Xeroderma Pigmentosum – 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.
Synonyms:
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
Pattern of inheritance:
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
Xeroderma Pigmentosum – 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.
Methodology
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 According to 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
- Rothmund-Thomson 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)
Cancer Predisposition
- 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)
Special Features of Treatment
- 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
Diagnosis of Xeroderma Pigmentosum- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Xeroderma Pigmentosum - What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
Below are the recommendations from the AACR 2024 Guidelines.
Haemato-oncology
- Avoid sunlight and ionising radiation from the time of diagnosis
- Ensure adequate vitamin D supplementation
- Early diagnosis and treatment of skin changes
- Be aware of tumour-related symptoms
- Complete blood count including reticulocytes every 3-6 months after diagnosis
- Consider bone marrow aspiration and biopsy with cytogenetics annually from diagnosis
- HPV vaccination
Dermatology
- Dermatological examination every 3 months
Ophthalmology
- Eye examination with screenimg for ocular neoplasia every 6-12 months
ENT
- Basic audiogram and as needed
- Screening for ENT tumours every 6-12 months
Gastroenterology/Nutrition
- Swallowing assessment, nutritional supplementation as required
Neurology
- Screening for developmental delay and progressive neurological changes
Orthopaedics
- Annual scoliosis assessment
