Does DKC1 Mutation Suffice to Define the Phenotype Severity of Hoyeraal-Hreidarsson Syndrome?


Both dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson Syndrome (HHS) are rare inherited bone marrow failure conditions. HHS is considered to be a variant of DC in which neurological deficits and immunodeficiencies are also present. We describe a very interesting familial cluster where an invariant point mutation of DKC1 located in the exon 11 is observed in the carrier mother and in two decedent males. The older child developed the classical phenotype of HHS at a very early age. The second affected child remains poorly symptomatic, with only mild haematological changes. Telomere shortening, with different severity, is also present in both cases. This paper discusses the clinical spectrum of inherited BM failure syndromes from the perspective different clinical presentation within a family with a DKC1 mutation.

Share and Cite:

E. Valera, M. Brassesco, S. Ferraz, P. Roxo Jr., B. Lemos-Santana, T. Vulliamy, R. Calado, C. Scrideli and L. Tone, "Does DKC1 Mutation Suffice to Define the Phenotype Severity of Hoyeraal-Hreidarsson Syndrome?," Open Journal of Blood Diseases, Vol. 3 No. 1, 2013, pp. 57-61. doi: 10.4236/ojbd.2013.31012.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] T. J. Vulliamy, A. Marrone, S. W. Knight, et al., “Mutations in Dyskeratosis Congenita: Their Impact on Telomere Length and the Diversity of Clinical Presentation,” Blood, Vol. 107, No. 7, 2006, pp. 2680-2685. doi:10.1182/blood-2005-07-2622
[2] R. T. Calado and N. S.Young, “Telomere Maintenance and Human Bone Marrow Failure,” Blood, Vol. 111, No. 9, 2008, pp. 4446-4455. doi:10.1182/blood-2007-08-019729
[3] F. Berthet, R. Caduff, U. B. Schaad, et al., “A Syndrome of Primary Combined Immunodeficiency with Microcephaly, Cerebellar Hypoplasia, Growth Failure and Progressive Pancytopenia,” European Journal of Pediatrics, Vol. 153, No. 5, 1994, pp. 333-338. doi:10.1007/BF01956413
[4] I. Dokal, “Dyskeratosis Congenita,” American Society of Hematology Education Program, Vol. 2011, No. 1, 2011, pp. 480-486.
[5] I. Dokal and T. Vulliamy, “Inherited Bone Marrow Failure Syndromes,” Haematologica, Vol. 95, No. 8, 2010, pp. 1236-1240. doi:10.3324/haematol.2010.025619
[6] B. P. Alter, P. S. Rosenberg, N. Giri, et al., “Telomere Length Is Associated with Disease Severity and Declines with Age in Dyskeratosis Congenita,” Haematologica, Vol. 97, No. 3, 2012, pp. 353-359. doi:10.3324/haematol.2011.055269
[7] E. T. Valera, M. S. Brassesco, P. Roxo Jr., et al., “Genomic Instability in Hoyeraal-Hreidarsson Syndrome,” Pediatric Blood & Cancer, Vol. 54, No. 5, 2010, pp. 779-780. doi:10.1002/pbc.22446
[8] P. Peitl, S. S. Mello, M. L. Camparoto, G. A. Passos, et al., “Chromosomal Rearrangements Involving Telomeric DNA Sequences in Balb/3T3 Cells Transfected with the Ha-ras Oncogene,” Mutagenesis, Vol. 17, No. 1, 2002, pp. 67-72. doi:10.1093/mutage/17.1.67
[9] Y. H. Du, M. Bessler and P. J. Mason, “Telomerase Mutations and Prematures Ageing in Humans,” In: K. L. Rudolph, Telomeres and Telomerase in Ageing, Disease and Cancer: Molecular Mechanisms of Adult Stem Cell Ageing, Springer-Verlag, Berlin, 2008, pp. 77-107. doi:10.1007/978-3-540-73709-4_5
[10] A. Marrone and P. J. Mason, “Dyskeratosis Congenita,” Cellular and Molecular Life Sciences, Vol. 60, 2003, pp. 507-517.
[11] A. Marrone, A. Walne, H. Tamary, et al., “Telomerase Reverse-Transcriptase Homozygous Mutations in Autosomal Recessive Dyskeratosis Congenita and Hoyeraal-Hreidarsson Syndrome,” Blood, Vol. 110, No. 13, 2007, pp. 4198-4205. doi:10.1182/blood-2006-12-062851
[12] H. Yamaguchi, R. T. Calado, H. Ly, et al., “Mutations in TERT, the Gene for Telomerase Reverse Transcriptase, in Aplastic Anemia,” New England Journal of Medicine, Vol. 352, 2005, pp. 1413-1424. doi:10.1056/NEJMoa042980
[13] S. A. Savage and A. A. Bertuch, “The Genetics and Clinical Manifestations of Telomere Biology Disorders,” Genetics in Medicine, Vol. 12, No. 12, 2010, pp. 753-764.
[14] A. J. Walne, T. Vulliamy, A. Marrone, et al., “Genetic Heterogeneity in Autosomal Recessive Dyskeratosis Congenita with One Subtype Due to Mutations in the Telomerase-Associated Protein NOP10,” Human Molecular Genetics, Vol. 16, No. 13, 2007, pp. 1619-1629. doi:10.1093/hmg/ddm111
[15] T. Vulliamy, R. Beswick, M. Kirwan, A. Marrone, et al., “Mutations in the Telomerase Component NHP2 Cause the Premature Ageing Syndrome Dyskeratosis Congenital,” Proceedings of the National Academy Sciences of the USA, Vol. 105, No. 23, 2008, pp. 8073-8078. doi:10.1073/pnas.0800042105
[16] S. A. Savage, N. Giri, G. M. Baerlocher, et al., “TINF2, a Component of the Shelterin Telomere Protection Complex, Is Mutated in Dyskeratosis Congenital,” American Journal of Human Genetics, Vol. 82, No. 2, 2008, pp. 501-509. doi:10.1016/j.ajhg.2007.10.004
[17] F. Touzot, I. Callebaut, J. Soulier, et al., “Function of Apollo (SNM1B) at Telomere Highlighted by a Splice Variant Identified in a Patient with Hoyeraal-Hreidarsson Syndrome,” Proceedings of the National Academy Sciences of the USA, Vol. 107, No. 22, 2010, pp. 10097-10102. doi:10.1073/pnas.0914918107
[18] T. J. Vulliamy, S. W. Knight, P. J. Mason and I. Dokal, “Very Short Telomeres in the Peripheral Blood of Patients with X-Linked and Autosomal Dyskeratosis Congenital,” Blood Cells, Molecules, and Diseases, Vol. 27, No. 2, 2001, pp. 353-357. doi:10.1006/bcmd.2001.0389
[19] B. P. Alter, G. M. Baerlocher, S. A. Savage, et al., “Very Short Telomere Length by Flow Fluorescence in Situ Hybridization Identifies Patients with Dyskeratosis Congenital,” Blood, Vol. 110, No. 5, 2007, pp. 1439-1447. doi:10.1182/blood-2007-02-075598
[20] N. Lamm, E. Ordan, R. Shponkin, et al., “Diminished Telomeric 3’Overhangs Are Associated with Telomere Dysfunction in Hoyeraal-Hreidarsson Syndrome,” PLoS One, Vol. 4, No. 5, 2009, p. e5666. doi:10.1371/journal.pone.0005666

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.