Dyskeratosis congenita is an inherited disorder characterised by abnormal skin pigmentation, nail dystrophy, and mucosal leucoplakia (figure). Since its first description by Zinsser in 1906, many variations in the clinical phenotype of the disease have been seen, and various non-cutaneous (dental, gastrointestinal, genitourinary, neurological, ophthalmic, pulmonary, and skeletal) abnormalities have come to be recognised as characteristic of the disorder. Bone marrow failure, or aplastic anaemia, is the principal cause of premature mortality in patients, who are also predisposed to cancer and fatal pulmonary complications. X-linked recessive, autosomal dominant, and autosomal recessive forms of the disease exist. Diagnosis based on clinical criteria alone is difficult and unreliable, especially where non-cutaneous abnormalities precede classical mucocutaneous features. A diagnostic test, therefore, had to be developed. However, as a result of the rarity of the disease and the paucity of biological material there was little information on metabolic or cellular abnormalities that could be explored as a basis for such a test. Eventually, a century after dyskeratosis congenita was first described, modern genetics has provided the answer. Linkage analysis in one large family, in which only the men were affected, localised the gene for the X-linked form of the disease to Xq28, the lower tip of the X chromosome. The availability of genetic markers and additional X-linked families then facilitated positional cloning of the gene (DKC1). Identification of DKC1 immediately made available a genetic test that could confirm diagnosis in suspected cases, and that could be used for antenatal diagnosis. Furthermore, since the gene has been cloned, a severe variant of dyskeratosis congenita, also caused by a mutation in DKC1, has been identified. Hoyeraal-Hreidarsson syndrome is characterised by severe growth failure, abnormalities of brain development, aplastic anaemia, and immunodeficiency. Knowledge of the genetics of dyskeratosis congenita has also led to insights into its pathogenesis. DKC1 is expressed in all tissues of the body, indicating that it has a vital “house-keeping function” in the human cell. This notion correlates well with the multisystem phenotype of the disease. Furthermore, DKC1 and its encoded protein, dyskerin, are highly conserved throughout evolution, and it seems likely that they are associated with the H/ACA class of small nucleolar RNAs (snoRNAs) and are involved in pseudouridylation of specific residues of ribosomal RNA (rRNA), a step that is essential for ribosome biogenesis. However, dyskerin also associates with the RNA component of telomerase (hTR), which contains an H/ACA consensus sequence. Telomerase is an enzyme complex, which is important in the maintenance of the ends (telomeres) of chromosomes. The precise composition of the telomerase complex is unknown, but two essential components, the RNA component (hTR) and the catalytic reverse transcriptase (hTERT), have been well characterised. In patients with X-linked disease, the concentration of hTR is reduced and telomere lengths are shorter than in age-matched controls. Telomeres are also shorter in cells from patients with autosomal forms of dyskeratosis congenita, which suggests that the disease might be caused by disturbed telomerase activity. This idea has been substantiated by linkage analysis, which showed that the gene for autosomal dominant disease is on chromosome 3q—ie, in the same place as the gene for hTR. Finally, mutation analysis confirmed that autosomal dominant dyskeratosis congenita was caused by mutations in the hTR gene. Since …