Definition
Xeroderma pigmentosum (OMIM #278700, #278720, #278730, #278740, #278750, #610651) is a genetic disease in which a defect in the DNA repair system prevents DNA damage caused by UV radiation from being detected and repaired, resulting in a high risk of tumor development in skin exposed to sunlight.
Key Data
< swipe to see entire table >
Synonym | XP, melanosis lenticularis progressiva |
Genes | DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, XPC |
Gene products | DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, XPC |
Function | Detection of UV-induced DNA damage and global genome repair |
Heredity | Autosomal recessive |
Prevalence | 1:1,000,000 in the USA and Europe, slightly elevated incidence in the Middle East, Japan, and North Africa |
Genotype-phenotype correlation | A genotype-phenotype correlation study is currently underway. |
Penetrance | High |
< swipe to see entire table >
Diagnosis
An integrated examination of the typical clinical symptoms and family history and/or molecular genetic evidence of biallelic pathogenic variants in DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, or XPC
Method
Genetic evidence can be confirmed by single-gene testing. The use of panel examinations consisting of multiple genes together with exome or genome sequencing may also be helpful.
Basic Variant After Localization
XPA
- India: c.335_338delTTATinsCATAAGAAA
- Japan: c.390-1G>C (carrier incidence of 1%)
- Tunisia: p.Arg228Ter
XPC
- North Africa: c.1643_1644delTG
ERCC2
- Iraqi Jews: p.Arg683Gln
POLH
- Tunisia / North Africa: Del exon 10
- Japan: c.490G>T (splice site variant); p.Ser242Ter; p.Glu306Ter and c.1661delA
- Basque region / North Spain: c.764+1G>A
Differential Diagnoses
Genetic syndrome with increased cutaneous photosensitivity due to a defective nucleotide excision repair system (NER):
- XP with neurological abnormalities
- Cockayne syndrome (CS)
- XP/CS complex
- Trichothiodystrophy (TTD)
- XP/TTD complex
- Cerebro-oculo-facio-skeletal (COFS) syndrome
- COFS/TTD complex
- CS/TTD complex
- UV-sensitive syndrome
Baller-Gerold Syndrome
Carney Complex
Clinical Presentation
Clinical Presentation
Increased sensitivity to sun exposure (severe sunburn with blistering, erythema formation after only minimal exposure to sunlight in around 60% of patients), freckle-like pigmentation changes in the face before the age of 2
Sunlight-related eye problems (photophobia, keratitis, eyelid skin atrophy)
Greatly increased risk of developing cutaneous neoplasia related to sunlight exposure (basal cell carcinomas, squamous epithelial carcinomas, melanomas)
Rare, severe neurological complications (progressive sensorineural hearing loss, cognitive impairment)
Predisposition to Cancer
Basal cell carcinomas
Melanomas
Squamous epithelial carcinomas (face, head, and neck region)
Leukemia
Cerebral and spinal gliomas
Other solid tumors (lungs, uterus, breasts, pancreas, kidneys, stomach, testicles)
Therapeutic Considerations
Dietary supplementation with oral vitamin D if there is a deficit
Avoiding exposure to UV light from sunlight (UV-A and UV-B) or to UV radiation (UV-C, e.g. halogen lights)
Consistently wearing clothing to cover the head, body, and eyes
Broad-spectrum sun protection with a high UV protection factor
Avoiding the consumption of tobacco
Training in self-examination to check for abnormal pigmentation changes
Treatment of pre-malignant lesions: cryotherapy
Larger areas: topical application of 5-fluorouracil, imiquimod preparations, with dermabrasion and dermatome shaving rarely necessary
Treatment of cutaneous neoplasia: curettage or excision
Surveillance Recommendations
Surveillance Recommendations
Evidence-based standards are lacking for early detection, particularly during childhood. The AACR consensus recommendations are listed for you as follows.
Hematology-oncology: following the diagnosis, avoidance of exposure to sunlight and ionizing radiation; early diagnosis and treatment of skin changes; screening for ocular neoplasia and tumors of the ENT area every 6-12 months
Dermatology: thorough skin examination every 3 months
Gastroenterology/nutrition: swallowing examination, need-based dietary supplementation
Ophthalmology: Medical examination every 6-12 months
Neurology: Testing for developmental retardation and progressive neurological changes
Orthopedics: annual scoliosis evaluation
ENT: basic audiogram (and as needed) and tumor screening every 6-12 months
Additional Information
Open Clinical Trials / Registries
There are currently no open clinical trials/registries for patients with Xeroderma Pigmentosum that we can recommend to you for more information.