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Diagnosis: Xeroderma Pigmentosum (XP)
The photograph shows the classic picture of xeroderma pigmentosum: the face (A) shows dense freckle-like pigmented macules (lentigines), mottled hyper- and hypopigmentation, dryness and early skin atrophy/telangiectasia confined to the sun-exposed areas (forehead, cheeks, nose), while the palm (B) - a site that gets far less UV exposure - is comparatively spared. This sun-exposure-dependent distribution with premature "photoaged" skin and pigmentary mottling in a young person is the hallmark of XP.
Cause
Xeroderma pigmentosum is a rare autosomal recessive disorder of DNA repair. It results from mutations in genes of the nucleotide excision repair (NER) pathway (XPA through XPG, and the variant form XPV/POLH), which normally removes UV-induced DNA lesions such as cyclobutane pyrimidine dimers. Because damaged DNA is not repaired, sun-exposed skin accumulates mutations in genes like RAS, TP53, and PTCH, leading to extreme UV sensitivity and a markedly increased cancer risk. Different complementation groups (XP-A to XP-G, XP-V) correspond to different genes and severity, with XP-C patients typically having skin disease without neurologic involvement (- Andrews' Diseases of the Skin, p. 3582-3591; - Fitzpatrick's Dermatology, p. 2749).
Clinical features
- Skin: Onset usually before age 2 - acute sunburn reactions, early freckling/lentigines, and progressive poikiloderma (mottled pigmentation, atrophy, telangiectasia) in sun-exposed areas.
- Skin cancer: Basal cell carcinoma and squamous cell carcinoma occur in ~45% of patients, melanoma in ~5%, most before age 10-20 - a roughly 10,000-fold increase in skin cancer risk before age 20, concentrated on the head and neck.
- Eyes: Photophobia, ectropion, corneal opacity, blepharospasm, and ocular surface neoplasms (~40% of patients).
- Neurologic: Progressive neurodegeneration in ~20% (more common in certain complementation groups), with hearing loss possible.
- De Sanctis-Cacchione syndrome: a severe variant combining XP with microcephaly, mental deficiency, dwarfism, and gonadal hypoplasia, seen mostly in complementation group D.
(- Andrews' Diseases of the Skin, p. 3584-3595)
Treatment
There is no cure; management is centered on rigorous photoprotection and cancer surveillance:
- Strict UV avoidance/protection: broad-brimmed UV-blocking hats (with face shields), UVA/UVB-blocking sunglasses, UV-protective clothing, and daily broad-spectrum sunscreen reapplied every 2-3 hours.
- Supportive measures: vitamin D supplementation (since sun avoidance causes deficiency), and possibly nicotinamide and zinc.
- Chemoprevention/treatment of skin lesions: oral retinoids (isotretinoin) can suppress new cancers but tumors rebound when stopped; topical imiquimod or 5-fluorouracil for precancerous/cancerous lesions; individual tumors excised or destroyed with cryotherapy.
- Investigational therapy: topical recombinant T4 endonuclease V (repairs UV-induced pyrimidine dimers) and gene therapy approaches are being studied.
- Regular multidisciplinary follow-up: routine dermatologic, ophthalmologic, and neurologic surveillance, per XP Society/NIH guidelines.
(- Andrews' Diseases of the Skin, p. 3593; - Fitzpatrick's Dermatology, p. 2749)
Recent literature note
A 2022 comprehensive review (PMID 36002347) and a 2025 case-based review on immune checkpoint inhibitors for advanced cutaneous SCC in XP patients (PMID 40052589) both reinforce the same core management (sun protection, chemoprevention, early lesion treatment) while noting immunotherapy (e.g., cemiplimab) as an emerging option for advanced, unresectable skin cancers in XP - this doesn't contradict textbook teaching but is a newer addition worth mentioning if the question includes management of advanced malignancy.
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