Xeroderma Pigmentosum (XP) is a rare autosomal recessive disorder that results in increased sensitivity to ultraviolet radiation. It is marked by a high risk for skin cancers like squamous cell carcinoma and basal cell carcinoma. Patients present with severe sun sensitivity in early childhood.

UV radiation, such as the radiation emitted by the sun, causes cross-linking of pyrimidine residues of the DNA, preventing its replication. Normally, DNA damage caused by UV rays is repaired by the nucleotide excision repair system, allowing for the removal of the damaged pyrimidine dimers. In xeroderma pigmentosum, there is a loss-of-function mutation that occurs in the genes that are involved in this system, thus leading to the accumulation of unrepaired DNA damage and disease progression. Eight different mutations are associated with different subtypes and clinical presentations of xeroderma pigmentosum (XPA, ERCC3, XPC, ERCC2, DDB2, ERCC4, ERCC5, and POLH). These genes function in DNA repair.

Xeroderma pigmentosum usually presents with early-onset pigmentary skin changes, early development of skin cancers, and ocular manifestations, such as photophobia, prominent conjunctival injection, and severe keratitis. Patients may also have oral, and/or neurologic manifestations of the disease.

Pigmentary skin changes caused by XP in early childhood manifest as hyperpigmented and hypopigmented macules over the face, neck, chest, and dorsal hands and forearms. They can also present with other skin changes secondary to UV damage including telangiectasias, actinic keratoses, and premature aging of the skin (i.e. atrophy, xerosis, and wrinkling). The risk of skin cancer is significantly increased in these patients. 

Xeroderma pigmentosum should be suspected in children that present with acute sun sensitivity from minimal exposure, early and notable freckling, and skin cancer within the first 10 years of life. The diagnosis of the disorder is established based on clinical manifestations, family history, and genetic inheritance. Confirmational tests are done via unscheduled DNA synthesis techniques (UDS) or by gene sequencing. 

Since there is no known exact cure for xeroderma pigmentosum, management of XP focuses on limiting malignant tumor development, early detection and treatment, and improving quality of life. Thus, the following are the mainstays of treatment:

• Strict sun protection and avoidance – the use of sunscreens, sun protective clothing (e.g. long sleeves and pants), and staying indoors during the daytime are recommended. Patients with XP may also need vitamin D supplementation due to deficiency caused by lack of sunlight.
• Treatment of skin cancer and premalignant lesions – Surgical excision is the treatment of choice for skin cancer patients with XP. Other treatments include cryotherapy, photodynamic therapy, and treatment with topical fluorouracil and imiquimod.
• Ocular management – UV protective glasses and lubricating eye drops (methylcellulose) may be used to avoid the effects of keratitis sicca (dry eyes). For severe eye damage, a corneal transplant may be advised.
• Neurologic management – Sensory-neural hearing loss is common in XP patients, thus hearing aids are recommended. Other neurological findings can be managed through appropriate therapy.

Xeroderma pigmentosum cannot be prevented however, steps may be done to allow for early diagnosis and prevent the development of skin cancer and other complications. Genetic counseling should be done especially for those with familial history for accurate diagnosis, recommendations for specialty assessments, and reproductive counseling. Research has shown positive effects of chemopreventive drugs that may impede the risk of skin cancer. This includes the use of systemic retinoids, topical fluorouracil and imiquimod, and oral nicotinamide and Polypodium leucotomos extract.

References:

Hand, JL. and Warner, CG. (2021). Xeroderma pigmentosum. UptoDate. Retreived from https://www.uptodate.com/contents/xeroderma-pigmentosum

Kumar, V., Abbas, A. K., & Aster, J. C. (2020). Robbins Basic Pathology (10th ed.). Elsevier – Health Sciences Division.

Lucero R, Horowitz D. Xeroderma Pigmentosum. [Updated 2022 Sep 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551563/