title: DNA repair defects and chromosome instability disorders.
abstract: Xeroderma pigmentosum (XP), Fanconi anaemia (FA), ataxia telangiectasia (AT) and Bloom disease (BS) are four rare autosomal recessive disorders in which there is defective DNA repair and/or chromosome instability and proneness to malignancy. Between 80 and 90% of patients with XP have a defect, demonstrable at cell level, of excision of DNA lesions induced by ultraviolet rays, while the remainder have a cellular error of post-replication repair. XP cells are also deficient in repairing DNA damage caused by a variety of chemical mutagens. There are at least five different complementation groups of the first, or classical, type of XP (A to D, etc.) Apparently group C patients, as well as those with defective post-replication repair, do not show the progressive neurological illness found in a proportion of the other patients. AT is heterogeneous clinically and genetically. Clinically it presents with a progressive neurological illness, progressive telangiectases and a developmental disorder of the thymus. AT is characterized by sensitivity to X-rays and AT cells are unable to repair gamma-ray-induced damage to bases in the DNA. It appears that in many cases of the disorder a chromosomally marked cellular clone is found. In BS the main defect, which results in growth retardation, sun-induced lesions of the face and susceptibility to infection, appears to be a slow DNA chain maturation during DNA synthesis. An increase of sister chromatid exchanges is characteristically seen in the chromosomes of cultured BS cells. In FA, in which there is progressive pancytopenia with eventual bone marrow exhaustion and a tendency to haemorrhage and infection, the cellular defect seems to consist of faulty removal of repair of cross-links in the DNA. In this condition, as in BS and AT, various structural chromosome changes are detected in cultured cells. Patients with XP develop skin cancers in early life and often maligant melanomas. In the other three disorders, in which an immune deficiency is often present, leukaemia and related proliferative disorders are a frequent cause of death while other malignancies also occur. There is some evidence that points to an increased risk of malignancy in heterozygotes who carry the FA and AT genes.
mesh_terms: D000015:Abnormalities, Multiple / Q000503:physiopathology; D001260:Ataxia Telangiectasia / Q000503:physiopathology; D002842:Chromatids / Q000502:physiology; D002869:Chromosome Aberrations / Q000235:genetics*; D025063:Chromosome Disorders; D002877:Chromosomes, Human; D003434:Crossing Over, Genetic; D004260:DNA Repair; D004261:DNA Replication; D004392:Dwarfism; D006801:Humans; D013577:Syndrome; D013684:Telangiectasis / Q000503:physiopathology*; D014178:Translocation, Genetic; D014983:Xeroderma Pigmentosum / Q000503:physiopathology