Xeroderma pigmentosum

Xeroderma pigmentosum is a rare hereditary disease caused by defective DNA nucleotide excision repair mechanisms. Individuals with xeroderma pigmentosum are at high risk for skin and eye damage from UV radiation exposure, e.g., sunburn, premalignant and malignant skin lesions, dry eyes, and keratitis. Some individuals with xeroderma pigmentosum also experience neurodegenerative disease that affects hearing, gait, and cognition. Genetic testing can confirm the diagnosis. Management is focused on the prevention of UV-related skin and eye damage with strict photoprotective measures, frequent screening for complications, and treatment of cutaneous, ocular, and/or neurological manifestations as indicated.

• Autosomal recessive inheritance ^[2]
• Genetic mutations cause defects in DNA nucleotide excision repair mechanisms.

• Prevalence: ∼1:1,000,000 in the US ^[1][3]
• ♂ = ♀ ^[3]

Epidemiological data refers to the US, unless otherwise specified.

• Cutaneous manifestations ^[2]
  • Slow healing, blistering burns after minimal exposure to sunlight in ∼ 60% of affected individuals ^[1]
  • Solar lentigines, xerosis, and poikiloderma due to repeated exposure to sunlight
  • Premalignant lesions (e.g., actinic keratoses) and malignant lesions often develop during early childhood. ^[2]
• Ocular manifestations ^[1][4]
  • Photophobia and dry eyes
  • Atrophy of eyelids, loss of eyelashes
  • Keratitis, corneal opacification, loss of vision
  • Malignancy
• Neurological manifestations: Progressive neurodegeneration affects ∼ 25% of patients. ^[2]
  • Cognitive impairment
  • Sensorineural hearing loss
  • Ataxia
  • Spasticity ^[3]
  • Decreased deep tendon reflexes

In patients with xeroderma pigmentosum, minimal UV radiation often causes severe skin damage and increases the risk of skin cancer. ^[1]

• Refer to a specialist (e.g., dermatology, genetics) for diagnosis.
• Confirmatory studies include:
  • Genetic testing ^[3]
  • Cellular testing for defective DNA nucleotide repair from a punch biopsy sample of minimally sun-exposed skin ^[1]

A prenatal diagnosis of xeroderma pigmentosum can be made using amniocentesis or chorionic villus sampling. ^[3]

Treatment of xeroderma pigmentosum is focused on preventing damage from UV exposure and early identification and treatment of complications.

Prevention of UV radiation damage ^[1][5]

• Advise strict photoprotective measures for skin and eyes.
• Perform skin cancer screening and ophthalmic examinations every 3–6 months. ^[5][6]
• Pharmacological keratinocyte carcinoma prophylaxis may be considered, e.g.: ^[4]
  • Systemic retinoids
  • Topical 5-fluorouracil or imiquimod ^[7]

Individuals with xeroderma pigmentosum are at increased risk of vitamin D deficiency due to reduced exposure to UV light. Assess for and treat vitamin D deficiency as indicated. ^[4][8]

Management of specific disease manifestations ^[1][6]

Management of xeroderma pigmentosum requires a multidisciplinary care team (e.g., dermatology, ophthalmology, and neurology).

• Cutaneous disease ^[3]
  • Treat premalignant skin lesions (e.g., actinic keratosis) aggressively to prevent progression.
  • For malignant lesions, radiotherapy is usually avoided. ^[3][9]
• Ocular disease
  • Provide treatment for dry eye disease as needed. ^[10]
  • Refer to ophthalmology for:
    • UV protective contact lenses.
    • Treatment of UV-induced eye damage and tumors.
• Neurological disease ^[1][5]
  • Refer affected patients to neurology.
  • Regularly screen patients for hearing loss.
  • Refer as needed to for physical, occupational therapy, and speech therapy. ^[6]

Supportive care ^[1]

• Offer genetic counseling to all patients.
• Provide resources for the management of psychosocial issues related to social isolation, e.g.: ^[8]
  • Support groups for patients with xeroderma pigmentosum
  • Psychological counseling

Individuals with xeroderma pigmentosum are at increased risk for lung cancer and should be advised to abstain from tobacco use. ^[4]

• Skin cancer (basal cell carcinoma, squamous cell carcinoma, melanoma) at a young age (< 20 years) ^[2]
• Malignant tumors of the:
  • Eyes
  • Eyelids
  • Central nervous system
• Lung cancer

We list the most important complications. The selection is not exhaustive.

• Life expectancy varies and can be significantly limited in patients with: ^[1][4]
  • Neurological disease
  • Insufficient UV protection
• Skin cancer is the most common cause of death in individuals with xeroderma pigmentosum. ^[4]