Xeroderma Pigmentosum

Xeroderma pigmentosum is a rare, autosomal recessive DNA repair disorder. Mutations affect the nucleotide excision repair pathway, the cellular mechanism that repairs ultraviolet radiation-induced DNA damage.

It produces extreme photosensitivity and a dramatically elevated risk of skin malignancy (basal cell carcinoma, squamous cell carcinoma, and melanoma) at a markedly younger age than in the general population.

A subset of affected individuals also develop progressive neurological degeneration, reflecting the relevance of the same repair pathway to neuronal maintenance.

No curative treatment exists for the genetic defect. Rigorous, lifelong ultraviolet radiation avoidance is therefore the single most important management intervention.

Pathophysiology and classification

• Nucleotide excision repair identifies and repairs bulky DNA lesions, most notably the pyrimidine dimers characteristically induced by ultraviolet radiation.
• Mutations in any of several genes in this pathway impair repair of ultraviolet-induced DNA damage. At least eight distinct complementation groups are identified, each corresponding to a specific gene. They differ somewhat in disease severity and, in some cases, in propensity for neurological involvement.
• Unrepaired DNA damage in sun-exposed skin drives progressive mutation accumulation in epidermal cells. This dramatically accelerates the cumulative ultraviolet-induced carcinogenesis that proceeds at a much slower rate in the general population. It accounts for the elevated skin malignancy risk at a markedly younger age.
• A subset of complementation groups is also associated with progressive neurological degeneration. This is believed to reflect the relevance of nucleotide excision repair to neuronal genome maintenance, including repair of DNA damage from endogenous rather than purely ultraviolet-induced sources in the central nervous system.

• Extreme photosensitivity presents in early infancy with severe sunburn after even brief, minimal sun exposure, disproportionate to the exposure.
• Progressive, premature skin changes develop in sun-exposed skin within the first few years of life: marked freckling, irregular pigmentation, skin atrophy and dryness, and telangiectasia. This is the characteristic early pattern.
• Skin malignancy (basal cell carcinoma, squamous cell carcinoma, and melanoma) develops at a dramatically younger age than in the general population, frequently within the first decade of life.
• Affected individuals are at risk of multiple, recurrent skin malignancies throughout life. These are the principal cause of morbidity and, without effective sun protection, mortality.
• Ocular manifestations include photophobia, conjunctival injection and, over time, degenerative changes of the cornea and conjunctiva. Risk of ocular surface malignancy is increased, reflecting the vulnerability of the ultraviolet-exposed ocular surface to the same repair defect.
• Progressive neurological degeneration occurs in a subset of individuals, particularly though not exclusively with specific complementation groups. It presents with progressive sensorineural hearing loss, cognitive decline, and other progressive neurological features.
• This neurological component is additional to the universal skin and ocular manifestations and carries distinct implications for prognosis and management.

• Diagnosis is suspected clinically based on the characteristic, dramatic photosensitivity and early, premature skin changes, particularly in the context of any relevant family history or parental consanguinity given the autosomal recessive inheritance pattern.
• Cellular assays demonstrating impaired nucleotide excision repair capacity, together with genetic testing identifying the specific, causative mutation and corresponding complementation group, provide definitive diagnostic confirmation, with identification of the specific complementation group carrying relevance to anticipated disease severity and the presence or absence of associated neurological involvement.
• Full baseline and ongoing dermatological assessment, together with formal ophthalmological evaluation, forms an essential component of full diagnostic and ongoing surveillance evaluation.

• Rigorous, lifelong ultraviolet radiation avoidance is the single most important management intervention. It means strict avoidance of direct sun exposure and physical sun protection (protective clothing, wide-brimmed hats, and ultraviolet-protective eyewear).
• Apply broad-spectrum, high-factor sunscreen to any residually exposed skin. Fit ultraviolet-filtering window film in indoor environments with significant window exposure.
• For many affected individuals this means a substantially modified lifestyle: living indoors by day, with outdoor activity confined to hours of darkness. This degree of avoidance is genuinely needed to reduce malignancy risk meaningfully.
• Regular, frequent dermatological surveillance with full skin examination at short intervals supports early identification and prompt treatment of any developing skin malignancy. Biopsy any new or changing lesion, given the dramatically elevated malignancy risk.
• Treat identified skin malignancy according to standard principles for basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma. Affected individuals frequently need treatment of multiple, recurrent lesions over their lives.
• Regular ophthalmological surveillance and ocular protection are further components of management.
• Where the complementation group and neurological involvement are relevant, provide neurological and audiological assessment and support.
• Psychosocial support should address the profound impact of the required lifestyle modification on the individual and family. This includes implications for education, because daytime schooling often needs substantial modification, and for broader social and family life.
• Provide genetic counselling on the autosomal recessive inheritance and the recurrence risk for future pregnancies, and connect families to specialist services and patient support organisations.