Xeroderma Pigmentosum
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Direct answer
Xeroderma pigmentosum is an autosomal recessive disorder in which the nucleotide excision repair pathway, which removes UV-induced DNA damage, is defective. Affected children develop severe sunburn, freckling and photophobia early in life, followed by skin cancers that often arise in childhood or early adult life. Strict photoprotection and regular skin and eye surveillance are the cornerstones of care.
What you must remember
- Defect: impaired nucleotide excision repair in most complementation groups (XPA to XPG), and impaired translesion synthesis in the variant form XP-V, caused by DNA polymerase eta deficiency.
- Early signs: freckle-like pigmentation on sun-exposed skin in early childhood, with sunburn after minimal exposure.
- Eyes: photophobia, conjunctivitis, corneal opacities and ocular tumours, so eye protection and eye review form part of care.
- Cancers: basal cell carcinoma, squamous cell carcinoma and melanoma arising at unusually young ages on sun-exposed skin.
- Neurology: progressive neurological degeneration in a subset of patients, notably in some complementation groups.
- Diagnosis: clinical suspicion from early freckling, supported by UV-induced DNA damage assays on cultured fibroblasts and complementation analysis.
- Key differential: Cockayne syndrome, another repair disorder, which does not carry a high skin cancer risk.
How XP differs from Cockayne syndrome
Xeroderma pigmentosum and Cockayne syndrome both involve faulty DNA repair and photosensitivity, which makes them easy to confuse in a vignette. The table separates them by cancer risk, freckling and growth. Both are autosomal recessive, so inheritance alone does not separate them.
| Feature | Xeroderma pigmentosum | Cockayne syndrome |
|---|---|---|
| Repair defect | Nucleotide excision repair | Transcription-coupled repair |
| Skin cancer risk | Very high, early onset | Not increased |
| Freckling | Prominent on sun-exposed skin | Absent |
| Growth | Usually normal | Short stature, cachectic dwarfism |
| Neurology | Progressive degeneration in some | Progressive, with microcephaly |
| Inheritance | Autosomal recessive | Autosomal recessive |
Freckling and cancer risk point to xeroderma pigmentosum, whereas photosensitivity with dwarfism and neurological decline points to Cockayne syndrome. Both need strict sun protection, but only xeroderma pigmentosum needs intensive skin cancer surveillance. Cockayne syndrome carries no raised skin cancer risk, so an early tumour in a photosensitive child points firmly to xeroderma pigmentosum. Growth and neurology are the other clues to check.
Where photoprotection questions catch the unwary
Management questions usually turn on what is protective and on what is not.
- Trap: assuming sunscreen alone is enough protection. Correct: clothing, shade, UV-filtering window films and avoidance of midday sun are also required.
- Trap: waiting for symptoms before starting cancer surveillance. Correct: regular skin and eye examinations start early, because tumours appear at young ages.
- Trap: treating XP as a cosmetic photosensitivity disorder. Correct: it carries high cancer and neurological risk and needs multidisciplinary follow-up.
- Trap: using photopatch testing to diagnose XP. Correct: photopatch testing detects photoallergy; DNA repair assays on fibroblasts are the diagnostic tests.
Frequently asked questions
Which DNA repair pathway is defective in xeroderma pigmentosum?
Most forms of xeroderma pigmentosum involve the nucleotide excision repair pathway, which removes bulky UV-induced lesions such as cyclobutane pyrimidine dimers. The variant form XP-V instead has a defect in translesion synthesis due to DNA polymerase eta deficiency.
What is the most important prevention in xeroderma pigmentosum?
Strict UV protection is the most important prevention in xeroderma pigmentosum, including avoiding midday sun, wearing protective clothing and applying broad-spectrum sunscreen. Indoor UV exposure from fluorescent lighting and car windows should also be reduced with UV-filtering covers and films.
Which skin cancers occur in xeroderma pigmentosum?
Basal cell carcinoma, squamous cell carcinoma and melanoma all occur in xeroderma pigmentosum, often at unusually young ages and on sun-exposed skin. Regular examination and early excision are the main ways to limit morbidity.
How is xeroderma pigmentosum diagnosed?
Diagnosis of xeroderma pigmentosum rests on early freckling in sun-exposed areas with a compatible history, supported by UV-induced DNA damage assays on cultured fibroblasts. Complementation analysis then identifies the specific group, which guides genetic counselling.
How does xeroderma pigmentosum differ from Cockayne syndrome?
Both are autosomal recessive repair disorders with photosensitivity, but xeroderma pigmentosum causes freckling and a high skin cancer risk, while Cockayne syndrome causes dwarfism and neurological decline without cancer predisposition. The distinction is essential in vignettes.