- Author: David T Robles, MD, PhD; Chief Editor: William D James, MD more...
Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, 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]
To date, there are 10 known genes that identify with DKC (DCK1, TERC, TERT, NOP10, NHP2, TINF2, USB1, TCAB1, CTC1, and RTEL1). 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[4, 5] ; 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.
In 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.[7, 8, 9] 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.[10, 11, 12]
In the autosomal dominant form, mutations in the RNA component of telomerase (TERC) or telomerase reverse transcriptase (TERT) are responsible for disease phenotype.[5, 13, 14]
Defects in the NOP10 gene were found in association with autosomal recessive DKC. 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.
A heterozygous mutation was found on the conserved telomere maintenance component 1 gene (CTC1). This implication is also associated with a pleiotropic syndrome, Coats plus.
Homozygous 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.
Patients with DKC have reduced telomerase activity and abnormally short tracts of telomeric DNA compared with normal controls.[19, 20] 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.
Analysis 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, recent 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. In addition, revertant mosaicism has been a new recurrent event in DKC.
DKC is estimated to occur in 1 in 1 million people. More than 200 individuals have been reported in the literature.
In 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.
No 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.
The male-to-female ratio is approximately 3:1.
Patients usually present during the first decade of life, with the skin hyperpigmentation and nail changes typically appearing first.
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 May. 22(3):313-9. [Medline].
Ballew 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].
Islam 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].
Bessler M, Du HY, Gu B, Mason PJ. Dysfunctional telomeres and dyskeratosis congenita. Haematologica. 2007 Aug. 92(8):1009-12. [Medline].
Garcia CK, Wright WE, Shay JW. Human diseases of telomerase dysfunction: insights into tissue aging. Nucleic Acids Res. 2007. 35(22):7406-16. [Medline].
Touzot 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.
Mason PJ, Wilson DB, Bessler M. Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance. Curr Mol Med. 2005 Mar. 5(2):159-70. [Medline].
Walne AJ, Marrone A, Dokal I. Dyskeratosis congenita: a disorder of defective telomere maintenance?. Int J Hematol. 2005 Oct. 82(3):184-9. [Medline].
Zeng 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].
Allenspach 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].
Brault 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].
Touzot 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].
Marrone 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].
Marrone 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].
Walne 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].
Ruggero 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].
Keller 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].
Ballew 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].
Alter 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].
Gadalla 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].
Alawi 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].
Qureishi 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].
Gleeson 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].
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 Nov. 34(11):1481-5. [Medline]. [Full Text].
Dokal I, Vulliamy T. Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev. 2003 Dec. 17(4):217-25. [Medline].
Field 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].
Alter 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].
Erduran 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].
Giri 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].
Gadalla 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].
Hartman RI, Hill-Kayser CE. Proton therapy and radiation sensitivity in dyskeratosis congenita. J Pediatr Hematol Oncol. 2014 Jan. 36(1):e51-3. [Medline].
Ostronoff 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].
Machado-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].
Serravallo 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].
Bohn 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].
Isoda 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].
Rackley 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].
Holman JD, Dyer JA. Genodermatoses with malignant potential. Curr Opin Pediatr. 2007 Aug. 19(4):446-54. [Medline].
Vulliamy TJ, Marrone A, Knight SW, Walne A, Mason PJ, Dokal I. Mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation. Blood. 2006 Apr 1. 107(7):2680-5. [Medline].