Xeroderma pigmentosum
Introduction
Xeroderma pigmentosum (XP) is a rare autosomal recessive neurocutaneous disorder. Individuals with XP show extreme sensitivity to ultraviolet (UV) radiation and an increased risk of skin cancer.
Defective DNA repair mechanisms prevent the correction of UV-induced DNA damage in XP. XP primarily affects the skin and eyes and leads to progressive damage in these organs that usually begins in early childhood. However, some patients develop neurological symptoms. The disorder is typically recognized in infancy or early childhood, often following severe sunburn or unusual freckling after minimal sun exposure.
Genetics
Mutations in genes involved in the nucleotide excision repair (NER) pathway, which repairs UV-induced DNA damage, cause xeroderma pigmentosum. Researchers have identified at least eight complementation groups (XPA–XPG and XPV), each associated with mutations in different genes. These genetic defects prevent cells from removing thymine dimers and other UV-induced DNA lesions. The condition follows an autosomal recessive inheritance pattern; accordingly, individuals inherit pathogenic variants from both parents and siblings have a 25% risk of recurrence.
Pathophysiology
XP patients cannot repair DNA damage after exposure to ultraviolet radiation. This defect leads to genetic mutations in skin cells, resulting in premature skin aging and a very high risk of malignancy. UV exposure generates DNA lesions such as pyrimidine dimers. In normal individuals, the nucleotide excision repair system repairs these lesions, but XP patients lack this ability. As a result, affected individuals accumulate early cellular damage, develop genomic instability, and experience carcinogenesis, particularly in sun-exposed tissues. Some individuals may undergo progressive neurodegeneration because neuronal cells cannot remove unrepaired DNA damage.
Epidemiology
Xeroderma pigmentosum is an extremely rare disorder, with an estimated prevalence of approximately 1 in 1,000,000 in Europe and the United States. The disorder appears more often in certain regions such as North Africa and Japan. Males and females are equally affected.
Clinical Manifestations
Infants or young children with xeroderma pigmentosum (XP) typically present with extreme photosensitivity, characterized by severe sunburn after minimal UV exposure. The skin often appears dry and mottled, with areas of hyper- and hypopigmentation, and signs of premature aging, including atrophy, telangiectasia, and wrinkling. There is an increased risk of cutaneous malignancies, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma.
Additionally, ocular involvement is relatively common and may include photophobia, conjunctivitis, keratitis, corneal opacification, and eyelid abnormalities. Along with cutaneous and ocular symptoms, in some patients, neurological involvement, including developmental delay, progressive cognitive decline, sensorineural hearing loss, epilepsy, ataxia, and peripheral neuropathy, occurs.
Diagnosis
Clinicians base diagnosis on clinical findings of extreme photosensitivity and characteristic skin changes, particularly early-onset freckling and skin cancers It can be confirmed by genetic testing that identifies pathogenic variants in one of the XP-related genes. In specialized settings, functional assays can also demonstrate defective DNA repair (e.g., reduced unscheduled DNA synthesis).
Differential Diagnosis
ther photosensitive and DNA repair disorders can be considered in the differential diagnosis, such as Cockayne syndrome, Trichothiodystrophy, Bloom syndrome, and Other genodermatoses with increased cancer risk.
Treatment
The absence of curative treatment for xeroderma pigmentosum means that management centers on rigorous avoidance of ultraviolet exposure and vigilant surveillance for malignancies. This implies minimizing time in the sunlight, using protective clothing, applying high-SPF sunscreen, and installing UV-filtering window films to reduce exposure.
Regular dermatological follow-up is crucial for the early detection and treatment of emerging skin cancers. Cutaneous malignancies are managed according to standard oncologic guidelines, and repeated surgical procedures are often necessary. While patients with ocular involvement require ophthalmologic care, those with central nervous system manifestations should be monitored neurologically.
Prognosis
UV sensitivity and neurological involvement are two prognostic determinants of xeroderma pigmentosum. Without adequate UV-protection, patients often develop multiple skin cancers early in life, which can significantly reduce life expectancy. Strict photoprotection and early treatment improve patient outcomes. Patients with neurological involvement experience progressive neurodegeneration, further affecting their quality of life, functional abilities, and prognosis.
