Clinical Picture

XP is inherited as an autosomal recessive disorder. It is distributed worldwide with a population incidence of about 1 per 250,000 in Europe and the United States to 1 in 40,000 in Japan (9). A review of 830 published cases was provided by Kraemer and colleagues in 1987 (10).

Patients with XP are extremely photosensitive, with the appearance of the first symptoms of freckling and progressive cell degeneration of the skin and eyes following sun exposure appearing around age 1 or 2 years (Fig. 2). Patients with XP show different types of pigmentation changes and an increased incidence of developing cancers in sun-exposed areas that is about 1000-fold greater than it is in the general population. The most frequent skin cancers are basal and squamous cell carcinomas and to a lesser extent melanomas. The eyelid, conjunctiva, and cornea are the main affected areas of the eyes, since they are exposed mostly to UV irradiation from sunlight. In addition, the appearance of squamous cell carcinoma on the tip of the tongue is 20,000 times greater in patients with XP than in healthy people. The mean age of onset for skin cancers in patients with XP is 8 years old—about 50 years earlier than for the general population. This reduction in the age of appearance of neoplasia may be one of the most dramatic for a recessive hereditary disease (11). Patients with XP under the age of 20 years show a 10- to 20-fold increased risk of developing internal tumors (12).

A significant proportion of patients with XP (18-20%) shows progressive degeneration of normally predeveloped neurons, which results in cortical and spinal atrophy, cochlear degeneration, and a mixed distal axonal neuropathy. Microcephaly, mental retardation, deteriorating hearing, and loss of tendon reflexes

Figure 2 Patients with XP. (A) Mildly affected patient. (B) Face of 16-year-old patient showing severe skin lesions. (C) Posterior view of same patient showing absence of skin damage on unexposed areas. (From Refs. 145 and 146.)

are other results of the premature neuronal death. Unlike several other chromosomal instability syndromes (e.g., CS, TTD, ataxia-telangiectasia, and Werner syndrome), patients with XP do not show signs of premature aging except for the accelerated neuronal degeneration in those individuals with neurological abnormalities. Patients with XP without neuronal abnormalities who survive to relatively advanced ages have no unusual aging indications. Likewise, neither the Xpa nor Xpc mouse models discussed below have premature aging features.

The severity of the repair defect and of the clinical symptoms is quite heterogeneous among the different XP complementation groups (Table 1). The most severely affected patients are XP-A, XP-B, XP-D, and XP-G individuals. The severity of the NER deficiency of the above groups seems also to be associated with neurological problems, since XP-F, XP-E, and XP-C patients, who show moderate UV sensitivity and have a partially impaired NER, do not develop neuronal degeneration.

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