Clinical features of xeroderma pigmentosum.

Background Xeroderma pigmentosum (XP) was first described in 1874 by Hebra and Kaposi. Albert Neisser was the first to report neurological abnormalities associated with XP in 1883. XP is an autosomal recessive disease with defective nucleotide excision repair (NER). It is characterized by easily recognizable clinical hallmarks (Table 1). These manifestations are due to cellular hypersensitivity to ultraviolet (UV) radiation resulting from a defect in DNA repair. Two types of NER exist: global genome (GG-NER) and transcription coupled (TC-NER). Eight complementation groups, XPA-XPG, corresponding to defects in the corresponding gene products of XPA-XPG genes and XP-variant, have been described. These entities occur with different frequencies (e.g., XPA is relatively common, whereas XPE is fairly rare) and they differ with respect to disease severity (e.g., XPG is severe, whereas XPF is mild) and involvement of skin, central nervous system and opthalmological manifestations (Table 2). Cockayne syndrome rarely occurs together with XPB, XPD and XPG. In addition to the DNA repair defects, UV radiation also exerts pronounced immunosuppressive eflFects that are likely to be involved in the pathogenesis of XP. Although typical symptoms of immune deficiency, such as multiple infections, are not usually observed in patients with XP, prominent depletion of Langerhans cells, induced by UV radiation, has been described in XP patients.^ Various other defects in cell-mediated immunity such as impaired cutaneous responses to recall antigens, impaired lymphocyte proliferative responses to mitogens and decreased production of interferon as well as reduced natural killer cell activity have been detected in XP patients. Epidemiology The frequency of XP in the United States is about 1 case/250.000 inhabitants. Not uncommonly, parental consanguinity and familiarity are present in patients with XP.̂ '̂ XPC is the most common group in the United States, constituting almost 1/3 of XP patients. The unscheduled DNA synthesis is usually between 15-30% of normal. Symptoms for neurological disorders are rare in XP-C. XPD is the second most common type of XP in the United States and accounts for the majority of US patients with symptoms for neurological disorder being present in about half of all those patients, while the cutaneous and immunologic presentations are quite heterogeneous. Internationally, the incidence of XP is about the same in Europe, whereas it is higher (1:40.000) in Japan, where XPA is the most common group. In Europe XPA and XPC are the two most prevalent forms of XP. There is no gender preference. As an autosomal recessive disorder, there is usually no positive family history as the heterozygous parents are clinically healthy.