Genetics

Eight complementation groups: XPA, XPB, XPC, XPD, XPE, XPF, XPG (NER pathway) and XPV (translesion DNA polymerase η, encoded by POLH). Inheritance autosomal recessive. Prevalence in the UK ~1 in 250,000; higher in some Middle Eastern, North African and South Asian populations due to consanguinity.

XPV accounts for ~20% of XP cases. Unlike the NER-deficient groups, XPV cells have intact nucleotide excision repair but a defect in translesion synthesis past UV-damaged DNA; affected patients have minimal or absent neurological involvement, although the cutaneous photosensitivity and skin-cancer risk are preserved. The principal neuro-XP groups are XPA and XPD, with lesser involvement in XPB and XPG.

Clinical features

Severe sunburn from minimal UV exposure in infancy.
Marked freckling on sun-exposed sites by age 2.
Skin atrophy, telangiectasia, poikiloderma.
Multiple skin cancers (BCC, cSCC, melanoma) — median age first cancer ~8 years (vs ~50 in general population).
Ophthalmic: photophobia, conjunctival injection, eyelid skin cancer, corneal opacity.
Neurological (in some complementation groups): progressive intellectual disability, ataxia, sensorineural hearing loss.

Diagnosis

Clinical recognition of severe early-onset photosensitivity and multiple skin cancers.
Cellular UV sensitivity testing (DNA repair assays).
Targeted gene panel for the eight XP genes.

Management

UV protection (the cornerstone)

Absolute UV avoidance from infancy: indoor-only daylight exposure with UV-filtered windows; UV-protective clothing including head and neck cover; broad-brim hat with neck flap; UV-protective glasses.
Daily broad-spectrum SPF 50+.
Vitamin D supplementation.

Surveillance & treatment

Skin examination by a dermatologist at minimum 3-monthly intervals lifelong.
Excision of any new lesion with low threshold.
Field therapy (5-FU, imiquimod, MAL-PDT) for AKs.
Avoid radiotherapy where possible — accelerates new tumour formation.
Ophthalmology, audiology and neurology surveillance per phenotype.
Genetic counselling, prenatal diagnosis discussion.

UK XP service

The UK has a nationally commissioned XP service at Guy's and St Thomas' NHS Foundation Trust, providing specialist multidisciplinary follow-up, genetic counselling, and pooled patient education resources. All UK XP patients should be registered.

Prognosis

Without strict UV avoidance, life expectancy is significantly reduced (median ~30–40 years; melanoma is the leading cause of death). With rigorous UV protection from infancy, life expectancy is substantially improved.

Xeroderma pigmentosum