The natural history of this disease begins in the first year of life, when sun sensitivity becomes apparent, and xerosis and pigmentary changes may occur in the skin. About half of XP patients have a history of severe burning on minimal sun exposure. Other XP patients do not have this reaction but develop freckle-like pigmentation before age 2 years on sun-exposed sites. These manifestations progress to skin atrophy and formation of telangiectasias. Approximately one-half of people with this disorder will develop nonmelanoma skin cancers, and approximately one-quarter of these individuals will develop melanoma. In the absence of sun avoidance, the median age of diagnosis for any skin cancer is 8 to 9 years.[53,54,55] On average, nonmelanoma skin cancer occurs at a younger age than melanoma in the XP population.
Noncutaneous manifestations of XP include ophthalmologic and neurologic abnormalities. Disorders of the cornea and eyelids associated with this disorder are also linked to exposure to UV radiation and include keratitis, corneal opacification, ectropion or entropion, hyperpigmentation of the eyelids, and loss of eyelashes. About 25% of the XP patients examined at the National Institutes of Health (NIH) between 1971 and 2009 had progressive neurological degeneration. Features included microcephaly, progressive sensorineural hearing loss, diminished deep tendon reflexes, seizures, and cognitive impairment. Neurological degeneration, which is most commonly observed in individuals with complementation groups XPA and XPC, was associated with a shorter lifespan (median age of death was 29 years in individuals with neurological degeneration and 37 years in individuals without neurological degeneration). De Sanctis-Cacchione syndrome is found in a subgroup of XP patients, who exhibit severe neurologic manifestations, dwarfism, and delayed sexual development. A variety of noncutaneous neoplasms, most notably SCC of the tip of the tongue, central nervous system cancers, and lung cancer in smokers, have been reported in people who have XP.[53,56] The relative risk for these cancers is estimated to be about 50-fold higher than in the general population.
The inheritance for XP is autosomal recessive. Seven complementation groups have been associated with this disorder. About 40% of the XP cases seen at the NIH were XPC. ERCC2 (XPD) mutations were present in about 20%. Complementation group A, due to mutation in XPA, accounts for approximately 10% of cases. Other mutated genes in this disorder include ERCC3 (XPB), ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), and ERCC5 (XPG). An XPH group had been described but is now considered to be a subgroup of the XPD group. Heterozygotes for mutations in XP genes are generally asymptomatic. Founder mutations in XPA (R228A) and XPC (V548A fs X572) have been identified in North African populations, and a founder mutation in XPC resulting in a splice alteration (IVS 12-1G>C) has been found in an East African (Mahori) population. It has been proposed that direct screening for these mutations would be appropriate in these populations.[59,60,61,62]