Skip to main content

Advertisement

Log in

Clinical and genetic features of dyskeratosis congenita, cryptic dyskeratosis congenita, and Hoyeraal-Hreidarsson syndrome in Japan

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Dyskeratosis congenita (DKC) is an inherited bone marrow failure (BMF) syndrome typified by reticulated skin pigmentation, nail dystrophy, and mucosal leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is considered to be a severe form of DKC. Unconventional forms of DKC, which develop slowly in adulthood but without the physical anomalies characteristic of DKC (cryptic DKC), have been reported. Clinical and genetic features of DKC have been investigated in Caucasian, Black, and Hispanic populations, but not in Asian populations. The present study aimed to determine the clinical and genetic features of DKC, HHS, and cryptic DKC among Japanese patients. We analyzed 16 patients diagnosed with DKC, three patients with HHS, and 15 patients with cryptic DKC. We found that platelet count was significantly more depressed than neutrophil count or hemoglobin value in DKC patients, and identified DKC patients with large deletions in the telomerase reverse transcriptase and cryptic DKC patients with RTEL1 mutations on both alleles. This led to some patients previously considered to have unclassifiable BMF being diagnosed with cDKC through identification of new gene mutations. It thus seems important from a clinical viewpoint to re-examine the clinical characteristics, frequency of genetic mutations, and treatment efficacy in DKC, HHS, and cDKC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Calado RT, Young NS. Telomere maintenance and human bone marrow failure. Blood. 2008;111(9):4446–55.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Walne AJ, Dokal I. Advances in the understanding of dyskeratosis congenita. Br J Haematol. 2009;145(2):164–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009;361(24):2353–65.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Sakaguchi H, Nakanishi K, Kojima S. Inherited bone marrow failure syndromes in 2012. Int J Hematol. 2013;97:20–9.

    Article  PubMed  Google Scholar 

  5. Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet. 1998;19(1):32–8.

    Article  CAS  PubMed  Google Scholar 

  6. Knight SW, Heiss NS, Vulliamy TJ, Greschner S, Stavrides G, Pai GS, et al. X-linked dyskeratosis congenita is predominantly caused by missense mutations in the DKC1 gene. Am J Hum Genet. 1999;65(1):50–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, et al. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature. 2001;413(6854):432–5.

    Article  CAS  PubMed  Google Scholar 

  8. Marrone A, Walne A, Tamary H, Masunari Y, Kirwan M, Beswick R, et al. Telomerase reverse transcriptase homozygous mutations in autosomal recessive dyskeratosis congenital and Hoyeraal-Hreidarsson syndrome. Blood. 2007;110(13):4198–205.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. 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;16(13):1619–29.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Vulliamy T, Beswick R, Kirwan M, Marrone A, Digweed M, Walne A, et al. Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci USA. 2008;105(23):8073–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Savage SA, Giri N, Baerlocher GM, Orr N, Lansdorp PM, Alter BP. TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet. 2008;82(2):501–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Walne AJ, Vulliamy T, Beswick R, Kirwan M, Dokal I. 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(9):3594–600.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Zhong F, Savage SA, Shkreli M, Giri N, Jessop L, Myers T, Chen R, et al. Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. Genes Dev. 2011;25(1):11–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Walne AJ, Vulliamy T, Kirwan M, Plagnol V, Dokal I. Constitutional mutations in RTEL1 cause severe dyskeratosis congenita. Am J Hum Genet. 2013;92(3):448–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Le Guen T, Jullien L, Touzot F, Schertzer M, Gaillard L, Perderiset M, et al. Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability. Hum Mol Genet. 2013;22(16):3239–49.

    Article  PubMed  Google Scholar 

  16. Ballew BJ, Yeager M, Jacobs K, Giri N, Boland J, Burdett L, et al. Germline mutations of regulator of telomere elongation helicase 1, RTEL1, in Dyskeratosis congenita. Hum Genet. 2013;132(4):473–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Ruggero D, Grisendi S, Piazza F, Rego E, Mari F, Rao PH, et al. Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. Science. 2003;299(5604):259–62.

    Article  CAS  PubMed  Google Scholar 

  18. Yamaguchi H. Mutations of telomerase complex genes linked to bone marrow failures. J Nippon Med Sch. 2007;74(3):202–9.

    Article  CAS  PubMed  Google Scholar 

  19. Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS, et al. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet. 2003;362:1628–30.

    Article  CAS  PubMed  Google Scholar 

  20. Yamaguchi H, Baerlocher GM, Lansdorp PM, Chanock SJ, Nunez O, Sloand E, et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood. 2003;102(3):916–8.

    Article  CAS  PubMed  Google Scholar 

  21. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005;352(14):1413–24.

    Article  CAS  PubMed  Google Scholar 

  22. Vulliamy TJ, Walne A, Baskaradas A, Mason PJ, Marrone A, Dokal I. Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure. Blood Cells Mol Dis. 2005;34(3):257–63.

    Article  CAS  PubMed  Google Scholar 

  23. Liang J, Yagasaki H, Kamachi Y, Hama A, Matsumoto K, Kato K, et al. Mutations in telomerase catalytic protein in Japanese children with aplastic anemia. Haematologica. 2006;91(5):656–8.

    CAS  PubMed  Google Scholar 

  24. Takeuchi J, Ly H, Yamaguchi H, Carroll KA, Kosaka F, Sawaguchi K, et al. Identification and functional characterization of novel telomerase variant alleles in Japanese patients with bone-marrow failure syndromes. Blood Cells Mol Dis. 2008;40(2):185–91.

    Article  CAS  PubMed  Google Scholar 

  25. Yamaguchi H, Inokuchi K, Takeuchi J, Tamai H, Mitamura Y, Kosaka F, et al. Identification of TINF2 gene mutations in adult Japanese patients with acquired bone marrow failure syndromes. Br J Haematol. 2010;150(6):725–7.

    Article  CAS  PubMed  Google Scholar 

  26. Ballew BJ, Savage SA. Updates on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. 2013;6(3):327–37.

    Article  CAS  PubMed  Google Scholar 

  27. Kunishima S, Okuno Y, Yoshida K, Shiraishi Y, Sanada M, Muramatsu H, et al. ACTN1 mutations cause congenital macrothrombocytopenia. Am J Hum Genet. 2013;92(3):431–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Yoshida K, Toki T, Okuno Y, Kanezaki R, Shiraishi Y, Sato-Otsubo A, et al. The landscape of somatic mutations in Down syndrome-related myeloid disorders. Nat Genet. 2013;45(11):1293–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hiroki Yamaguchi.

Ethics declarations

Conflict of interest

The authors reported no potential conflicts of interest.

Additional information

H. Yamaguchi and H. Sakaguchi contributed equally to this work.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamaguchi, H., Sakaguchi, H., Yoshida, K. et al. Clinical and genetic features of dyskeratosis congenita, cryptic dyskeratosis congenita, and Hoyeraal-Hreidarsson syndrome in Japan. Int J Hematol 102, 544–552 (2015). https://doi.org/10.1007/s12185-015-1861-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-015-1861-6

Keywords

Navigation