GTS5:Dyskeratosis congenita (DKC1, TERT, TERC, TINF2, Other IBMFS genes)

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Genetic Tumour Syndromes (Who Classification, 5th ed.)

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WHO Classification of Disease

Structure Disease
Book Genetic Tumour Syndromes (5th ed.)
Category Telomere maintenance
Family Telomere biology disorders
Type Dyskeratosis congenita (DKC1, TERT, TERC, TINF2, Other IBMFS genes)
Subtype(s) N/A

Related Terminology

Acceptable Zinsser-Engman-Cole syndrome; Hoyeraal-Hreidarsson syndrome
Not Recommended N/A

Definition/Description of Disease

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Dyskeratosis Congenita (DC)

Dyskeratosis congenita (DC) is a rare, genetically heterogeneous inherited bone marrow failure syndrome (IBMFS) and a prototypical telomere biology disorder, caused by pathogenic variants in genes involved in telomere maintenance and protection, including DKC1, TERT, TERC, TINF2, and other telomere-associated genes[1][2][3]. These genes encode components of the telomerase complex or proteins required for telomere stabilization, replication, and capping. The fundamental pathogenic mechanism underlying DC is accelerated telomere shortening, resulting from impaired telomerase activity or defective telomere protection. Critically short telomeres lead to chromosomal instability, premature cellular senescence, and apoptosis, particularly affecting tissues with high proliferative demand such as the hematopoietic system, skin, mucosa, lungs, liver, and gastrointestinal tract[2][4]. Clinically, DC is classically defined by a mucocutaneous triad of reticulated skin pigmentation, nail dystrophy, and oral leukoplakia, although this triad may be incomplete or absent, particularly in individuals with adult-onset disease[1]. Progressive bone marrow failure is the most common and life-threatening manifestation and may present as pancytopenia, aplastic anemia, or progress to myelodysplastic syndrome[3][4]. Extra hematopoietic complications are frequent and contribute significantly to morbidity and mortality. These include pulmonary fibrosis, hepatic disease (such as nodular regenerative hyperplasia or cirrhosis), gastrointestinal strictures or enteropathy, immunodeficiency, and reproductive abnormalities[2][5]. Individuals with DC also have a markedly increased risk of malignancy, particularly myelodysplastic syndrome, acute myeloid leukemia, and squamous cell carcinomas of the head and neck and anogenital regions[6][1]. DC demonstrates substantial clinical and genetic heterogeneity, with variable age of onset, disease severity, and organ involvement. Severe childhood onset forms may present early with bone marrow failure and developmental abnormalities, whereas milder adult onset forms may manifest later with isolated pulmonary or hepatic disease[3]. Multiple modes of inheritance have been described, including X-linked recessive (most commonly associated with DKC1), autosomal dominant (e.g., TERT, TERC, TINF2), and autosomal recessive inheritance. In autosomal dominant cases, genetic anticipation has been observed, reflecting progressive telomere shortening across generations[1][2]. DC exists on a clinical spectrum with other telomere biology disorders, including Hoyeraal–Hreidarsson syndrome, underscoring the importance of telomere length testing and comprehensive genetic evaluation in individuals with unexplained bone marrow failure or telomere-associated organ disease[2][4].


Epidemiology/Prevalence

Dyskeratosis congenita (DC) is considered very rare, and its true population prevalence is not well defined, in part because clinical presentation is highly variable and many individuals do not show the classic mucocutaneous triad. GeneReviews notes that the prevalence in the general population is unknown and that, as of 2015, at least ~400 families worldwide were recognized[7]. Orphanet similarly states that prevalence is unknown and highlights that >400 families have been reported globally[8]. Despite uncertainty, multiple clinical resources commonly cite an approximate frequency of ~1 in 1,000,000 for “classic” DC (often described as estimated occurrence rather than a measured prevalence)[9].Importantly, the broader telomere biology disorder (TBD) spectrum (e.g., isolated pulmonary fibrosis, liver disease, or bone marrow failure with very short telomeres) is likely more common than classic DC, with one pediatric center estimating the broader spectrum may affect ~10–100× as many individuals as classic DC[10].Sex distribution can be skewed toward males because the most common historically recognized form involves X-linked DKC1; one clinical summary reports males affected about three times more often than females[11].From a molecular epidemiology standpoint, several resources note that a substantial fraction of diagnosed individuals have pathogenic variants in core genes such as TERT, TERC, DKC1, or TINF2 (with many additional telomere-associated genes also implicated), though the exact gene frequencies vary by cohort, ascertainment, and testing approach[12].

Genetic Abnormalities: Germline

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Gene Genetic Variant or Variant Type Molecular Pathogenesis Inheritance, Penetrance, Expressivity Notes
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~30% penetrant for carriers

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Genetic Abnormalities: Somatic

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Gene Genetic Variant or Variant Type Molecular Pathogenesis Inheritance, Penetrance, Expressivity Notes
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Genes and Main Pathways Involved

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Gene; Genetic Alteration Pathway Pathophysiologic Outcome
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Genetic Diagnostic Testing Methods

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Additional Information

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Links

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References

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  1. ↑ 1.0 1.1 1.2 1.3 Nelson ND, Bertuch AA. Dyskeratosis congenita as a disorder of telomere maintenance. Mutat Res. 2012 Feb 1;730(1-2):43-51. doi: 10.1016/j.mrfmmm.2011.06.008. Epub 2011 Jul 2. PMID: 21745483; PMCID: PMC3208805.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Armanios M. The Role of Telomeres in Human Disease. Annu Rev Genomics Hum Genet. 2022 Aug 31;23:363-381. doi: 10.1146/annurev-genom-010422-091101. Epub 2022 Jun 24. PMID: 35609925; PMCID: PMC10111244.
  3. ↑ 3.0 3.1 3.2 Niewisch MR, Savage SA. An update on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. 2019 Dec;12(12):1037-1052. doi: 10.1080/17474086.2019.1662720. Epub 2019 Sep 10. PMID: 31478401; PMCID: PMC9400112.
  4. ↑ 4.0 4.1 4.2 Dokal I, Vulliamy T. Inherited bone marrow failure syndromes. Haematologica. 2010 Aug;95(8):1236-40. doi: 10.3324/haematol.2010.025619. PMID: 20675743; PMCID: PMC2913069.
  5. ↑ Roka K, Solomou EE, Kattamis A. Telomere biology: from disorders to hematological diseases. Front Oncol. 2023 May 19;13:1167848. doi: 10.3389/fonc.2023.1167848. PMID: 37274248; PMCID: PMC10235513.
  6. ↑ Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018 Jan;103(1):30-39. doi: 10.3324/haematol.2017.178111. Epub 2017 Oct 19. PMID: 29051281; PMCID: PMC5777188.
  7. ↑ Savage SA, Niewisch MR. Dyskeratosis Congenita and Related Telomere Biology Disorders. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025. Updated 2020.
  8. ↑ Orphanet. Dyskeratosis congenita — ORPHA:1775. Orphanet: Rare Disease Database; 2024.
  9. ↑ MedlinePlus Genetics. Dyskeratosis congenita [Internet]. Bethesda (MD): National Library of Medicine (US), Genetics Home Reference; 2024 [cited 2024 Jul 19].
  10. ↑ Boston Children’s Hospital. (2024). Dyskeratosis congenita. Retrieved July 19, 2024
  11. ↑ Dokal I, Vulliamy T. Dyskeratosis congenita and related telomere biology disorders. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025.
  12. ↑ U.S. National Library of Medicine. Dyskeratosis congenita [Internet]. MedlinePlus Genetics; 2024

Notes

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