Dyskeratosis Congenita, Autosomal Dominant 1

A number sign (#) is used with this entry because of evidence that autosomal dominant dyskeratosis congenita-1 (DKCA1) is caused by heterozygous mutation in the gene encoding telomerase RNA component (TERC; 602322) on chromosome 3q26.

Description

Dyskeratosis congenita is a rare multisystem disorder caused by defective telomere maintenance. Clinical features are highly variable and include bone marrow failure, predisposition to malignancy, and pulmonary and hepatic fibrosis. The classic clinical triad of abnormal skin pigmentation, leukoplakia, and nail dystrophy is not always observed. Other features include premature graying of the hair, osteoporosis, epiphora, dental abnormalities and testicular atrophy, among others (review by Bessler et al., 2007 and Bessler et al., 2010).

Hoyeraal-Hreidarsson syndrome (HHS) refers to a clinically severe variant of DKC that is characterized by multisystem involvement and early onset in utero. Patients with HHS show intrauterine growth retardation, microcephaly, delayed development, bone marrow failure resulting in immunodeficiency, cerebellar hypoplasia, and sometimes enteropathy. Death often occurs in childhood (summary by Walne et al., 2013).

Genetic Heterogeneity of Dyskeratosis Congenita and Hoyeraal-Hreidarsson Syndrome

Dyskeratosis congenita is a genetically heterogeneous disorder, showing autosomal recessive, autosomal dominant, and X-linked inheritance. Additional autosomal dominant forms include DKCA2 (613989), caused by mutation in the TERT gene (187270) on chromosome 5p15; DKCA3 (613990), caused by mutation in the TINF2 gene (604319) on chromosome 14q12; DKCA4 (see 615190), caused by mutation in the RTEL1 gene (608833) on chromosome 20q13, DKCA5 (268130), caused by mutation in the TINF2 gene (604319) on chromosome 14q12, and DKCA6 (616553), caused by mutation in the ACD gene (609377) on chromosome 16q22.

Autosomal recessive forms include DKCB1 (224230), caused by mutation in the NOLA3 gene (606471) on chromosome 15q14; DKCB2 (613987), caused mutation in the NOLA2 gene (606470) on chromosome 5q35; DKCB3 (613988), caused by mutation in the TCAB1 gene (WRAP53; 612661) on chromosome 17p13; DKCB4 (see 613989), caused by mutation in the TERT gene; DKCB5 (615190), caused by mutation in the RTEL1 gene (608833) on chromosome 20q13; DKCB6 (616353), caused by mutation in the PARN gene (604212) on chromosome 16p13; and DKCB7 (see 616553), caused by mutation in the ACD gene (609377) on chromosome 16q22. X-linked recessive DKCX (305000) is caused by mutation in the dyskerin gene (DKC1; 300126) on Xq28.

Hoyeraal-Hreidarsson syndrome, the severe clinical variant of DKC, can be caused by mutation in several different DKC-associated genes; see, e.g., DKC1 (300136), TINF2 (604319), TERT (187270), and RTEL1 (608833).

See also adult-onset telomere-related pulmonary fibrosis and/or bone marrow failure-1 and -2 (PFBMFT1, 614742 and PFBMFT2, 614743), which are caused by mutations in the TERT and TERC genes, respectively. These disorders share some features of DKC, but show later onset and do not have skin abnormalities. The disorders related to telomere shortening are part of a phenotypic spectrum.

Mutation in the CTC1 gene (613129) on chromosome 17p13 causes cerebroretinal microangiopathy with calcifications and cysts (CRMCC; 612199), another telomere-related disorder with overlapping features of DKC.

Clinical Features

Scoggins et al. (1971) described a black family with a form of dyskeratosis congenita inherited as an autosomal dominant trait. Features included reticular hyperpigmentation of the skin, dystrophic nails, osteoporosis, premalignant leukokeratosis of the oral mucosa, absent fingerprints, scant hair, poor dentition, absent lacrimal puncta, palmar hyperkeratosis, anemia, endoreduplication on chromosome studies, and an immune defect. The skin changes were due to melanin having been released by melanocytes and taken up by dermal phagocytes. The hematologic, immunologic, and chromosomal changes were similar to those of Fanconi pancytopenia (227650). Three generations were affected, with male-to-male transmission.

Reticulated hyperpigmentation is usually the first cutaneous manifestation of dyskeratosis congenita. The pigmentary change may be limited to neck, upper chest, and proximal parts of the limbs initially, but within affected areas the involvement is always diffuse. Baselga et al. (1998) described a patient with typical diffuse cutaneous signs of DKC superimposed with hyperpigmentation that was more pronounced along Blaschko lines. To explain this phenomenon, they assumed that the patient had the autosomal dominant type and that loss of heterozygosity occurred in a somatic cell, giving rise to a population of cells that migrated along these lines during embryogenesis. The cells that migrated along Blaschko lines and expressed an intensified clinical picture would be homozygous or hemizygous for the defect. Happle (1996) suggested this mechanism for the occurrence of severe segmental lesions superimposed on a milder, diffuse manifestation of autosomal skin disorders such as neurofibromatosis, epidermolytic hyperkeratosis, or porokeratosis.

Vulliamy et al. (2001) reported a large family with autosomal dominant DKCA1. In addition to leukoplakia, dysplastic nails, and reticulate pigmentation pattern, affected individuals had variable features of premature graying, early dental loss, bone marrow failure, liver cirrhosis, pulmonary disease, and skin cancer. Genetic analysis identified a heterozygous deletion in the TERC gene (602322.0001).

Inheritance

Tchou and Kohn (1982) reported a presumed autosomal dominant form of DKC.

In a review of DKC, Davidson and Connor (1988) noted that X-linked recessive, autosomal dominant, and autosomal recessive patterns of inheritance had been described. The authors cited a family reported by Tchou and Kohn (1982), in which 5 females were affected. In this family the age of onset was later and the features milder and less typical than usual in the X-linked form, particularly in the 3 affected males. Davidson and Connor (1988) concluded that autosomal inheritance should be suspected in families with affected females.

Genetic Anticipation

Vulliamy et al. (2004) demonstrated that anticipation occurs in DKCA1 and that the molecular basis resides in progressive telomere shortening in successive generations. In 8 families, the disease became more severe in succeeding generations. Of affected parents, 7 of 12 were asymptomatic, ranging in age from 36 to 61 years. In these cases, dyskeratosis congenita was diagnosed only by the identification of a TERC mutation; subtle signs of the disease were often detected subsequently. For the 5 remaining affected parents, the median age at which disease features were first identified was 37 years. Of the affected children, only 5 of 15 remained asymptomatic; they were aged 3, 7, 11, 14, and 20 years and were diagnosed only through mutation analysis. For the remaining 10 affected children, symptoms presented at a median age of 14.5 years.

Diagnosis

Jongmans et al. (2012) observed somatic reversion of the mutant TERC allele in blood cells of 2 affected members of a family with variable manifestations of DKCA1 due to a germline heterozygous TERC mutation (602322.0011). In both cases, the reversion occurred by acquired uniparental disomy of chromosome 3q, including TERC, during mitotic recombination. Four additional cases of a mosaic-reversion pattern in blood cells were found among a cohort of 17 patients with germline TERC mutations. None of the patients with somatic mosaic reversion had bone marrow failure, and all had a small deletion in the TERC gene. The findings indicated that revertant somatic mosaicism is a recurrent event in DKCA1, which has important implications for diagnostic testing, often performed on peripheral blood, and may help explain the variable phenotype of the disorder.

Pathogenesis

In an isolated case in a female patient, the daughter of young, unrelated parents, Kehrer et al. (1992) found a markedly increased frequency of chromosomal breaks, hypodiploidy, and premature centromere disjunction in skin fibroblast cultures. The frequency of mitotic disturbances was almost as great as that in cultures from 2 severely affected patients with Fanconi anemia.

Goldman et al. (2008) characterized CD34+ cells derived from the bone marrow and peripheral blood of 5 patients with DKC (Vulliamy et al., 2001) after G-CSF mobilization. Patients had severely decreased numbers of CD34+ cells, both before and after mobilization, compared to controls. Patient cells also had markedly reduced telomere lengths compared to controls; however, differentiation of mature lineages from these cells was not grossly perturbed. Goldman et al. (2008) concluded that bone marrow failure in DKC results from a quantitative impairment of hematopoietic stem cells to sustain their own numbers, perhaps because these cells enter a state of proliferative arrest or death due to accumulated shortening of telomeres over multiple generations.

Molecular Genetics

In a large pedigree with autosomal dominant DKC, Vulliamy et al. (2001) mapped the disorder to a 30-cM region, with a lod score of 1.8 for marker D3S3725. The TERC gene maps to 3q21-q28 and was considered a likely candidate because it is known to interact with dyskerin (300126), the gene mutated in X-linked DKC (305000). Vulliamy et al. (2001) identified a heterozygous 821-bp deletion (602322.0001) that removed the 3-prime 74 bases of TERC in all affected individuals of the large family. All unaffected individuals had 2 wildtype alleles. Of the 2 individuals in the second generation with undetermined clinical status, one carried the mutation and was 37 years old. Other affected members of his generation were diagnosed between 29 and 48 years of age. Heterozygous TERC mutations were also identified in 2 other families with autosomal dominant DKCA1 (602322.0002 and 602322.0003, respectively).

Genotype/Phenotype Correlations

Patients with the X-linked form of DKC (305000) tend to have a more severe disorder with earlier onset and a higher frequency of mucocutaneous manifestations compared to those with TERT or TERC mutations, who have later onset and may not have mucocutaneous manifestations. DKC due to TERT or TERC mutations shows genetic anticipation (review by Bessler et al., 2007).

Kirwan and Dokal (2008) discussed the clinical and genetic heterogeneity of dyskeratosis congenita.

Animal Model

Hockemeyer et al. (2008) noted that mice lacking components of telomerase fail to show phenotypes typical of DKC. They developed a mouse model in which key characteristics of DKC were induced by enhanced telomere degradation. Mice lacking the shelterin component Pot1b (606478) (Pot1b -/-) and also deficient in Terc (Terc +/-) developed progressive bone marrow failure, hyperpigmentation, and nail abnormalities. Bone marrow failure was fatal between 4 and 5 months of age in Pot1b -/- Terc +/- mice.

Armanios et al. (2009) generated wildtype mice with short telomeres. In these mice, Armanios et al. (2009) identified hematopoietic and immune defects that resembled those present in patients with dyskeratosis congenita. Patients with dyskeratosis congenita have a premature aging syndrome that can be caused by mutations in the RNA or catalytic component of telomerase (see TERC, 602322 and TERT, 187270). When mice with short telomeres were interbred, telomere length was only incrementally restored, and even several generations later, wildtype mice with short telomeres still displayed degenerative defects. Armanios et al. (2009) concluded that their findings implicated telomere length as a unique heritable trait and demonstrated that short telomeres are sufficient to mediate the degenerative defects of aging.