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, ... 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 5p1; DKCA3 (613990), caused by mutation in the TINF2 gene (604319) on chromosome 14q12; and DKCA4 (see 615190), caused by mutation in the RTEL1 gene (608833) on chromosome 20q13. Autosomal recessive forms include DKCB1 (224230), caused by mutation in the NOLA3 gene (606471) on chromosome 15q14-q15; 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; and DKCB5 (615190), caused by mutation in the RTEL1 gene (608833) on chromosome 20q13. 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.
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, ... 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).
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 ... 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.
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 ... 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).