Xeroderma pigmentosum

Overview

Xeroderma pigmentosum (XP) is a rare, inherited genetic disorder characterized by extreme sensitivity to ultraviolet (UV) rays from sunlight. Individuals with XP have a greatly increased risk of developing skin cancers and other sun-induced skin and eye damage at an early age. The condition primarily affects the skin, eyes, and sometimes the nervous system. XP is caused by a defect in the body's ability to repair DNA damage caused by UV radiation, making even minimal sun exposure dangerous.

Causes

XP is caused by mutations in any one of several genes involved in the nucleotide excision repair (NER) pathway - a cellular mechanism that repairs DNA damaged by UV light. These genes include XPA, XPB, XPC, XPD, XPE, XPF, and XPG. A mutation in any of these genes leads to defective DNA repair, allowing UV-induced damage to accumulate, which in turn leads to premature aging of the skin and a high risk of skin cancer.

XP is inherited in an autosomal recessive pattern, meaning a child must inherit two copies of the defective gene (one from each parent) to develop the condition. Carriers (with one defective gene) typically do not show symptoms.

Symptoms

Symptoms of XP often appear in infancy or early childhood and worsen with sun exposure. Common clinical features include:

• Severe sunburn after minimal sun exposure (in about 50% of cases)

• Freckling or pigmentation changes in sun-exposed areas (usually before age 2)

• Dry, thin, or prematurely aged skin (xeroderma)

• Development of multiple skin cancers at a young age, especially basal cell carcinoma, squamous cell carcinoma, and melanoma

• Eye abnormalities such as photophobia (light sensitivity), keratitis, conjunctivitis, and eyelid tumors

• Neurological problems (in some cases), including hearing loss, intellectual disability, or poor coordination

The severity and range of symptoms can vary depending on the specific gene involved and the degree of DNA repair deficiency.

Diagnosis

Diagnosis of XP involves a combination of clinical evaluation and specialized laboratory tests. Diagnostic steps include:

• Clinical history and physical exam: Noting extreme sun sensitivity, early-onset freckling, and skin changes

• DNA repair assays: Testing a skin biopsy sample to measure cellular response to UV light

• Genetic testing: To identify mutations in one of the XP-related genes and confirm the diagnosis

• Ophthalmologic and neurologic evaluations: To assess eye involvement and any central nervous system symptoms

Early diagnosis is critical for preventing further damage by initiating strict sun protection measures.

Treatment

There is no cure for XP. Treatment focuses on preventing UV exposure and managing skin damage and other complications. Main strategies include:

• Strict sun avoidance: Staying indoors during daylight hours and using UV-protective clothing, wide-brimmed hats, and sunglasses

• High-SPF sunscreen: Broad-spectrum sunscreen applied regularly to all exposed skin, even indoors near windows

• Regular skin exams: Dermatologic surveillance for early detection and removal of precancerous lesions and skin cancers

• Eye care: Protective eyewear and monitoring by an ophthalmologist

• Neurological monitoring: If neurological symptoms are present

• Retinoid therapy: Oral retinoids may help reduce the risk of new skin cancers in some patients

Gene therapy and other experimental treatments are being researched, but are not yet available for routine clinical use.

Prognosis

The prognosis for individuals with XP depends largely on early diagnosis and strict adherence to sun protection measures. Without preventive care, many patients develop multiple skin cancers in childhood or adolescence, which can be life-threatening. With early intervention, avoidance of UV exposure, and ongoing medical care, individuals with XP can reduce their risk of complications and lead longer, healthier lives. However, those with neurological involvement may experience progressive deterioration and reduced life expectancy.