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Dyskeratosis Congenita

  • Author: David T Robles, MD, PhD; Chief Editor: William D James, MD  more...
 
Updated: Jul 10, 2014
 

Background

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]

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Pathophysiology

To date, there are 10 known genes that identify with DKC (DCK1, TERC, TERT, NOP10, NHP2, TINF2, USB1, TCAB1, CTC1, and RTEL1).[3] 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.[6]

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.[15] 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.[16]

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.[17]

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.[18]

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.[21]

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.[6] In addition, revertant mosaicism has been a new recurrent event in DKC.[22]

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Epidemiology

Frequency

International

DKC is estimated to occur in 1 in 1 million people. More than 200 individuals have been reported in the literature.

Mortality/Morbidity

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.

Race

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.

Sex

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

Age

Patients usually present during the first decade of life, with the skin hyperpigmentation and nail changes typically appearing first.

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Contributor Information and Disclosures
Author

David T Robles, MD, PhD Dermatologist, Chaparral Medical Group

David T Robles, MD, PhD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Edward F Chan, MD Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Edward F Chan, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Philip Fleckman, MD Professor, Department of Internal Medicine, Division of Dermatology, University of Washington

Philip 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

Disclosure: Nothing to disclose.

Jacquiline Habashy, MSc Western University of Health Sciences College of Osteopathic Medicine of the Pacific

Jacquiline Habashy, MSc is a member of the following medical societies: American Osteopathic College of Dermatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Richard 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

Richard 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

Disclosure: Nothing to disclose.

Van Perry, MD Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Van Perry, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Jean Paul Ortonne, MD Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France

Jean Paul Ortonne, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Acknowledgements

Jonathan M Olson, MD Fellow, Division of Dermatology, University of Washington Medical Center

Jonathan M Olson, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

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