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Xeroderma pigmentosum

Xeroderma pigmentosum
Authors:
Jennifer L Hand, MD
Catherine Gupta Warner, MD
Section Editors:
Jeffrey Callen, MD, FACP, FAAD
Moise L Levy, MD
Deputy Editor:
Rosamaria Corona, MD, DSc
Literature review current through: Sep 2022. | This topic last updated: May 14, 2021.

INTRODUCTION — Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder of DNA repair characterized by increased sensitivity to ultraviolet radiation (UVR), early development of pigmentary changes and UVR-induced skin and mucous membrane cancers, and, in some patients, progressive neurodegeneration [1]. XP was first described in 1874 by dermatologist Moritz Kaposi, who coined the term "xeroderma" in reference to the dry or xerotic skin quality of his four patients with XP. While early investigations supported the importance of UVR in the pathogenesis of the disease, it was not until 1968 that the disease was associated with defective DNA repair in cultured skin fibroblasts. This led to the discovery of XP subtypes or "complementation groups"; XP-variant is the only form of XP with intact DNA excision repair capability [2-5].

This topic will discuss the pathogenesis, clinical manifestations, diagnosis, and management of XP. Other disorders associated with increased photosensitivity are discussed separately. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment" and "Congenital erythropoietic porphyria".)

EPIDEMIOLOGY — Xeroderma pigmentosum (XP) equally affects males and females and is present worldwide, but incidence varies significantly across countries. Based upon retrospective studies, the estimated incidence in the United States and Western Europe is approximately one per million live births [6]. Other studies have shown incidences as high as 15 to 20 per million in Libya and 10 to 50 per million in Japan [6,7]. Incidences in Northern African and Western Asian countries, such as Libya, Tunisia, Morocco, and Pakistan, may be higher due to more frequent consanguineous marriages [7-10]. However, consanguinity is not felt to account for the entirety of the variations worldwide.

MOLECULAR GENETICS AND PATHOGENESIS — Xeroderma pigmentosum (XP) is caused by mutations in any of eight genes involved in the recognition and repair of ultraviolet radiation (UVR)-induced DNA damage (ie, cyclobutane pyrimidine dimers and pyrimidine [6-4] pyrimidone photoproducts [6-4PPs]) in a pathway called nucleotide excision repair (NER) [4]. XP is inherited in an autosomal recessive pattern with 100 percent penetrance.

NER can be subdivided into two pathways: the transcription-coupled repair (TCR) and the global genome repair (GGR).

In the TCR pathway, specialized proteins recognize the abnormal photoproduct of DNA and block subsequent RNA polymerase II activity.

In the GGR pathway, a different set of proteins recognizes abnormal, ultraviolet (UV)-altered DNA and marks it for repair.

Ultimately, both pathways lead to unwinding of the DNA helix and excision of small fragments of affected DNA. The defects are then repaired via DNA synthesis pathways involving DNA polymerase and ligases.

Based upon the specific gene affected, XP can be divided into seven XP subgroups or complementation groups, group A (XPA) through G (XPG), and xeroderma pigmentosum variant (XPV). The XP complementation groups, the involved genes, and associated proteins are as follows [11]:

XPA (XPA) – protein that assists with DNA unwinding

XPB (ERCC3) – helicase involved with DNA unwinding

XPC – protein recognizing global genome defects

XPD (ERCC2) – helicase involved with DNA unwinding

XPE (DDB2) – protein recognizing global genome defects

XPF (ERCC4) – forms an endonuclease together with ERCC1 that incises damaged DNA for repair

XPG (ERCC5) – endonuclease that incises damaged DNA

XPV (POLH) – DNA polymerase eta that protects DNA using a translesion DNA synthesis mechanism of postreplication repair

Subtypes XPA to XPG have NER defects, whereas XPV is associated with a defect in postreplication repair. Specifically, the XPC and XPE proteins play a role in the GGR pathway, while XPA, XPB, XPD, XPF, and XPG function at the culmination of the TCR/GGR pathways once the abnormal DNA has been recognized and tagged for unwinding/excision.

Unlike the typical XPA to XPG subtypes, XPV has a defect in DNA polymerase eta. This protein is required for DNA replication of damage (UV photoproducts) that has not been repaired by the NER pathway. This process is known as translesion DNA synthesis [2,12].

The pathogenesis of neurodegenerative disease in XP patients is poorly understood and is independent from UVR-induced DNA damage. Multiple studies support the theory that unrepaired oxidative DNA damage (eg, the generation of 8,5-cyclopurine-2-deoxynucleosides), some of which may be repaired by NER, accumulates in the brain, leading to neuronal death [13-15].

In a cohort of 161 XP patients from 142 consanguineous French families of North African ancestry, a very high frequency of early-onset hematologic malignancies, including myelodysplastic syndrome with an excess of blast cells, acute myeloid leukemia, or T cell acute lymphoblastic leukemia, has been noted [16]. All patients in this cohort exhibited the homozygous founder mutation XPC c.1643_1644 delTG; p.Val548AlafsX572 (delTG) mutation, leading to complete absence of the XPC protein.

CLINICAL FINDINGS — Consistent findings across all xeroderma pigmentosum (XP) groups include early-onset pigmentary skin changes, early development of skin cancers (often in the first decade of life), and ocular manifestations, including photophobia, prominent conjunctival injection, and severe keratitis. Some patients present with neurologic disorders, such as sensorineural hearing loss, and progressive cognitive impairment.

Sunburn and pigmentary skin changes — The majority of XP patients experience a severe and prolonged sunburn reaction after minimal sun exposure. Specifically, severe sunburning is associated with XP subtypes XPA, XPB, XPD, XPF, and XPG; in contrast, XPC, XPE, and XPV have a normal sunburn response, yet still develop abnormal skin pigmentation [17]. Patients without an abnormally severe sunburn response have been shown to paradoxically develop skin cancer earlier than those who experience sunburn, likely due to less strict sun-protective measures in these patients [15].

Freckling generally begins at the age of one to two years, predominantly on sun-exposed areas, such as the face and hands (picture 1) [18]. Over time, the skin develops signs of premature photoaging, including progressive atrophy, dryness, telangiectasias, early-onset lentigos, and intermixed hyper- and hypopigmentation [11].

Skin cancer — Squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and melanoma all occur in XP with much greater frequency and at a younger age compared with the general population. In a 40-year National Institutes of Health follow-up study of 106 XP patients, the risks of nonmelanoma skin cancer (NMSC) and melanoma were found to be 10,000-fold and 2000-fold higher, respectively, than in the general population [19].

In contrast with what is observed in the general population, in XP patients, NMSC develops at a younger age than melanoma, with an average age of onset of 9 years for NMSC (picture 2) and 22 years for melanoma. This age reversal suggests a different carcinogenetic mechanism between NMSC and melanoma in XP patients [20]. DNA sequencing studies of melanomas in XP patients have demonstrated phosphatase and tensin homolog (PTEN) mutations to be far more frequent than BRAF mutations, which are the most common mutations found in melanoma in the general population [21]. Of the PTEN mutations, 91 percent have ultraviolet (UV)-signature mutations occurring at adjacent pyrimidines, indicating an important role for sun exposure in the induction of these melanomas [22].

Oral cancers — In patients with XP, the incidence of intraoral cancers is estimated to be 3000 to 10,000 times higher than in the general population [23,24]. The most common locations are the tip of the tongue and the dorsal tongue. Carcinoma of the palate and gingiva are less common but still occur more often in XP patients than in patients without XP [25]. Other oral tumors reported in XP patients include angiosarcoma, fibrosarcoma, and pyogenic granuloma [18,25,26].

Eye findings — XP patients experience a variety of ophthalmologic changes, mainly affecting the anterior parts of the eye and cornea that are exposed to ultraviolet radiation (UVR) directly with less protection from the lid. Eye disease has been described in 40 to 100 percent of XP patients [27-30]. The most common disorders are ectropion, lagophthalmos, conjunctival injection, conjunctival melanosis, corneal neovascularization, corneal scarring, pterygium, and cancers of both the ocular surface and eyelids [27-29]. Commonly reported symptoms include photophobia and dry eyes [31,32].

Patients in complementation groups XPC, XPE, and XPV, who have preserved transcription-coupled nucleotide excision repair (TC-NER), are noted to have significantly more ocular surface abnormalities compared with those in the XPA, XPB, XPD, XPF, and XPG groups, who have impaired TC-NER [30]. This is assumed to be due to a lack of aggressive sun-protective measures at an early age in patients with preserved TC-NER, who do not experience severe sunburn reactions.

Neurologic manifestations — The central nervous system (CNS) is affected in approximately 25 percent of patients with XP [15]. The most common subtypes of XP associated with the development of progressive neurodegeneration are XPA and XPD. Neurologic manifestations have also been reported in XPB, XPF, and XPG but only rarely in XPC and XPE [28].

Abnormalities include sensorineural hearing loss, intellectual impairment, speech delays, spasticity, areflexia, ataxia, dysphagia, and peripheral neuropathy. Imaging studies and histopathologic examination have correlated these abnormalities with neuronal loss, cortical atrophy, and ventricular dilation [28]. (See "Neuropathies associated with hereditary disorders".)

XP patients have been shown to have a significantly increased risk of CNS malignancies, including medulloblastoma, glioblastoma, spinal cord astrocytoma, and schwannoma [2,33].

Systemic cancers — While skin cancer is the most common type of cancer associated with XP, several studies suggest that XP patients may have an increased risk of other types of cancer as well. Increased frequency of hematologic malignancies, including myelodysplastic syndrome, acute myeloid leukemia, and acute lymphoblastic leukemia, was noted in 142 consanguineous French families of North African ancestry with an XPC mutation [16]. XPG single nucleotide polymorphisms have been shown to confer increased colorectal cancer susceptibility, especially in Asians [34]. XPD polymorphisms were shown to correlate with non-small cell lung cancer risk in nonsmoking Chinese female patients [35].

Reproductive health — A 2019 natural history study performed at the National Institutes of Health found that women with XP underwent menarche at a normal age but had increased incidence of premature menopause [36]. The study included 60 females aged ≥9 years who were evaluated at the National Institutes of Health from 1971 to 2018. Of the 60 women evaluated, 31 completed a questionnaire and a gynecologic evaluation, 14 completed a questionnaire without an examination, and 15 had only their records reviewed. Menarche occurred at a median age of 12 years, which was comparable with the United States general population. Among the 18 patients who had undergone menopause, the median age was 29.5 years. This is significantly lower than the United States general population, which is approximately 52.9 years. There were 32 live births among 21 of the women, 5 of whom subsequently developed premature menopause. While this study was small and the first to report premature menopause in patients with XP, it suggests that the possibility of premature menopause should be discussed with female XP patients, as they may want to consider having children earlier. This study also indicates that DNA repair may be important in maintaining normal ovarian function.

DIAGNOSIS — The diagnosis of xeroderma pigmentosum (XP) should be suspected in a child presenting with acute sun sensitivity with minimal exposure, early and marked freckling (before the age of two years), and skin cancer within the first decade of life. Additional clinical findings that suggest the diagnosis include photophobia with prominent conjunctival injection, severe keratitis, sensorineural hearing loss, and progressive cognitive impairment. (See 'Clinical findings' above.)

The diagnosis is established based upon the clinical presentation, a family history consistent with autosomal recessive inheritance, and/or confirmatory genetic testing [37]. (See 'Genetic testing' below.)

Genetic testing — Molecular testing approaches for the diagnosis of XP include serial single-gene testing, use of a multigene panel, or full genomic testing. While single-gene testing is generally not the preferred test due to low sensitivity, it may be warranted in cases where more complete testing is not available.

The choice of the genes to analyze can be guided by the patient's clinical features and consideration of the patient's birth country [37]. For example, XP subtype C (XPC) accounts for approximately 43 percent of cases in the United States, and XP subtype A (XPA) accounts for approximately 55 percent of cases in Japan [15,38]. As a result, a patient in the United States without neurologic findings may be diagnosed by genetic testing for XPC alone.

When available, a multigene panel provides a higher diagnostic sensitivity. Methods used in a panel may include sequence analysis, deletion/duplication analysis, or other non-sequencing-based tests. Generally, the multigene panels include probes for the eight known XP complementation groups. The presence of biallelic (at least one mutation on each of two chromosomes), pathogenic mutations confirms the diagnosis [37].

If clinical suspicion remains high in the face of negative single- or multigene panel results, more comprehensive genomic testing, including exome sequencing and genome sequencing, may be considered. The benefit of this type of testing is that it may uncover a mutation in a novel gene or suggest a diagnosis not previously considered [37].

Prenatal diagnosis — In families with a known diagnosis of XP and molecularly confirmed mutations, DNA testing can be performed on chorionic villus-derived cells or on amniocytes from the pregnant mother. Early diagnosis in utero can undoubtedly lead to earlier and stricter adoption of sun protection measures for the affected child. Early referral for genetics consultation prior to pregnancy and planning of pregnancies is recommended for couples interested in prenatal diagnosis.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of xeroderma pigmentosum (XP) includes a number of autosomal recessive disorders of nucleotide excision repair (NER) that are allelic to XP and present with cutaneous photosensitivity and overlapping phenotypical features:

Cockayne syndrome (CS) (see "Neuropathies associated with hereditary disorders", section on 'Cockayne syndrome')

XP/CS complex

Trichothiodystrophy (TTD)

CS/TTD complex

XP/TTD complex

Cerebrooculofacioskeletal (COFS) syndrome

COFS/TTD

Ultraviolet (UV)-sensitive syndrome

The involved genes and clinical features of these autosomal recessive NER disorders are summarized in the table (table 1).

Other diseases that present with cutaneous photosensitivity unrelated to NER defects include:

Bloom syndrome – Bloom syndrome (MIM #210900) is a rare autosomal recessive chromosomal instability disorder caused by mutations in the BLM gene on chromosome 15q26.1, which encodes RECQL3 helicase [39]. Bloom syndrome is characterized by photosensitivity, short stature, distinctive facies, immunodeficiency, cancer predisposition, and various developmental defects. A facial erythema with a butterfly distribution and occasionally associated with blistering and bleeding typically develops in the first years of life after sun exposure (picture 3). Chronic cutaneous changes include poikiloderma (dyspigmentation, telangiectasias, and atrophy) and scarring. (See "Bloom syndrome".)  

Rothmund-Thomson syndrome – Rothmund-Thomson syndrome is a rare disorder characterized by poikiloderma (reticulate pigmentation, telangiectasias, and atrophy) (picture 4); sparse hair, eyelashes, and/or eyebrows; small stature; skeletal and dental abnormalities; cataracts; and an increased risk for cancer, especially osteosarcoma [40]. Erythema and swelling following sun exposure develop in the first months of life.

Erythropoietic protoporphyria – Erythropoietic protoporphyria (EPP) is an inherited cutaneous porphyria characterized by painful, nonblistering photosensitivity that manifests acutely after sunlight exposure with painful erythema and edema but resolves with little or no scarring. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

MANAGEMENT — The management of patients with xeroderma pigmentosum (XP) requires a multidisciplinary team including dermatologists, ophthalmologists, oral surgeons, genetics professionals, and neurologists. Strict sun protection and avoidance, close clinical follow-up with regular skin and eye examination, and appropriate and early management of any premalignant and malignant skin lesions are the mainstays of treatment.

Sun protection and avoidance — Avoidance of sun exposure is usually very difficult, often requiring help from a clinician to implement special protection in places such as schools. Patients must constantly use sunscreen, sun-protective clothing, and ultraviolet (UV)-protective goggles. They must be kept away from windows when indoors and properly covered when outdoors. Most indoor lighting is not problematic. However, fluorescent light sources also emit ultraviolet radiation (UVR). The majority of the UVR emitted by fluorescent bulbs is absorbed by the internal coating of the bulbs and transmitted as lower-energy wavelengths in the visible spectrum, but small amounts of UVR are still transmitted. Often, fluorescent bulb fixtures are covered by a standard acrylic plastic cover that acts to diffuse most of the remaining UV light produced. If the fluorescent bulbs are not covered, patients should maintain a safe distance from the bulbs as UV emissions decrease rapidly with distance from the source.

Patients with XP who are under strict sun protection may have vitamin D deficiency [41,42]. Vitamin D supplementation is recommended for patients with low serum concentrations of vitamin D. (See "Vitamin D insufficiency and deficiency in children and adolescents".)

Treatment of skin cancer and premalignant lesions

Surgical treatment — Surgical excision is the treatment of choice for skin cancers in XP patients. Due to the high number of tumors that may occur in neighboring sites, margins should be as narrow as possible, with frequent follow-up and re-excision when needed.

In the past, patients treated with multiple surgical excisions performed with wide margins were often left with large defects in areas with no skin due to previous surgeries. This resulted in confusion between sites of inadequately treated skin cancer and defects due to surgery. In addition, wide excisions did not prevent the development of new tumors in the same field [43].

Mohs micrographic surgery can be helpful to limit surgical margins but may be impractical in patients requiring frequent and recurrent surgical excisions [43]. (See "Mohs surgery".)

Nonsurgical treatments — Nonsurgical treatments for skin cancer and actinic keratoses (AKs) in XP patients include the following:

Cryotherapy – In XP patients, AKs may be treated with cryotherapy using liquid nitrogen. Cryotherapy is best suited for isolated AKs, while field treatment with topical fluorouracil or imiquimod is preferred for widespread AKs.

Cryotherapy has also been used in XP patients for the treatment of basal cell carcinomas (BCCs). In a series 18 patients with XP, 45 primary facial BCCs (mean size 10 mm) were treated by cryosurgery with good cosmetic results [44]. Relapse occurred in one case after a mean follow-up period of 30 months.

Photodynamic therapy – A few reports have documented successful treatment of nonmelanoma skin cancer (NMSC) in XP patients with the use of a photosensitizer and photodynamic therapy (PDT) [45,46]. PDT may be appropriate for superficial skin cancers or to reduce the tumor size prior to surgery.

Topical fluorouracil and imiquimod – Treatment of XP patients with either topical fluorouracil or imiquimod has been documented in numerous case reports. Fluorouracil is an antimetabolite that disrupts and blocks DNA synthesis, while imiquimod is an immune response modifier that activates toll-like receptors and is thought to promote apoptosis in skin cancer cells [47]. The most common side effects of both these agents are erythema, inflammation, and pain at the site of application.

Chemoprevention of skin cancer

Systemic retinoids — Systemic retinoids, including acitretin and isotretinoin, given at high doses have been used for chemoprevention of NMSC in patients with XP [48,49]. The mechanism whereby retinoids help to prevent skin cancer is thought to involve the modulation of cell proliferation, differentiation, and apoptosis [50].

In one study, five XP patients who had had a total of 121 BCCs or squamous cell carcinomas surgically removed were treated with high-dose (2 mg/kg/day) oral isotretinoin for two years [51]. Only 25 tumors developed during the two years of treatment, whereas the tumor frequency increased by 8.5 times after treatment discontinuation. However, all five patients developed severe mucocutaneous effects, and some developed hypertriglyceridemia or liver function or skeletal abnormalities [52,53].

Although studies in solid organ transplant recipients suggest that lower doses of retinoids may be effective for the prevention of NMSC, evidence on the efficacy of low to moderate doses of retinoids in XP patients is limited to a few case reports [53,54]. (See "Prevention and management of skin cancer in solid organ transplant recipients", section on 'Acitretin'.)

Topical fluorouracil and imiquimod — Topical fluorouracil and/or imiquimod have been proposed for the chemoprevention of skin cancer in XP patients. In one report, five patients were treated with prophylactic topical fluorouracil 2% to 8% in an aqueous cream preparation; the cream was applied daily to all sun-exposed areas for three weeks, repeated three months later, and then every three to six months [43]. Over a follow-up period of eight years, this treatment was effective in preventing skin cancer of exposed sites.

The authors propose starting prophylactic intermittent treatment with topical fluorouracil or imiquimod at the initiation of symptoms in childhood. Such symptoms include skin dyspigmentation, xerosis, or development of skin cancer. Once initiated, treatment should be repeated every three to six months indefinitely. The concentration of topical fluorouracil or imiquimod should be dictated by patient tolerance. A lower concentration may be used initially and then gradually increased over time. As topical fluorouracil is associated with increased photosensitivity, patients should be especially careful to avoid sun exposure during treatment.

The most common side effects of topical fluorouracil are erythema, inflammation, and pain at the site of application; some children may experience systemic adverse effects due to accidental ingestion of the fluorouracil preparation applied in the perioral area [43].

Oral nicotinamide and Polypodium leucotomos extract — No studies have specifically evaluated the effects of nicotinamide (vitamin B3) or oral Polypodium leucotomos (PL; an extract derived from a tropical fern of the Polypodiaceae family) in XP patients. However, emerging data supports their role in decreasing UV-related skin damage and skin cancer.

Several studies have shown that nicotinamide has a chemoprotective effect [55,56]. In a large, multicenter, randomized trial including 386 immunocompetent participants with a history of NMSC, patients taking nicotinamide developed a lower number of tumors during the 12-month intervention period than patients in the placebo group [57].

Multiple in vitro and animal studies have demonstrated PL's chemoprotective, anti-inflammatory, and antioxidative effects [58,59]. One study including 22 individuals with skin phototypes I to III found that oral PL extract administered before skin irradiation with visible and UV light decreased erythema intensity and histologic biomarkers of UV damage in most participants [60].

As both of these supplements have shown positive safety profiles and are available over-the-counter, they may be an additional management option for patients with XP going forward.

Ocular management — UV-protective glasses and lubricating eye drops, such as methylcellulose eye drops, may be used to keep the cornea moist and protect against the inflammatory effects of keratitis sicca or dry eyes. Keratoplasty or corneal transplantation has been used to restore vision in individuals with severe keratitis [61]. However, the immunosuppressive therapy needed for the prevention of transplant rejection may lead to an increased risk of skin cancer. Use of a keratoprosthesis or artificial cornea has been reported successfully with decreased risk of graft rejection and no need for immunosuppressive medications [62]. Tumors of the lids, conjunctiva, and cornea are generally treated with surgical excision.

Neurologic management — Sensory-neural hearing loss is a common finding in XP patients with neurologic disease. The hearing loss is progressive and is best treated with hearing aids. Other neurologic findings, such as cognitive delays, ataxia, dysphagia, and dysarthria, may require special care, including special education classes as well as physical and occupational therapy. Later-stage disease may require patients to have wheelchairs, feeding tubes, and long-term nursing home care.

Genetic counseling — Consultation with a clinical geneticist is key for accurate diagnosis, recommendations for specialty assessments, and reproductive counseling. Apparently asymptomatic siblings of an individual with XP should be evaluated to identify as early as possible those who are also affected and would benefit from prompt initiation of treatment and preventive measures.

An updated genetic consultation is recommended prior to childbearing years, so that the affected individual can better understand their own reproductive risks and options. Early referral for genetics consultation prior to pregnancy and planning of pregnancies is recommended for couples interested in prenatal diagnosis.

INVESTIGATIONAL THERAPIES — Ideally, treatment of xeroderma pigmentosum (XP) should be aimed at replacing the deficient repair enzyme or fixing the defective pathway. Two such modalities, the topical application of xenogenic repair enzymes and gene therapy, have been investigated, but none is available for use in XP patients [63-67]:

Immune checkpoint blockade – Multiple case reports have shown benefit of treating patients with immune checkpoint blockade therapy [68-70]. The anti-programmed cell death (PD)-1 antibody, pembrolizumab, has been shown to not only treat complicated or unresectable cutaneous squamous cell carcinoma (cSCC) but also to decrease the development of subsequent cSCC. While this suggests that these medications could potentially be used to prevent squamous cell carcinoma (SCC) in XP patients, it is unknown whether extended immune checkpoint blockade would lead to resistant malignant clones. The side effect profile of these medications also limits their extensive use. Given the importance of finding additional cancer treatments in these high-risk patients, this remains a potentially exciting development.

T4 endonuclease V – T4 endonuclease V is a bacterial DNA repair enzyme that has been shown to be able to temporarily repair pyrimidine dimers in XP cella in vitro [71]. In a randomized trial, 30 patients with XP were treated with daily application of a lotion containing T4 endonuclease V in a liposome vehicle (T4N5 lotion) or placebo for one year [63]. Every three months, new actinic keratoses and basal cell carcinomas were identified and removed. At the end of the study, the annual number of new actinic keratoses was lower in patients in the active treatment group than in the placebo group (8.2 versus 25.9). The number of basal cell carcinomas was also lower in patients treated with the endonuclease lotion than in those treated with placebo (3.8 versus 5.4).

Although given a "fast track" designation from the US Food and Drug Administration, the T4N5 lotion has not been approved for the treatment of XP [72].

Gene therapy – A few preclinical studies have investigated corrective gene transfer in nucleotide excision repair (NER)-deficient keratinocyte stem cells. In one study, the wild-type XPC gene was introduced into clonogenic human primary XPC keratinocytes using a retroviral vector, leading to restoration of full NER capacity [66]. In another study, the mutated XPC gene in a cell line derived from the fibroblasts of XPC patients was corrected using an engineered nucleases [67]. Finally, one study used the aminoglycoside antibiotics geneticin and gentamicin for translational readthrough of premature stop codons in XP genes and facilitated expression of full-length proteins [73]. Other aminoglycoside antibiotics, such as paromomycin, neomycin, and kanamycin, appear to increase the expression of XPC mRNA and XPC protein in vitro [65].

Although promising, these methods need further studies and development before they can be tested in clinical trials.

PROGNOSIS — Metastatic skin cancer is the leading cause of death for patients with xeroderma pigmentosum (XP), followed by neurodegeneration. The median age of death in patients with neurodegeneration is also notably lower than that of patients without neurodegeneration, specifically 29 versus 37 years [15].

ONLINE RESOURCES AND SUPPORT GROUPS — Several online resources and patient organizations can provide information and support for patients with xeroderma pigmentosum (XP) and their families:

The National Organization for Rare Diseases provides a helpful overview of XP for health providers and families.

The Xeroderma Pigmentosum Society is a United States support group for XP patients and parents that includes Camp Sundown, a summer camp program oriented specifically for patients with photosensitive disorders.

The Xeroderma Pigmentosum Family Support Group is a United States group that helps raise awareness and educate the public and families about XP.

The XP Support Group is a United Kingdom group that provides advice and support to patients with XP and families.

The Teddington Trust is a United Kingdom organization that provides advice and support to XP patients and families.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management" and "Society guideline links: Cutaneous squamous cell carcinoma".)

SUMMARY AND RECOMMENDATIONS

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder due to mutations in any of eight genes involved in repair of ultraviolet (UV)-induced DNA damage. XP is inherited in an autosomal recessive pattern with 100 percent penetrance. (See 'Introduction' above and 'Epidemiology' above.)

Based upon the specific gene affected, XP can be divided into seven XP complementation groups, group A (XPA) through G (XPG), and xeroderma pigmentosum variant (XPV). (See 'Molecular genetics and pathogenesis' above.)

The primary manifestations of XP are severe photosensitivity with minimal sun exposure, marked freckling before the age of two years, skin cancer within the first decade of life, photophobia and ocular disease (eg, ectropion, conjunctival injection, severe keratitis, cancers of ocular surface and eyelids), and, in some cases, progressive neurodegenerative changes (eg, intellectual impairment, hearing loss, speech delays, spasticity, ataxia, dysphagia) and increased risk of central nervous system malignancies. (See 'Clinical findings' above.)

The diagnosis of XP is suspected based upon the clinical findings and family history. Genetic testing is necessary to confirm the diagnosis and determine the XP complementation group. (See 'Diagnosis' above.)

Strict sun protection and avoidance, close clinical follow-up with regular skin and eye examination, and appropriate and early management of any premalignant and malignant skin lesions are the mainstays of treatment for XP. Vitamin D supplementation may be needed for patients with low serum concentrations of vitamin D. (See 'Management' above.)

Systemic retinoids and topical fluorouracil have been used in some XP patients for chemoprevention of skin cancer. However, their frequent and potentially severe adverse effects limit their use. (See 'Chemoprevention of skin cancer' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Lawrence F Eichenfield, MD, who contributed to an earlier version of this topic review.

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Topic 15466 Version 9.0

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