Xeroderma pigmentosum (XP) is a genetic disorder in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light. Symptoms may include a severe sunburn after only a few minutes in the sun, freckling in sun-exposed areas, dry skin and changes in skin pigmentation. Nervous system problems, such as hearing loss, poor coordination, loss of intellectual function and seizures, may also occur. Complications include a high risk of skin cancer, with about half having skin cancer by age 10 without preventative efforts, and cataracts. There may be a higher risk of other cancers such as brain cancers. XP is autosomal recessive, with mutations in at least nine specific genes able to result in the condition. Normally, the damage to DNA which occurs in skin cells from exposure to UV light is repaired by nucleotide excision repair. In people with xeroderma pigmentosum, this damage is not repaired. As more abnormalities form in DNA, cells malfunction and eventually become cancerous or die. Diagnosis is typically suspected based on symptoms and confirmed by genetic testing. There is no cure for XP. Treatment involves completely avoiding UV exposure. This includes protective clothing, sunscreen and dark sunglasses when out in daylight. Prognosis/life expectancy in XP depends on three key factors, (1) the specific type (genetic variant) of XP a patient has (and within that the most important factor is whether they have an XP subtype which is associated with neurological involvement); (2) what level of UV exposure they have had over their lifetime (which directly leads to the increased risk of skin and eye cancers) and (3) the extent to which they can access regular specialist medical care, including skin and eye checks, surgeries, other oncology treatment if needed and supportive care when their needs are palliative. Research from the National XP service in the UK () shows that patients who regularly attend the XP service have significantly increased life expectancies compared to the previously published US data, both for patients with a neurological deterioration and those without. This is likely to be multifactorial. Patients are diagnosed early and are better educated on the need to UV protect and know the optimum methods for this. Often patients become good at recognising early skin cancers and this along with the regular medical checks means skin and eye cancers can be removed in a timely manner. Lastly patients can access modern treatments that can be effective with high grade cancers or in decreasing the complications associated with neurological variants of XP. Research shows that patients in the UK with XP who attend the National XP service have a life expectancy of 50 years for those with neurological involvement and 81 years for those without () . The latter is comparable to the general UK population. These estimates may be inappropriate for patients from other countries, where their exposure to UV is much greater and/or access to medical care significantly harder. They may also be effected by inconsistent data collection and follow-up care. Retinoid creams may help decrease the risk of skin cancer. Vitamin D supplementation is generally required. If skin cancer occurs, it is treated in the usual way. The disease affects about 1 in 100,000 worldwide. By region, it affects about 1 in 20,000 in Japan, 1 in 250,000 people in the United States and 1 in 430,000 in Europe. It occurs equally commonly in males and females. Xeroderma pigmentosum was first described in the 1870s by Moritz Kaposi. In 1882, Kaposi coined the term xeroderma pigmentosum for the condition, referring to its characteristic dry, pigmented skin. Individuals with the disease have been referred to as "children of the night" or "moon children".
Signs and symptoms
Signs and symptoms of xeroderma pigmentosum may include:
Severe sunburn when exposed to only small amounts of sunlight. Development of many freckles at an early age Rough-surfaced growths (solar keratoses), and skin cancers Eyes that are painfully sensitive to the sun and may easily become irritated, bloodshot and clouded Blistering or freckling on minimum sun exposure Telangiectasia (spider veins) Limited growth of hair on chest and legs Scaly skin Xeroderma (dry skin) Irregular hyperpigmented spots on the skin Corneal ulcerations
Genetics
One of the most frequent defects in xeroderma pigmentosum is an autosomal recessive genetic defect in which nucleotide excision repair (NER) enzymes are mutated, leading to a reduction in or elimination of NER. If left unchecked, damage caused by ultraviolet light can cause mutations in individual cell's DNA. The causes of the neurological abnormalities are poorly understood and are not connected with exposure to ultraviolet light. The most current theories suggest that oxidative DNA damage is generated during normal metabolism in the central nervous system, and that some types of this damage must be repaired by NER. Since DNA repair is under genetic control, it can mutate. Many genetic disorders such as are caused by mutations in genes that repair damaged DNA, including xeroderma pigmentosum (XP), which arises from a mutation affecting the mechanism that repairs UV damage in skin cell DNA. Those affected with the autosomal recessive disorder XP are extremely sensitive to UV light produced by the sun and develop pigmented spots, tumors, and skin cancer with minimal exposure. Individuals with XP are about 1,000 times more likely to develop skin cancer than individuals without the disorder. Pigmentation changes and heightened risk for skin cancers are accounted for by the increased mutation rate in the skin of XP-affected individuals, which itself is caused by mutations in DNA repair proteins. Examination of mutations in the p53 gene in tumors from XP patients reveal p53 mutations characteristic of UV exposure in the majority of tumors. As with all genetic disorders, genetic counseling and psychological support is appropriate for the families to discuss probability of occurrence in future pregnancies, feelings of isolation and concern about career prospects. There is no cure for xeroderma pigmentosum. The most common fate for individuals with XP is early death from cancer.
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