Dyskeratosis Congenita, Autosomal Dominant 2

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.

Description

Dyskeratosis congenita is a multisystem disorder caused by defective telomere maintenance. Features are variable and include bone marrow failure, pulmonary and liver fibrosis, and premature graying of the hair (summary by Armanios et al., 2005).

For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).

Clinical Features

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.

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).

Pathogenesis

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.

Molecular Genetics

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.