Xeroderma pigmentosum and genetics
Xeroderma pigmentosum (XP) is a rare genetic disorder characterized by extreme sensitivity to ultraviolet (UV) light, which can lead to severe skin damage and an increased risk of skin cancers. It arises from defects in genes responsible for repairing DNA damage caused by UV exposure, specifically in a process known as nucleotide excision repair. The condition is inherited in an autosomal recessive manner, meaning that a child must receive a defective gene from both parents to be affected. XP typically manifests in early childhood, and while it affects individuals across all ethnicities, higher incidences have been noted in regions such as Japan and the Middle East.
The disorder encompasses several subtypes, each associated with mutations in different DNA repair genes. These subtypes vary in severity, with the classic form (XPA) linked to significant neurological complications, while others, like XPV, can still repair UV-damaged DNA but lack a specialized enzyme for effective replication. Symptoms include severe sunburns after brief sun exposure, skin lesions, photophobia, and potential neurological delays. Currently, there is no cure for XP; management focuses primarily on rigorous sun protection and monitoring for skin cancer. Regular dermatological and ophthalmological checkups are crucial for early detection and treatment of skin malignancies.
Xeroderma pigmentosum and genetics
ALSO KNOWN AS: Melanosis lenticularis progressiva; Kaposi disease; atrophoderma pigmentosum; XP
DEFINITION Xeroderma pigmentosum is a group of rare skin disorders characterized by extreme sensitivity to sunlight (photosensitivity), with possible ocular and neurologic involvement. An inherited disease, it results from a defect in the genes involved in the repair of DNA damage caused by ultraviolet light.
Risk Factors
A child born to parents who each carry a copy of the defective DNA repair gene responsible for this disorder has a 25 percent chance of being affected. The disorder usually manifests at age one to two years and affects both sexes across ethnic groups, although a higher incidence is reported in Japan and the Middle East. Typically, it results from mutations in genes XPA, ERCC3, XPC, ERCC2, DDB2, ERCC4, ERCC5, and ERCC1—involved in DNA repair—or in the gene POLH that encodes an (a specialized polymerase) that replicates ultraviolet-damaged DNA.
Etiology and Genetics
Xeroderma pigmentosum is an autosomal recessive disease that manifests as hypersensitivity to the sun’s ultraviolet rays. Exposure to ultraviolet light induces the formation of dimers by favoring the cross-linking of adjacent pyrimidine bases present in DNA. These structures distort the DNA double helix, thus preventing and gene expression. Normally, several distinct enzymes, involved in a process termed “nucleotide excision repair,” work in concert to remove the lesion. The resulting gap is then filled in by a that restores the original base sequence.
Persons with xeroderma pigmentosum carry a mutation in any of the known genes that specify the enzymes that participate in excision repair. Several genetic subtypes of the disorder exist. They differ in disease severity and frequency of occurrence and are classified according to the defective repair gene involved. Thus, the classic form of xeroderma pigmentosum, known as XPA, results from a mutation in gene XPA. The other subtypes, designated XPB through XPH, are defective in other DNA repair genes and a variant form, known as XPV, is defective in gene POLH. Subgroups XPA and XPC encompass about half of xeroderma pigmentosum cases, with very rare cases reported of XPB, XPE, and XPH.
Accumulation of damaged DNA causes progressive degenerative alterations of the skin, thus greatly increasing the likelihood of mutagenesis and skin cancers, such as basal cell carcinoma, squamous cell carcinoma, or melanoma. Classic XPA, which shows the lowest level of DNA repair, is more likely to be associated with progressive neurologic complications. Individuals with subtypes XPB, XPD, XPF, XPG, and XPH show varying degrees of neurologic abnormalities, whereas individuals with subtypes XPC, XPE, and XPV generally do not. Although form XPV is clinically indistinguishable from classic XPA, it is genetically distinct from the other subtypes. In fact, XPV cells have the ability to repair DNA damage induced by ultraviolet light but lack the specialized polymerase that replicates ultraviolet-damaged DNA.
Symptoms
Persons with xeroderma pigmentosum typically experience unusually severe sunburn with skin redness and blistering after only brief exposure to sunlight. The condition is characterized by excessive skin dryness, pigmentary changes, skin atrophy, lesions termed solar keratoses, and a 2,000-fold risk of developing sunlight-induced skin cancer before age twenty. Eye damage from ultraviolet radiation causes photophobia and irritation in about 80 percent of cases and may lead to ocular tumors. Neurologic complications are present in 20 to 30 percent of cases and include poor coordination, deafness, developmental delay, and mental retardation.
Screening and Diagnosis
Clinical diagnosis usually is based on a visual examination of the skin and eyes and on a history of photosensitivity, freckling, and skin tumors in young children. A blood test or skin biopsy can reveal a DNA repair defect. For persons with a family history of xeroderma pigmentosum, prenatal tests, including amniocentesis, are available, as are genetic counseling and genetic testing to determine carrier status for individuals with subtypes XPA and XPC.
Treatment and Therapy
Currently, no treatment for xeroderma pigmentosum exists. Disease management consists of preventing sun-induced damage and ensuring the prompt removal of precancerous and cancerous lesions. Premalignant solar keratoses may be removed by cryotherapy or dermabrasion. More aggressive tumors, such as melanoma, may require radiation and chemotherapy in addition to surgical excision. Retinoid therapy, moisturizers, and vitamin D supplements are recommended. Topical lotion containing a DNA repair enzyme has been reported to have reduced the development of solar keratoses and basal cell carcinoma in clinical trials.
Prevention and Outcomes
Avoidance of all sources of ultraviolet radiation, including fluorescent lights, can improve outcome. Protective clothing, a wide-brimmed hat, ultraviolet-absorbing sunglasses, and a sunscreen with high sun-protection factor are mandatory when outdoors. Medications that increase sensitivity to sunlight should be used with caution and tobacco smoking avoided. Regular checkups by a dermatologist (every three months) and an ophthalmologist (annually) are important for disease surveillance. By taking measures that reduce deadly skin cancer, affected persons with no neurologic complications can achieve a normal life span.
Bibliography
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