GeneReviews(®)

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GeneReviews(®)

Book. 1993

Authors: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Ledbetter N, Mefford HC, Smith RJH, Stephens K

Abstract
CLINICAL CHARACTERISTICS: Xeroderma pigmentosum (XP) is characterized by: Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals), with marked freckle-like pigmentation of the face before age two years in most affected individuals; Sunlight-induced ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); Greatly increased risk of sunlight-induced 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).
DIAGNOSIS/TESTING: The diagnosis of XP is made on the basis of clinical findings and family history and/or by the identification of biallelic pathogenic variants in DDB2, ERCC1,ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, or XPC.
MANAGEMENT: Treatment of manifestations: Small, premalignant skin lesions such as actinic keratoses can be treated by freezing with liquid nitrogen; larger areas can be treated with field treatments such as topical 5-fluorouracil or imiquimod. Rarely, therapeutic dermatome shaving or dermabrasion has been used; skin neoplasms can be treated (as in persons without XP) with electrodesiccation and curettage, or surgical excision; skin cancers that are recurrent or in locations at high risk for recurrence are best treated with Mohs micrographic surgery. Oral isotretinoin or acitretin can prevent new skin neoplasms but have many side effects. Neoplasms of the eyelids, conjunctiva, and cornea can be treated surgically; corneal transplantation may improve the visual impairment resulting from severe keratitis. Hearing loss may be treated with hearing aids. Prevention of primary manifestations: Avoid sun and other UV exposure to the skin and eyes; measurement of UV light with a light meter in an affected individual’s home, school, and/or work environment so that high levels of environmental UV can be identified and eliminated. Prevention of secondary complications: Dietary supplementation with oral vitamin D as needed. Surveillance: Skin examinations by a physician every three to 12 months; periodic routine eye and neurologic examinations and audiograms. Agents/circumstances to avoid: UV exposure from sunlight and artificial sources of UV radiation, cigarette smoke. Evaluation of relatives at risk: If family-specific pathogenic variants have been identified, molecular genetic testing of at-risk sibs can permit early diagnosis and rigorous sun protection from an early age. Pregnancy management: Systemic retinoids (isotretinoin, acitretin) may be used as skin cancer chemopreventive agents. These drugs are known to be teratogenic to a developing fetus and pose a high risk for birth defects. Women of reproductive age who are taking a systemic retinoid must use effective contraception and be monitored with regular pregnancy tests.
GENETIC COUNSELING: 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. Once the pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible options.

PMID: 20301571

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