A number sign (#) is used with this entry because autosomal dominant dyskeratosis congenita-3 (DKCA3) is caused by heterozygous mutation in the TINF2 gene (604319) on chromosome 14q12.

Dyskeratosis congenita is an inherited bone marrow failure syndrome classically characterized by the triad of mucosal leukoplakia, nail dysplasia, and abnormal skin pigmentation. Affected individuals have an increased risk of aplastic anemia and malignancy. Less common features include epiphora, premature gray hair, microcephaly, developmental delay, pulmonary fibrosis, portal hypertension, immunodeficiency, and gastrointestinal disease. The phenotype is highly variable. All affected individuals have shortened telomeres due to a defect in telomere maintenance (summary by Savage et al., 2008).

For a discussion of genetic heterogeneity of dyskeratosis congenita, see DCKA1 (127550).

Savage et al. (2008) reported a family with autosomal dominant DKC affecting 6 individuals, including 2 monozygotic male twins. Age at onset ranged from 10 to 31 years, and common clinical features included leukoplakia, nail dystrophy, and lacey reticular skin pigmentation. Three patients had severe aplastic anemia, and most had epiphora. One of the twins died at age 37 years from aplastic anemia and pulmonary hemorrhage, and the other died at age 43 of aplastic anemia, non-Hodgkin lymphoma, and pulmonary failure. Both of these individuals developed bilateral avascular necrosis of the hip.

Tsangaris et al. (2008) reported an 18-month-old girl with DKC who presented with pancytopenia and ataxia. Brain imaging showed cerebellar hypoplasia. She later developed a small area of leukoplakia but had no nail dystrophy or skin hyperpigmentation. Laboratory studies showed shortened telomeres and decreased telomerase activity (92.5% reduction compared to control values). The authors emphasized that DKC is a pleomorphic disorder and that ataxia can be an additional feature found in up to 6.8% of patients (Kirwan and Dokal, 2008). Tsangaris et al. (2008) noted that the combination of ataxia and pancytopenia without other typical features of DKC has been considered a distinct disorder (159550), but concluded that ataxia-pancytopenia is part of the phenotypic spectrum of DKC.

Walne et al. (2008) identified heterozygous mutations in the TINF2 gene in 33 (18.9%) of 175 cases of uncharacterized DKC. Most of the mutations were de novo. All the DKC patients with a TINF2 mutation had severe disease, with variable features of aplastic anemia, developmental delay, short stature, retinopathy, microcephaly, osteoporosis, cerebellar hypoplasia, alopecia, intracranial calcification, and dental loss.

Sasa et al. (2012) reported 2 unrelated patients with DKCA3 confirmed by genetic analysis (Q269X; 604319.0005 and Q271X; 604319.0007, respectively). One was a 4-year-old Hispanic boy who presented with pancytopenia and was found to have nail dystrophy, oral leukoplakia, and lacy hyperpigmentation of the neck and genital regions. He also had undescended testis and phimosis. Telomere flow-FISH analysis showed telomere lengths below the first percentile in all white blood cell subsets tested. He underwent hematopoietic stem cell transplantation. The second child was a Caucasian girl who presented at age 21 months with severe aplastic anemia and underwent hematopoietic stem cell transplantation. Subsequently, she developed skin hyperpigmentation, nail dystrophy, and oral leukoplakia, as well as epiphora, esophageal stricture, and osteopenia-related fractures. At age 10 years, she had progressive interstitial lung disease with fibrosis, gastrointestinal bleeding secondary to enteropathy, esophageal stricture, and noncirrhotic portal hypertension. She died at age 12 years from multiorgan failure.

Vulliamy et al. (2012) identified 16 new families with mutations in exon 6 of the TINF2 gene ascertained from 224 consecutive patients with different forms of bone marrow failure, including 46 with criteria meeting dyskeratosis congenita, 122 with aplastic anemia, and 57 with some features of DKC. Seven of the 46 patients with DKC carried TINF2 mutations, 5 of whom had the R252H mutation (604319.0002). Two of the DKC patients with the R252H mutation had a severe from of the disorder, with additional features including growth retardation, retinopathy, ataxia, developmental delay, and cerebellar hypoplasia, consistent with a clinical diagnosis of Hoyeraal-Hreidarsson syndrome. Nine of 57 patients with bone marrow failure and some features of DKC were found to carry mutations, including 2 with R282H, and 4 with nonsense or frameshift mutations (see, e.g., 604319.0005 and 604319.0008). Telomere length was only available for 7 of the mutation carriers, 6 of whom had shortened telomeres. The seventh patient had a missense variant that was also found in an asymptomatic individual, and both had normal telomere lengths, suggesting that this variant was not disease causing. Vulliamy et al. (2012) concluded that TINF2 mutations can cause a spectrum of clinical features and that telomere length should be able to distinguish pathogenic mutations from polymorphic variants in the absence of functional data. Most of the mutations appeared to occur de novo.

The transmission pattern of DKCA3 in the family reported by Savage et al. (2008) was consistent with autosomal dominant inheritance.

The heterozygous mutation in the TINF2 gene that was identified in a patient with DKCA3 by Tsangaris et al. (2008) occurred de novo.

Using a candidate gene approach with evidence for linkage to chromosome 14q11.2, Savage et al. (2008) identified a heterozygous missense mutation in the TINF2 gene (K280Q; 604319.0001) as the cause of dyskeratosis congenita in a family with autosomal dominant inheritance. The mutation was present only in individuals with telomere lengths below the first percentile for age. Subsequent screening of TINF2 in 8 molecularly uncharacterized probands with very short telomeres revealed mutations in 4. Three of these 4 probands carried the same mutation; all mutations were in extremely close proximity and near the end of the TRF1 (600951)-binding domain of the TIN2 protein.

Tsangaris et al. (2008) identified a de novo heterozygous mutation in the TINF2 gene (R282H; 604319.0002) in an 18-month-old girl with DKC who presented with pancytopenia and ataxia.

Walne et al. (2008) identified heterozygous mutations in the TINF2 gene in 33 (18.9%) of 175 cases of uncharacterized DKC. Of these 33 samples, 21 were found to have a mutation in arg282 in exon 6 (see, e.g., R282H, 604319.0002 and R282C, 604319.0004). The remaining 12 mutations were all in a tight cluster between residues 280 and 298. No additional mutations were found elsewhere in the gene. Most of the mutations were de novo. Clinically, all the DKC patients with a TINF2 mutation had severe disease associated with shorter telomeres compared to patients with DKC1 mutations (300126).

The 2 truncating mutations identified by Sasa et al. (2012) in 2 unrelated children with severe DKC (Q269X; 604319.0005 and Q271X; 604319.0007, respectively) both occurred in exon 6, but affected the more N-terminal region compared to earlier reported mutations and thus extended the affected segment of the gene to amino acid 269. In vitro functional expression studies in HEK293 cells showed that the Q269X mutant protein was markedly impaired in its ability to interact with TERF1 (600951). This was in contrast to R282H (604319.0002), which retained substantial ability to interact with TERF1. These findings indicated that disrupted TERF1 binding is not the main factor driving disease pathogenesis, but may contribute to a more severe phenotype.