Xeroderma pigmentosum (XP) is characterized by sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure, marked freckle-like pigmentation of the face before age two years), ocular involvement (photophobia, keratitis, atrophy of the skin of the lids), and a greatly increased risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma). Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).
The diagnosis of XP is made on the basis of clinical findings and family history. The preferred method of laboratory diagnosis is functional testing to screen cells for abnormalities in DNA repair. XP has been classified by complementation group (XP-A, XP-B, XP-C, XP-D, XP-E, XP-F, XP-G) based on research laboratory testing. The XP complementation groups are associated with biallelic mutations in XPA, ERCC1, ERCC3 (XP-B), XPC, ERCC2 (XP-D), DDB2 (XP-E), ERCC4 (XP-F), and ERCC5 (XP-G). In addition XP is associated with mutations in POLH.
XP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the disease-causing mutations have been identified in the family, carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible through laboratories offering either testing for the gene of interest or custom testing.