Other entities represented in this entry:
ORPHA: 1775, 3322; DO: 0070016;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5p15.33 | Dyskeratosis congenita, autosomal dominant 2 | 613989 | Autosomal dominant; Autosomal recessive | 3 | TERT | 187270 |
| 5p15.33 | Dyskeratosis congenita, autosomal recessive 4 | 613989 | Autosomal dominant; Autosomal recessive | 3 | TERT | 187270 |
A number sign (#) is used with this entry because autosomal dominant dyskeratosis congenita-2 (DKCA2) and autosomal recessive dyskeratosis congenita-4 (DKCB4) are caused by heterozygous and homozygous or compound heterozygous mutation, respectively, in the TERT gene (187270) on chromosome 5p15.
Dyskeratosis congenita is a multisystem disorder caused by defective telomere maintenance. Features are variable and include bone marrow failure, pulmonary and liver fibrosis, premature graying of the hair, immunodeficiency, and gastrointestinal disease (Armanios et al., 2005; Jonassaint et al., 2013).
For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).
Armanios et al. (2005) reported a 3-generation family in which at least 6 members had autosomal dominant dyskeratosis congenita without skin manifestations. Common but variable features included gray forelock or premature graying, aplastic anemia, low platelets, osteoporosis, pulmonary fibrosis, liver fibrosis, and abnormal dentition. Anticipation of clinical features was observed, and all affected individuals showed increased frequency of short telomeres compared to unaffected family members. Molecular analysis excluded the TERC gene (602322) and identified a pathogenic heterozygous mutation in the TERT gene (187270.0007).
Basel-Vanagaite et al. (2008) reported an Iraqi Jewish family with autosomal dominant dyskeratosis congenita-2. Affected males presented with thrombocytopenia, and later developed aplastic anemia, premature graying of the hair, and pulmonary and hepatic fibrosis. One patient developed cardiac fibrosis and another developed dilated cardiomyopathy. Anticipation for these features was observed. Whereas all 6 males of the family were severely affected, 2 female mutation carriers had only premature gray hair; however, all mutation carriers had a similar shortening of telomere length.
Jonassaint et al. (2013) identified significant gastrointestinal disease in 6 (16%) of 38 individuals from a registry of patients with short telomere syndromes due to various genetic defects. One of these patients (patient 4) was a 16-year-old girl with DKCA2 due to a heterozygous missense mutation in the TERT gene (V1025F; 187270.0025). In addition to aplastic anemia requiring a bone marrow transplant, she had failure to thrive, early satiety, and watery diarrhea. Upper endoscopy showed inflammatory changes in the esophagus; lower endoscopy was not performed. Her gastrointestinal symptoms progressed after the bone marrow transplant, and she was placed on total parenteral nutrition. Other features in this patient included pulmonary fibrosis and immunodeficiency.
Autosomal Recessive Dyskeratosis Congenita 4
Marrone et al. (2007) reported 2 unrelated patients, both born of consanguineous parents, with autosomal recessive dyskeratosis congenita-4. A 13-year-old Libyan girl had poor growth, bone marrow failure, reticulated pigmentation of the skin, leukoplakia, and nail dysplasia. Her parents had mild manifestations, such as dysplastic toenails and hyperpigmented skin. The second patient was a 3-year-old girl, born of consanguineous Iranian-Jewish parents, who had early bone marrow failure, leukoplakia, failure to thrive, cerebellar hypoplasia, microcephaly, and developmental delay. Telomere lengths were severely shortened in the patient and at the low-normal level in each parent. Marrone et al. (2007) noted that the presence of developmental delay and cerebellar hypoplasia in the second patient was consistent with a clinical diagnosis of Hoyeraal-Hreidarsson syndrome, which is a severe variant of DKC.
Du et al. (2008) reported a 31-year-old Scottish man with DKCB4 who had a severe phenotype, including short stature, elfin appearance, esophageal stricture, leukoplakia of the buccal mucosa, anus, and penis, abnormal pigmentation, hyperkeratosis of his palms, ridged fingernails, avascular necrosis of both hips, tooth loss, chronic diarrhea, learning difficulties, pulmonary infiltrates, and progressive bone marrow failure. Laboratory studies showed very short telomeres, and genetic analysis showed a homozygous mutation in the TERT gene (187270.0014).
Cepni et al. (2022) reported a child, born of Turkish consanguineous parents, who on examination at 9 months of age had microcephaly and dysmorphic facial features including bitemporal narrowing, strabismus, smooth philtrum, and low-set ears. She had a history of anemia starting at 3 months of age. At 18 months of age, severe immunodeficiency was diagnosed. She had short stature, low body weight, and microcephaly. Brain MRI showed cerebral atrophy, pachygyria, and severe cerebellar hypoplasia. She also had developmental delay and was unable to walk, crawl, or talk. She had hematopoietic stem cell transplantation at 23 months of age. She had very short telomeres in lymphocytes and granulocytes, consistent with an infantile telomere biology disorder. Genetic analysis identified a homozygous missense mutation in the TERT gene (R671W; 187270.0024). Her father, mother, and maternal grandfather, who were mutation carriers, had premature graying of the hair and short or very short telomeres of their lymphocytes and granulocytes.
Batista et al. (2011) showed that even in the undifferentiated state, induced pluripotent stem cells (iPSCs) from dyskeratosis congenita patients harbor the precise biochemical defects characteristic of each form of the disease and that the magnitude of the telomere maintenance defect in iPSCs correlates with clinical severity. In iPSCs from patients with heterozygous mutations in TERT, the telomerase reverse transcriptase, a 50% reduction in telomerase levels blunts the natural telomere elongation that accompanies reprogramming. In contrast, mutation of dyskerin (DKC1; 300126) in X-linked dyskeratosis congenita severely impairs telomerase activity by blocking telomerase assembly and disrupts telomere elongation during reprogramming. In iPSCs from a form of dyskeratosis congenita caused by mutations in TCAB1 (also known as WRAP53, 612661), telomerase catalytic activity is unperturbed, yet the ability of telomerase to lengthen telomeres is abrogated, since telomerase mislocalizes from Cajal bodies to nucleoli within the iPSCs. Extended culture of DKC1-mutant iPSCs leads to progressive telomere shortening and eventual loss of self-renewal, indicating that a similar process occurs in tissue stem cells in dyskeratosis congenita patients. Their findings in iPSCs from dyskeratosis congenita patients led Batista et al. (2011) to conclude that undifferentiated iPSCs accurately recapitulate features of a human stem cell disease and may serve as a cell culture-based system for the development of targeted therapeutics.
In all 6 affected members of a family with autosomal dominant dyskeratosis congenita, Armanios et al. (2005) identified a heterozygous mutation in the TERT gene (K902N; 187270.0007).
In affected members of an Iraqi Jewish family with DKCA2, Basel-Vanagaite et al. (2008) identified a heterozygous mutation in the TERT gene (R631Q; 187270.0011).
Autosomal Recessive Dyskeratosis Congenita 4
Marrone et al. (2007) identified homozygous TERT mutations (187270.0012 and 187270.0013) in patients with a severe form of autosomal recessive dyskeratosis congenita-4.
In a Turkish child, born to consanguineous parents, with DKCB4, Cepni et al. (2022) identified a homozygous missense mutation (R671W; 187270.0024) in the TERT gene. The mutation, which was found by trio whole-exome sequencing, was present in heterozygous state in both parents and multiple other maternal and paternal family members. The patient's father, mother, and carrier maternal grandfather had short telomeres in lymphocytes and granulocytes, and all 3 had premature graying of the hair.
Armanios, M., Chen, J.-L., Chang, Y.-P. C., Brodsky, R. A., Hawkins, A., Griffin, C. A., Eshleman, J. R., Cohen, A. R., Chakravarti, A., Hamosh, A., Greider, C. W. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc. Nat. Acad. Sci. 102: 15960-15964, 2005. [PubMed: 16247010] [Full Text: https://doi.org/10.1073/pnas.0508124102]
Basel-Vanagaite, L., Dokal, I., Tamary, H., Avigdor, A., Garty, B. Z., Volkov, A., Vulliamy, T. Expanding the clinical phenotype of autosomal dominant dyskeratosis caused by TERT mutations. (Letter) Haematologica 93: 943-944, 2008. [PubMed: 18460650] [Full Text: https://doi.org/10.3324/haematol.12317]
Batista, L. F. Z., Pech, M. F., Zhong, F. L., Nguyen, H. N., Xie, K. T., Zaug, A. J., Crary, S. M., Choi, J., Sebastiano, V., Cherry, A., Giri, N., Wernig, M., Alter, B. P., Cech, T. R., Savage, S. A., Pera, R. A. R., Artandi, S. E. Telomere shortening and loss of self-renewal in dyskeratosis congenita induced pluripotent stem cells. Nature 474: 399-402, 2011. [PubMed: 21602826] [Full Text: https://doi.org/10.1038/nature10084]
Cepni, E., Satkin, N. B., Moheb, L. A., Rocha, M. E., Kayserili, H. Biallelic TERT variant leads to Hoyeraal-Hreidarsson syndrome with additional dyskeratosis congenita findings. Am. J. Med. Genet. 188A: 1226-1232, 2022. [PubMed: 34890115] [Full Text: https://doi.org/10.1002/ajmg.a.62602]
Du, H.-Y., Pumbo, E., Manley, P., Field, J. J., Bayliss, S. J., Wilson, D. B., Mason, P. J., Bessler, M. Complex inheritance pattern of dyskeratosis congenita in two families with 2 different mutations in the telomerase reverse transcriptase gene. Blood 111: 1128-1130, 2008. [PubMed: 18042801] [Full Text: https://doi.org/10.1182/blood-2007-10-120907]
Jonassaint, N. L., Guo, N., Califano, J. A., Montgomery, E. A., Armanios, M. The gastrointestinal manifestations of telomere-mediated disease. Aging Cell 12: 319-323, 2013. [PubMed: 23279657] [Full Text: https://doi.org/10.1111/acel.12041]
Marrone, A., Walne, A., Tamary, H., Masunari, Y., Kirwan, M., Beswick, R., Vulliamy, T., Dokal, I. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood 110: 4198-4205, 2007. [PubMed: 17785587] [Full Text: https://doi.org/10.1182/blood-2006-12-062851]