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Therapeutics in Dermatology
A reference textbook in dermatology

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Xeroderma pigmentosum

16 April 2013, by ROBERT C. & SARASIN A.

Francisco Gil is the author of this chapter.

ACKNOWLEDGEMENTS

Chapter written with the help of the EADV, the Fondation René Touraine and the Therapeutics in Dermatology

OVERVIEW

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by hypersensitivity to sun exposure and a several thousand-fold increase in the risk of developing ultraviolet (UV)-induced skin and mucous membrane cancers.

XP was initially described in the 19th century but only later the mechanistic link between UV hypersensitivity, DNA repair abnormalities, somatic mutations and skin cancer was established. Due to genetic defects, patients with XP have a reduced DNA repair capacity, allowing UV-induced lesions to persist and cause skin cancer. XP is characterized by severe actinic changes leading to early onset of skin cancers, various ocular manifestations and occasional neurological abnormalities. Both genotypes and phenotypes can be quite variable, making clinical and molecular-genetic diagnostics challenging. Optimal therapy includes avoidance of sun exposure and diagnosis and treatment of the associated neoplasms.

SIGNS AND SYMPTOMS

XP exhibits a significant phenotypic variability and genotype–phenotype correlations are particularly complicated as clinical manifestations are not predictable according to the type of XP gene defect. There are, however, common denominators to all XP variants: photophobia, skin hypersensitivity to UV radiation, actinic damage to the skin, cancer of UV-exposed areas of the skin and mucous membranes of the eyes and mouth and, in some patients, progressive neurological degeneration. Mutations in XP genes result in different clinical entities. Photosensitivity, neurological abnormalities and skin cancer are important pathological features which can be used to distinguish between three archetypes: XP, trichothiodystrophy and Cockayne syndrome. There are several related or overlapping disorders with similar features that form a family of syndromes involving neural, oncologic, cutaneous, developmental and other abnormalities. Individuals with XP present with a variety of signs depending on the severity of their disease.

Skin:

At birth an individual’s skin is healthy but cutaneous signs and symptoms usually emerge in children under the age of 2 years. Signs of premature aging of the skin are almost universal with freckle and lentigo-like pigmentary changes in sun-exposed areas. Actinic changes accumulate leading to poikiloderma, characterized by patches of hyper and hypopigmentation, atrophy and telangiectasias.

XP patients under 20 years have a 10.000-fold increased risk for basal cell and squamous cell carcinomas (SCC) and a 2,000-fold increased melanoma risk compared to healthy subjects. XP patients can develop hundreds of skin cancers. The mean age at diagnosis of skin cancer is 8 years but may already have developed by the third or fourth year of life.

Eyes:

Between 40% and 80% of individuals with XP have ocular abnormalities, caused by UV-induced DNA alteration to epithelial cells of the conjunctiva, cornea, lens and eyelid. Patients may have photophobia, conjunctivitis, keratitis that may lead to corneal opacification, cataract and pterygium formation, hyperpigmentation of the eyelids and loss of eyelashes. There is also a 1000-fold increased risk for malignancies involving sun-exposed tissues of the eye.

Nervous system:

Between 20% and 30% of patients with XP develop neurological abnormalities, with variable age of onset, severity and rate of progression. It is presumed to be a consequence of DNA damage induced by oxidative metabolism, causing apoptosis with progressive loss of neurons.

Neurological involvement in XP includes progressive sensorineural hearing loss, cognitive decline, speech and gait disturbances, loss of fine motor control and dysphagia. XP patients under 20 years have an approximately 50-fold increase in the risk of brain and other central nervous system cancers. Neurological degeneration was shown to be the second cause of death in XP patients.

XP is also associated with leukoplakia, erythroplakia and a 100.000-fold increased risk for tongue cancers. SCC of the tip of the tongue affects patients younger than 20 years of age and runs a slowly progressive course. Higher incidences of actinic cheilitis and SCC of the lip have also been described.

Individuals with XP are also at a 10 to 20-fold increased risk for other internal malignancies including sarcomas, lung, uterine, breast, pancreatic, gastric, renal and testicular tumors, as well as leukemias.

WHO GETS AND CAUSES

XP occurs worldwide, affecting all ethnic groups and phototypes. Although geographically variable, the general prevalence of XP is approximately 1:250 000.

The role of UV radiation as a cause of skin cancer and the importance of an intact DNA repair system in providing protection are well-known and both are particularly well demonstrated in XP patients, where UV damage leads to an increased frequency and early onset of both non-melanoma skin cancer and melanoma. In fact, the human genome is constantly exposed to endo and exogenous threats to the integrity of DNA and UV light is one of the most common causes of DNA damage. Patients with XP have molecular defects in the genes of the components of the pathway of nucleotide excision repair (NER). This cascade, a multi-step mechanism associated with at least 28 genes, aims to recognize and repair UV-induced helix-distorting lesions of DNA. These defects cause hypersensitivity to UV radiation, with accumulation of unrepaired UV-induced DNA damage, which either promotes cellular apoptosis contributing to accelerated skin and ocular aging, or promotes cellular transformation resulting in the development of cancer.

DIAGNOSIS AND TREATMENT

Diagnosis of XP is usually achieved clinically and confirmed at the molecular level. XP clinical criteria include the presence of a xerotic, hyper and/or hypopigmented, slightly scaly skin on sun-exposed areas, acute burning on minimal sun exposure, early onset of severe actinic changes and numerous premalignant and malignant skin lesions. Molecular genetic testing for mutations in the XP genes is available to confirm the diagnosis. For the molecular diagnosis of XP, functional DNA-repair assays, gene and protein expression analyses, as well as sequence analyses of the affected genes, may be utilized. The diagnosis of patients with XP requires the cooperation of various clinical specialities, imaging methods as well as human genetics.

The treatment of XP is challenging because it is a multisystem disease, there are no causative treatment options available and, usually, by the time of diagnosis significant tissue damage has already occurred. For optimal care a patient with XP should be followed regularly by a team of physicians according to the severity of an individual’s clinical disease. Early diagnosis is of utmost importance and immediate implementation of strict and consistent UV-protective measures is mandatory. Regular examination of the skin with early diagnosis and treatment of pre-malignant and malignant lesions should be undertaken to improve prognosis. XP-associated cutaneous, ocular and oral lesions should be treated according to the standard therapy guidelines, including topical therapies, electrodessication and curettage or surgical excision. High-dose oral retinoids can reduce the number of skin tumors occurring. However, due to the predictable toxic systemic effects, it should be used only in patients with high numbers of newly developed tumors. Resurfacing procedures like full-thickness grafting, dermabrasion and chemical peels and the topical application of xenogenic repair enzymes in cream form (photolyase or T4 endonuclease, a bacterial DNA repair enzyme) have been shown to be effective as additional skin cancer prophylaxis in patients with XP. Recently, vismodegib, an oral inhibitor of the hedgehog signaling pathway, showed promising results in the treatment of nodular basal cell carcinoma, and anti-programmed cell death protein 1 therapy was very effective in inducing regression of melanoma metastases and also non-melanoma skin cancer, especially in metastatic basal cell carcinoma with amplification of programmed cell death 1 ligand 1.The role of gene therapy at this point is unclear and further research is necessary to evaluate its clinical applicability.

TIPS FOR MANAGING

Preventative measures must begin immediately in childhood. After the diagnosis is made, the family must be advised about XP and methods of skin and eye protection, instructive materials for the school must be provided and contact with patient support groups can be helpful in identifying resources for the family. A broad avoidance of sun exposure is obligatory, including the use of sunscreens with high factor ratings, long-sleeved protective clothing, wide-brimmed hats and UV-absorbing eye glasses when outdoors. It is also advisable to use films with UV filters on window glass and to check the environmental UV level with UV-measuring devices. All sources of UV radiation in the home, school or work environment should be identified and eliminated, if possible. Patients with XP are put at risk by exposure even to low-level sources of UV radiation and should implement precautions while indoors, protecting from fluorescent, halogen and mercury-vapour lights and, preferably, sitting away from windows. Proper protection from sunlight may predispose to vitamin D deficiency and these patients should routinely be started on supplementation.

Individuals should be taught to recognize new lesions and monitor for any changes, including size and color, in pre-existing skin lesions. Complete photo documentation of the entire skin surface might be particularly valuable in the early detection of skin cancer in patients with XP. Eye examinations must be performed periodically and, frequently associated with a delay in diagnosis, neurological involvement must be monitored, with special emphasis on detection and management of hearing loss. Other precautions XP patients must be advised about include the avoidance of smoking and second hand smoke and perioperative protection from damaging light if surgery is required, as well as avoidance of all drugs that harm DNA.

Genetic testing can be used for confirmation of diagnosis, not only in patients but also in utero and for future pregnancy planning.

Prognosis varies with the severity of the disorder, the success in avoiding UV light and the efficacy of clinical vigilance. The lack of implementation of sun-protection measures in a climate with intense sunlight exposure results in a markedly reduced life expectancy. However, the initiation of UV-protective measures at an early stage combined with access to modern medical care, especially in the absence of neurological disease, creates the possibility of a normal lifespan for patients with XP.

Althought some accomplishments have been fulfilled, there is still a long way to go. At this point, the most appropriate therapy for XP is early initiation of protection against UV light and continued vigilance for the development of new skin lesions and subsequent treatment.

REFERENCES

Feller L, Wood NH, Motswaledi MH, Khammissa RA, Meyer M, Lemmer J. Xeroderma pigmentosum : a case report and review of the literature. J Prev Med Hyg. 2010 ;51:87-91.

Lehmann J, Seebode C, Martens MC, Emmert S. Xeroderma Pigmentosum – Facts and Perspectives. Anticancer Res. 2018 ;38:1159-64.

DiGiovanna J, Kraemer K. Shining A Light On Xeroderma Pigmentosum. J Invest Dermatol. 2012 ;132:785–96

Lichon V, Khachemoune A. Xeroderma pigmentosum : beyond skin cancer. J Drugs Dermatol. 2007 ;6(3):281-8.

Lehmann J, Schubert S, Emmert S. Xeroderma pigmentosum : diagnostic procedures, interdisciplinary patient care, and novel therapeutic approaches. J Dtsch Dermatol Ges. 2014 ;12(10):867-72.

LINKS

www.genodermatoses-network.org/Xeroderma-Pigmentosum

www.patient.co.uk/Xeroderma-Pigmentosum

www.xps.org

www.rarediseases.org/rare-disease-information

www.xpfamilysupport.org

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