cook EF. (Eds), Dyskeratosis Congenita Outreach, Inc, 2015. (Available online at www.dcoutreach.org/guidelines)
  49. Tsilou ET, Giri N, Weinstein S, et al. Ocular and orbital manifestations of the inherited bone marrow failure syndromes: Fanconi anemia and dyskeratosis congenita. Ophthalmology 2010; 117:615.
  50. Giri N, Lee R, Faro A, et al. Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review. BMC Blood Disord 2011; 11:3.
  51. Atkinson JC, Harvey KE, Domingo DL, et al. Oral and dental phenotype of dyskeratosis congenita. Oral Dis 2008; 14:419.
  52. Jyonouchi 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; 22:313.
  53. Jonassaint NL, Guo N, Califano JA, et al. The gastrointestinal manifestations of telomere-mediated disease. Aging Cell 2013; 12:319.
  54. Savage SA. Dyskeratosis Congenita. 2009 Nov 12 [Updated 2016 May 26]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/sites/books/NBK22301/
  55. Kelmenson DA, Hanley M. Dyskeratosis Congenita. N Engl J Med 2017; 376:1460.
  56. Knight S, Vulliamy T, Copplestone A, et al. Dyskeratosis Congenita (DC) Registry: identification of new features of DC. Br J Haematol 1998; 103:990.
  57. Calado RT. Telomeres in lung diseases. Prog Mol Biol Transl Sci 2014; 125:173.
  58. Petrovski S, Todd JL, Durheim MT, et al. An Exome Sequencing Study to Assess the Role of Rare Genetic Variation in Pulmonary Fibrosis. Am J Respir Crit Care Med 2017; 196:82.
  59. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet 2017.
  60. Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in dyskeratosis congenita. Blood 2009; 113:6549.
  61. Alter BP, Giri N, Savage SA, et al. Malignancies and survival patterns in the National Cancer Institute inherited bone marrow failure syndromes cohort study. Br J Haematol 2010; 150:179.
  62. Alter BP, Savage SA. Cancer in Dyskeratosis Congenita. In: Dyskeratosis Congenita and Telomere Biology Disorders: Diagnosis and Management Guidelines, 1st edition, Savage SA, Cook EF (Eds), Dyskeratosis Congenita Outreach, Inc, 2015.
  63. Horiguchi N, Kakizaki S, Iizuka K, et al. Hepatic Angiosarcoma with Dyskeratosis Congenita. Intern Med 2015; 54:2867.
  64. Olson TS, Chan ES, Paessler ME, et al. Liver failure due to hepatic angiosarcoma in an adolescent with dyskeratosis congenita. J Pediatr Hematol Oncol 2014; 36:312.
  65. Khincha PP, Savage SA. Neonatal manifestations of inherited bone marrow failure syndromes. Semin Fetal Neonatal Med 2016; 21:57.
  66. Knight SW, Heiss NS, Vulliamy TJ, et al. Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. Br J Haematol 1999; 107:335.
  67. Burris AM, Ballew BJ, Kentosh JB, et al. Hoyeraal-Hreidarsson Syndrome due to PARN Mutations: Fourteen Years of Follow-Up. Pediatr Neurol 2016; 56:62.
  68. Lim BC, Yoo SK, Lee S, et al. Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing. Gene 2014; 546:425.
  69. Crow YJ, McMenamin J, Haenggeli CA, et al. Coats' plus: a progressive familial syndrome of bilateral Coats' disease, characteristic cerebral calcification, leukoencephalopathy, slow pre- and post-natal linear growth and defects of bone marrow and integument. Neuropediatrics 2004; 35:10.
  70. Savage SA. Connecting complex disorders through biology. Nat Genet 2012; 44:238.
  71. Walne AJ, Bhagat T, Kirwan M, et al. Mutations in the telomere capping complex in bone marrow failure and related syndromes. Haematologica 2013; 98:334.
  72. Keller RB, Gagne KE, Usmani GN, et al. CTC1 Mutations in a patient with dyskeratosis congenita. Pediatr Blood Cancer 2012; 59:311.
  73. Dokal I, Vulliamy T, Mason P, Bessler M. Clinical utility gene card for: Dyskeratosis congenita - update 2015. Eur J Hum Genet 2015; 23.
  74. Baerlocher GM, Lansdorp PM. Telomere length measurements in leukocyte subsets by automated multicolor flow-FISH. Cytometry A 2003; 55:1.
  75. Babushok DV, Grignon AL, Li Y, et al. Disrupted lymphocyte homeostasis in hepatitis-associated acquired aplastic anemia is associated with short telomeres. Am J Hematol 2016; 91:243.
  76. Armanios M. Telomeres and age-related disease: how telomere biology informs clinical paradigms. J Clin Invest 2013; 123:996.
  77. Garcia CK, Armanios M. Pulmonary Fibrosis. In: Dyskeratosis Congenita and Telomere Biology Disorders: Diagnosis and Management Guidelines, 1st edition, Savage SA, Cook EF (Eds), Dyskeratosis Congenita Outreach, Inc, 2015.
  78. Kossiva L, Vartzelis G, Harisi M, et al. Too short stature, too many stigmata. BMJ Case Rep 2010; 2010.
  79. Dietz AC, Mehta PA, Vlachos A, et al. Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2017; 23:726.
  80. Dietz AC, Orchard PJ, Baker KS, et al. Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita. Bone Marrow Transplant 2011; 46:98.
  81. Nishio N, Takahashi Y, Ohashi H, et al. Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita. Pediatr Transplant 2011; 15:161.
  82. Ayas M, Nassar A, Hamidieh AA, et al. Reduced intensity conditioning is effective for hematopoietic SCT in dyskeratosis congenita-related BM failure. Bone Marrow Transplant 2013; 48:1168.
  83. Barbaro P, Vedi A. Survival after Hematopoietic Stem Cell Transplant in Patients with Dyskeratosis Congenita: Systematic Review of the Literature. Biol Blood Marrow Transplant 2016; 22:1152.
  84. Lehmann LE, Williams DA, London WB, et al. Full Donor Myeloid Engraftment with Minimal Toxicity in Dyskeratosis Congenita Patients Undergoing Allogeneic Bone Marrow Transplantation without Radiation or Alkylating Agents. Blood 2014; 124:2941.
  85. https://clinicaltrials.gov/ct2/results?term=NCT01659606 (Accessed on March 22, 2017).
  86. Nambudiri VE, Cowen EW. Dermatologic Manifestations in Dyskeratosis Congenita. In: Dyskeratosis Congenita and Telomere Biology Disorders: Diagnosis and Management Guidelines, 1st edition, Savage SA, Cook EF (Eds), Dyskeratosis Congenita Outreach, Inc, 2015.
  87. Silhan LL, Shah PD, Chambers DC, et al. Lung transplantation in telomerase mutation carriers with pulmonary fibrosis. Eur Respir J 2014; 44:178.
  88. Khincha PP, Wentzensen IM, Giri N, et al. Response to androgen therapy in patients with dyskeratosis congenita. Br J Haematol 2014; 165:349.
  89. Islam A, Rafiq S, Kirwan M, et al. Haematological recovery in dyskeratosis congenita patients treated with danazol. Br J Haematol 2013; 162:854.
  90. Yang TB, Chen Q, Deng JT, et al. Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche. Nat Commun 2017; 8:14766.
  91. Woo DH, Chen Q, Yang TL, et al. Enhancing a Wnt-Telomere Feedback Loop Restores Intestinal Stem Cell Function in a Human Organotypic Model of Dyskeratosis Congenita. Cell Stem Cell 2016; 19:397.
  92. Gu BW, Apicella M, Mills J, et al. Impaired Telomere Maintenance and Decreased Canonical WNT Signaling but Normal Ribosome Biogenesis in Induced Pluripotent Stem Cells from X-Linked Dyskeratosis Congenita Patients. PLoS One 2015; 10:e0127414.
  93. Jäger K, Walter M. Therapeutic Targeting of Telomerase. Genes (Basel) 2016; 7.