Xeroderma Pigmentosum

General Information

An autosomal recessive genetic disease with defective UV radiation induced damage repair (dysfunctional DNA excision repair mechanisms)

Risk Factors: genetic predisposition (e.g., mutations in XPV variants), family history

Evaluation:

Clinical presentation
- Early freckling and lentigene manifestations (<2 yrs) on facial regions, dorsal hands and forearms
- Both hyper- and hypopigmentation
- Premature skin aging
- Telangiectasias
- Severe sunburn, blistering
- Complication-related symptoms (e.g., skin carcinoma findings, oral/ophthalmologic manifestations)
Diagnosis
- Unscheduled DNA synthesis techniques (UDS): assessing ability of patient fibroblast culture to repair DNA
- Complementation analysis to determine gene mutation, other genetic testing
- Biopsy, CBC
- Visual or audiological testing

Anatomical Blurb: Freckles & Lentigos

Freckles (ephelides): localized, small areas of pigmentation and increased melanin synthesis; fade without sun exposure

Lentigos: irregular borders, due to abnormal melanocytes; don’t fade

Lentigenes: multiple hyperpigmented regions, not raised, typically larger than lentigos

DNA Repair & XP Etiology

Effects of UV:

Thymine dimerization (covalent bonds, inhibits DNA rep by disrupting antiparallel strand H-bonds)
Misincorporation of bases during DNA rep

Repair mechanisms

Light repair (photoreactivation): visible light (400-750nm) stimulates photoreactivation repair enzyme (PRE), which breaks covalent bonds between thymine
Dark excision repair: occurs in the absence of light
- (1) Endonuclease (UVrABC1) nicks DNA backbone on both sides of dimerization, disrupting the H-bonds
- (2) The disrupted strand is excised
- (3) DNA polymerase fills in missing bases at 3’OH primer; DNA ligase seals in new strand to repair nicks

UV-induced DNA damage (e.g., thymine dimerization, pyrimidones) doesn’t undergo the same cellular processes for repair
XP mutation variants (i.e., XPC, most common form in US, XPA, XPB, XPD-G) code for either different enzymes and molecules pertinent in DNA rep
- XPC (3p25): endonuclease

Minimizing sun exposure: broad spectrum SPF, sun protective clothing

Vit D supplementation

Regular screening for carcinoma findings, precancerous lesions

Medication: oral tretinoin, treating secondary side efects