Foundations · Year 1 · from Foundations
Case 1: Xeroderma Pigmentosum (Nucleotide Excision Repair Deficiency)
Clinical Image
Source: Wikipedia - Xeroderma pigmentosum - CC BY-SA 3.0
Case Presentation
A 6-year-old girl is referred to dermatology for evaluation of severe freckling and multiple skin lesions. Her parents report that she develops severe sunburns even with brief sun exposure and has had progressive skin changes since infancy. Physical examination reveals hundreds of freckles (lentigines) concentrated on sun-exposed areas, areas of skin atrophy, and several suspicious pigmented and scaly lesions. Biopsy of one lesion confirms squamous cell carcinoma. She has already had three basal cell carcinomas removed. She also has photophobia and some developmental delay. Given her extreme sun sensitivity and early-onset skin cancers, xeroderma pigmentosum (XP) is suspected. Genetic testing confirms mutations in the XPA gene, which is essential for nucleotide excision repair (NER). Without functional NER, she cannot repair UV-induced thymine dimers and other bulky DNA adducts. The family is extensively counseled on rigorous sun protection: specialized UV-blocking clothing, sunscreen, UV-filtering film on windows, and shifting activities to nighttime when possible. She will require lifelong dermatologic surveillance with frequent skin examinations and early excision of suspicious lesions. Her lifetime skin cancer risk exceeds 10,000-fold compared to the general population.
Key Learning Points
- Xeroderma pigmentosum results from defects in nucleotide excision repair (NER), the pathway that removes bulky, helix-distorting lesions including UV-induced thymine dimers
- Without NER, UV damage accumulates with each sun exposure, leading to mutations and dramatically elevated skin cancer risk; neurological problems also occur in some XP complementation groups
- NER involves damage recognition, dual incisions flanking the lesion (by XPF-ERCC1 and XPG endonucleases), excision of a 24-32 nucleotide segment, and gap filling by DNA polymerase