Dyskeratosis Congenita (DC) Registry: identification of new features of DC

Dyskeratosis congenita (DC) is an inherited disorder characterized by skin pigmentation, nail dystrophy and mucosal leucoplakia. In 1995 a Dyskeratosi s Congenita Registry was established at the Hammersmith Hospital. In the 46 families recruited, 76/83 patients were male, suggesting that the major fo rm of DC is X-linked. As well as a variety of noncutaneous abnormalities, t he majority (93%) of patients had bone marrow (BM) failure and this was the principal cause (71%) of early mortality In addition to BM hypoplasia, som e patients also developed myelodysplasia and acute myeloid leukaemia. Pulmo nary abnormalities were present in 19% of patients. In affected females the phenotype was less severe. Some female carriers of X-linked DC had clinica l features. Carriers of X-linked DC showed skewed X-chromosome inactivation patterns (XCIPs), suggesting that cells expressing the normal DC allele ha ve a growth/survival advantage over cells that express the mutant allele. L inkage analysis in multiplex families confirmed that the DKC1 gene, respons ible for the X-linked form of DC, is located within Xq28 and facilitated it s positional cloning. The high incidence of BM failure in association with a wide range of somatic abnormalities together with the ubiquitous expressi on of DKC1 suggest that, as well as having a critical role in normal haemop oiesis, this gene has a key role in normal cell biology.