## Clinical Context: Xeroderma Pigmentosum (XP) **Key Point:** XP is a rare autosomal recessive disorder caused by mutations in nucleotide excision repair (NER) genes (XPA–XPG). Patients cannot repair UV-induced thymine dimers and 6–4 photoproducts, leading to extreme photosensitivity and 1000× increased risk of skin and ocular malignancies. ## DNA Repair Defect in XP ### Normal NER Pathway ```mermaid flowchart TD A[UV damage: Thymine dimer, 6-4 photoproduct]:::outcome --> B[XPA recognizes lesion]:::action B --> C[XPB/XPD unwind DNA helix]:::action C --> D[XPF/XPG excise damaged oligonucleotide]:::action D --> E[DNA polymerase fills gap]:::action E --> F[DNA ligase seals nick]:::action F --> G[Normal DNA restored]:::outcome ``` ### In XPA Mutation - **Recognition step fails** → thymine dimers persist - **Unrepaired lesions** → mutations accumulate in skin fibroblasts and melanocytes - **Result:** Severe photosensitivity, pigmentary changes, early-onset skin cancers (basal cell, squamous cell, melanoma by age 20–30), and ocular complications (keratitis, cataracts, corneal opacification) ## Management Strategy: Photoprotection & Surveillance **High-Yield:** XP management is **prevention + early detection**. There is no cure; the goal is to minimize UV exposure and detect malignancies at an early, treatable stage. ### Immediate Next Steps | Intervention | Rationale | | --- | --- | | **Strict photoprotection** | Avoid all unnecessary sun exposure; use high-SPF sunscreen (SPF ≥50), protective clothing, UV-blocking windows | | **Baseline skin examination** | Full-body skin mapping; photograph all lesions for serial comparison | | **Baseline ophthalmology** | Document corneal status, lens clarity, retinal health | | **Dermatology surveillance** | Every 3–6 months: examine for new or changing lesions | | **Ophthalmology surveillance** | Every 6–12 months: monitor for keratitis, cataracts, corneal opacification | | **Genetic counselling** | Discuss inheritance, family screening, reproductive options | **Clinical Pearl:** Patients with XP should **avoid all non-essential sun exposure**, including outdoor activities during daylight hours. Even brief, incidental exposure can trigger severe sunburn and accelerate malignancy risk. ### Why NOT the Other Options **Retinoids (Option 1):** - Retinoids (isotretinoin, acitretin) may reduce the incidence of non-melanoma skin cancers in XP, but they are not first-line and require careful monitoring for teratogenicity and hepatotoxicity - Photoprotection is the primary intervention; retinoids are adjunctive, not immediate **Wide excision of all lesions (Option 2):** - Premature excision of benign pigmented macules is not indicated - Many lesions are benign; excision should be reserved for suspicious or confirmed malignant lesions - Photoprotection prevents future lesions; excision does not address the underlying defect **Systemic immunosuppression (Option 4):** - XP is not an immune disorder; immunosuppression has no role - The defect is in DNA repair, not immune function - Immunosuppression would increase infection risk without benefit ## Mnemonic: **XP-SAFE** **X**eroderma **P**igmentosum → **S**urveillance, **A**void sun, **F**ull-body exam, **E**arly detection [cite:Robbins 10e Ch 7; Kraemer KH. Xeroderma pigmentosum. In: Goldsmith LA, Katz SI, eds. Fitzpatrick's Dermatology in General Medicine. 9th ed. McGraw-Hill; 2019.]
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.