Xeroderma Pigmentosum (XP) is a rare genetic disorder that impairs the body’s ability to repair DNA damage, especially that caused by ultraviolet (UV) light. This condition is characterized by extreme sensitivity to sunlight, often leading to severe reactions after minimal exposure. Individuals with XP face an increased risk of developing skin cancers at a much younger age than the general population. The disorder affects approximately 1 in 1 million people in the United States, though incidence can be higher in some populations, such as in Japan, where it’s reported at 45 per million.
Genetic Roots of XP
Xeroderma Pigmentosum stems from mutations within specific genes, primarily those involved in the nucleotide excision repair (NER) pathway. These genes include XPA, XPB, XPC, XPD, XPE, XPF, and XPG. An additional gene, XPV, also known as DNA polymerase eta (POLH), is associated with a variant form of XP where the NER pathway functions, but DNA replication across damaged sites is faulty.
XP is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a mutated gene—one from each parent—to develop the condition. Parents who carry one copy of the mutated gene typically do not show symptoms. These genetic mutations result in a defective or absent protein crucial for the proper functioning of DNA repair mechanisms.
For example, the XPA gene produces a protein that helps assemble other DNA repair proteins at sites where DNA has been damaged. The XPC gene product forms a complex that initiates the recognition of DNA damage in the global genomic nucleotide excision repair pathway. When these proteins are impaired, the body’s capacity to mend damaged DNA is compromised, leading to the characteristic features of XP.
How DNA Repair is Affected
The genetic mutations in XP directly impact the nucleotide excision repair (NER) pathway, which corrects various types of DNA damage, especially those induced by UV radiation. Normally, NER works by identifying damaged sections of the DNA double helix, such as cyclobutane pyrimidine dimers and 6-4 photoproducts caused by UV light. Once identified, specialized enzymes cut out the damaged segment of the DNA strand.
Following the excision of the faulty fragment, DNA polymerase enzymes synthesize new, correct DNA to fill the gap, using the undamaged complementary strand as a template. DNA ligase seals the newly synthesized segment into the DNA strand, restoring its integrity. In individuals with XP, mutations in NER genes like XPA or XPC disrupt this multi-step process. This impairment prevents the effective removal of UV-induced DNA lesions, leading to their accumulation within cells.
Unrepaired DNA damage can have severe consequences, including cell dysfunction, new mutations, and uncontrolled cell growth. This persistent damage increases the risk of developing skin cancers, as the cells cannot adequately correct errors that arise from environmental exposures. The inability to repair these lesions makes individuals with XP susceptible to the carcinogenic effects of sunlight.
Recognizing the Signs
The most notable symptom of Xeroderma Pigmentosum is extreme sensitivity to sunlight, often manifesting as severe sunburns and blistering after only a few minutes of sun exposure. This hypersensitivity frequently becomes apparent in early childhood, sometimes during a child’s first significant sun exposure. Affected individuals typically develop extensive freckling in sun-exposed areas, such as the face, before the age of two years.
As the condition progresses, the skin can exhibit premature aging, including dryness, thinning, and the appearance of irregular dark and light spots. There is a significantly increased risk of various skin cancers, including basal cell carcinoma, squamous cell carcinoma, and melanoma, often appearing in childhood or adolescence. Patients with XP have a risk of non-melanoma skin cancer that is approximately 10,000 times higher, and a risk of melanoma that is about 2,000 times higher, compared to the general population.
Beyond skin manifestations, eye abnormalities are common, affecting nearly 80-93% of patients. These can include painful light sensitivity (photophobia), inflammation of the conjunctiva, corneal damage, and eyelid degeneration. In some cases, neurological issues may develop, affecting about 20-25% of individuals. These symptoms can range from developmental delays and progressive hearing loss to issues with coordination and speech.
Living with Xeroderma Pigmentosum
Managing Xeroderma Pigmentosum centers on rigorous protection from ultraviolet (UV) radiation to prevent DNA damage and subsequent complications. This involves strict sun avoidance, particularly during peak UV hours, and consistent use of protective clothing, such as long-sleeved shirts, pants, wide-brimmed hats, and gloves. High-SPF broad-spectrum sunscreens (SPF 30 or greater) should be applied generously to all exposed skin, including hands, neck, ears, and lips.
Patients also benefit from UV-blocking eyewear, including sunglasses with side shields, and UV-resistant films on windows in homes and vehicles. Regular dermatological check-ups are necessary for early detection and prompt surgical removal of any precancerous lesions or skin cancers. Ophthalmological monitoring is also recommended to address eye complications, including lubricating eye drops or, in severe cases, corneal transplants.
Neurological assessments are part of comprehensive care for individuals who develop these symptoms, involving hearing aids or other supportive therapies. While there is no cure for XP, a multidisciplinary approach involving dermatologists, ophthalmologists, neurologists, and other specialists helps manage symptoms and improve quality of life. Ongoing research explores new therapies, including gene therapy and topical DNA repair enzymes, which may offer future advancements in care.