What is xeroderma pigmentosum?

From the Guidelines

Xeroderma pigmentosum is a rare genetic disorder characterized by extreme sensitivity to ultraviolet (UV) radiation, particularly from sunlight, caused by inherited pathogenic variants in nucleotide excision repair genes, leading to severe sunburns, early development of freckles, and significantly increased risk of skin cancers, including melanoma, basal cell carcinoma, and squamous cell carcinoma. People with this condition have a defect in their DNA repair mechanisms, specifically in the nucleotide excision repair pathway, which prevents their cells from properly repairing damage caused by UV light 1. This leads to severe sunburns, early development of freckles, and significantly increased risk of skin cancers. The condition typically manifests in early childhood with severe sunburns after minimal sun exposure. Beyond skin problems, some patients may develop neurological abnormalities, including hearing loss, poor coordination, intellectual disability, or seizures.

Key Characteristics of Xeroderma Pigmentosum

• Extreme sensitivity to ultraviolet (UV) radiation
• Defect in DNA repair mechanisms, specifically in the nucleotide excision repair pathway
• Severe sunburns, early development of freckles, and significantly increased risk of skin cancers
• Neurological abnormalities, including hearing loss, poor coordination, intellectual disability, or seizures
• Estimated to affect 1 in 1,000 in the United States, with varying frequencies in different populations 1

Management and Prevention

Management focuses on strict sun protection through protective clothing, high-SPF sunscreens, UV-blocking films on windows, and avoiding outdoor activities during peak sunlight hours. Regular skin examinations are essential for early detection of cancerous changes 1. A multidisciplinary team approach to care, including dermatology, ophthalmology, otolaryngology, and neurology assessments and follow-up, is necessary. Consuming foods and supplements rich in vitamin D is recommended to prevent vitamin D deficiency.

Cancer Surveillance and Screening

• Dermatologic exams every 3 months
• Ophthalmologic and oral exams by specialists at least twice a year
• CBC (once or twice yearly) and annual bone marrow should be considered for the risk of AML in patients with PVs in XPC 1

From the Research

Definition and Characteristics of Xeroderma Pigmentosum

• Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme sensitivity to sunlight, resulting in sunburn, pigment changes in the skin, and a greatly elevated incidence of skin cancers 2.
• It is defined by a defective DNA nucleotide excision repair, leading to an increased risk of developing multiple skin tumors and neurologic alterations in the most severe form 3.
• XP is characterized by photosensitivity, progressive pigmentary change, and an increased incidence of ultraviolet (UV)-induced skin and mucous membrane cancers 4.

Clinical Features and Diagnosis

• The first features of XP are either extreme sensitivity to sunlight, triggering severe sunburn, or abnormal lentiginosis (freckle-like pigmentation) on sun-exposed areas 2.
• Diagnosis is made clinically by the presence of an acute and prolonged sunburn response at all exposed sites, unusually early lentiginosis in sun-exposed areas, or onset of skin cancers at a young age 2.
• The clinical diagnosis is confirmed by cellular tests for defective DNA repair, and a definite diagnosis can be made by the identification of biallelic mutation in one of the causative genes 5.

Management and Treatment

• There is no cure for XP, but the skin effects can be minimized by rigorous protection from sunlight and early removal of pre-cancerous lesions 2.
• Treatment options include cryotherapy, topical imiquimod, topical 5-fluorouracil, chemical peeling, excision, CO2 laser resurfacing, fractional/pulsed laser therapy, and photodynamic therapy for actinic keratosis and cutaneous malignancy 5.
• Investigational therapies include the use of T4 endonuclease-V liposome lotion and oral nicotinamide to reduce the rate of actinic keratoses and non-melanoma skin cancers, and gene therapy for radical cure of this condition 5.

Prognosis and Quality of Life

• The prognosis for XP patients is good if they have no neurological problems and receive lifetime protection against sunlight 2.
• However, patients with neurological problems have a progressive condition, leading to disabilities and a shortened lifespan 2.
• Increased awareness and early diagnosis of the condition, followed by rigorous sun avoidance and protection and optimal management, can dramatically improve the quality of life and life expectancy 5.