A 32-year-old Indian woman presents to the dermatology clinic with multiple pigmented lesions and severe photosensitivity that began in childhood. She reports freckling on sun-exposed areas and has had two episodes of skin cancer (basal cell carcinoma at age 28 and squamous cell carcinoma at age 31). Her parents are consanguineous. On examination, she has dry, atrophic skin with poikiloderma. Genetic testing reveals mutations in the XPA gene. Which of the following DNA repair mechanisms is primarily defective in this patient?

Explanation

## Clinical Diagnosis: Xeroderma Pigmentosum (XP) This patient presents with the classic triad of xeroderma pigmentosum: 1. Severe photosensitivity and sunburn-like reactions 2. Pigmentary changes (hyperpigmentation and hypopigmentation) 3. Early-onset skin cancers (often by age 20–30) ## Pathophysiology of XPA Deficiency **Key Point:** XPA (Xeroderma Pigmentosum group A) protein is a critical component of the nucleotide excision repair (NER) pathway. It recognizes and binds to DNA lesions, particularly UV-induced thymine dimers and 6-4 photoproducts. ### NER Mechanism and XPA's Role ```mermaid flowchart TD A[UV-induced DNA lesion<br/>Thymine dimer or 6-4 photoproduct]:::outcome --> B[XPA recognizes lesion<br/>Recruits TFIIH complex]:::action B --> C[Unwinding of DNA<br/>around lesion]:::action C --> D[Excision of 24-32 nucleotide<br/>oligomer by XPF-ERCC1]:::action D --> E[DNA polymerase fills gap<br/>DNA ligase seals nick]:::action E --> F[Lesion removed<br/>Normal DNA restored]:::outcome G[XPA mutation]:::urgent --> H[NER pathway blocked<br/>at recognition step]:::urgent H --> I[Accumulation of<br/>unrepaired UV lesions]:::urgent I --> J[Increased mutations<br/>& skin cancer risk]:::urgent ``` **High-Yield:** Without functional XPA, the entire NER pathway is crippled because the initial recognition and recruitment step cannot occur. This leads to: - Accumulation of UV-induced DNA lesions - Increased mutation rate (1000-fold higher skin cancer risk) - Severe photosensitivity - Neurological degeneration (in some XP groups) ## Why NER, Not Other Repair Pathways? | Repair Pathway | Primary Lesion | Defect in XP? | Result | |---|---|---|---| | **NER** | UV lesions, bulky adducts | **YES (XPA)** | **Cannot remove thymine dimers** | | MMR | Mismatched bases | No | Would cause Lynch syndrome, not XP | | BER | Oxidative damage, single-base lesions | No | Would cause different phenotype | | NHEJ | Double-strand breaks | No | Would cause radiosensitivity, not photosensitivity | **Clinical Pearl:** XP patients have normal repair of oxidative damage and mismatches, but catastrophic failure in UV lesion removal. This explains why they are exquisitely photosensitive but not necessarily radiosensitive. ## Genetic and Epidemiological Notes **Key Point:** XP shows **autosomal recessive inheritance** (confirmed by consanguineous parents in this case). There are 7 complementation groups (XPA–XPG), each with mutations in different NER genes. XPA is one of the most severe groups. **Mnemonic for XP complications:** **SKIN CANCER** - **S**evere photosensitivity - **K**eratitis, keratoconjunctivitis - **I**ncreased skin cancers (1000× risk) - **N**eurological degeneration (progressive) - **C**ancer (internal organs in some groups) - **A**trophic, poikilodermatous skin - **N**ucleotide excision repair defect - **C**onsanguinity (often in pedigrees) - **E**arly onset (childhood) - **R**ecessive inheritance