This is classically an X-linked condition although other inheritance patterns have been described in some families, suggesting genetic heterogeneity, characterized by reticulated hyperpigmentation of the skin, with depigmented spots, nail dystrophy (in 98 % of patients, sometimes apparent at birth), and leukoplakia of the mucous membranes (87 %) with atrophy of the lingual papillae in affected males. Signs of the condition usually develop in the first decade of life, but may not occur until puberty. There may be enamel dystrophy of the teeth. The skin changes are progressive, with the development of poikiloderma, telangiectasia, and atrophy. Hypertrophic squamous epithelium occurs in mucous epithelia. Bullous skin eruptions and hyperkeratosis, especially of the palms and soles, may occur, and atrophy of the skin of the palms may lead to loss of dermatoglyphics. Blepharitis, ectropion, and nasolacrimal obstruction may occur, and there are dental caries. Subnormal intelligence is sometimes a feature (42 % of cases).
Leukoplakia develops, particularly of the oral mucosa, and also in the rectum and genitourinary tract (Davidson and Connor 1988; Fogarty et al. 2003). There is thought to be an immune dysfunction, with reduced cellular immunity and T cell function, leading to opportunistic infections.
Complications include pancytopenia (due to bone marrow failure) and squamous and basal cell carcinomas of the skin and mucous membranes, often developing in areas of leukoplakia, after the age of 20 years. Squamous cell carcinoma of the mouth, rectum, cervix, vagina, esophagus, and skin may occur, and there may be multiple primaries. An increased incidence of solid Tumours (which can be multiple) has been claimed, with a total incidence of malignancy of 12 % (Kawaguchi et al. 1990). Female carriers are generally normal. Excessive spontaneous chromatid breaks have been reported in some cases of this condition, and an increased X-irradiation-induced chromatid breakage has been demonstrated in fibroblasts. Hematopoietic stem cell transplantation has been tried as therapy in affected patients (Nobili et al. 2002).
Linkage to markers at Xq28(D9S52) was demonstrated, and mutation in the gene encoding dyskerin (DKC1) KKC1 gene is responsible for the condition. Dyskeratin is a protein necessary for the function of telomerase, so the disorder is caused by a defect in the maintenance of telomeres with reduced apoptosis (Kirwan and Dokal 2008). Late-onset cases, or of aplastic anemia, may also be due to mutations in TERC (Arngrimsson et al. 1993). Disease anticipation has been shown to be associated with progressive telomere shortening (Montanaro et al. 2003; Shay and Wright 2004; Vuilamy et al. 2004).