Xeroderma pigmentosum

INTRODUCTION — Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder caused by defective nucleotide excision repair (NER), most notably of ultraviolet (UV)-induced deoxyribonucleic acid (DNA) helix-distorting lesions. Most individuals with XP experience a very high rate of skin cancer beginning early in life. Additional features are associated with different variants associated with specific genes. A subset of patients, associated with certain genetic variants, develop progressive neurologic deterioration, vision and hearing loss, and internal malignancies.

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".)

●(See "Porphyrias: An overview".)

●(See "Kindler epidermolysis bullosa".)

EPIDEMIOLOGY — The prevalence of XP is estimated to be approximately 1:1,000,000 in the United States and Europe and 1:22,000 in Japan [1,2]. A founder XPA gene variant with a frequency of 1 percent in Japan accounts for the higher prevalence of XP in Japan [2]. Increased incidence is observed in some Asian and African countries, including Bangladesh, Somalia [3], Pakistan [4], Egypt [5], Tunisia [6], and Morocco [7], possibly due to more frequent consanguinity.

MOLECULAR GENETICS AND PATHOGENESIS — The eight genes (complementation groups) involved in the pathogenesis of XP are associated with either the repair (XPA, XPB, XPC, XPD, XPE, XPF, and XPG) or the tolerance (XP variant [XPV]) of ultraviolet (UV)-induced DNA damage and other DNA helix-distorting lesions [8-10]. Before specific variants were identified using molecular technology, incubation of an affected individual's cells could be restored to normal function using cells from an individual with a different variant, establishing complementation groups. Complementation group is now known to refer to the gene in which the variant occurs. Individuals with different variants within the same gene would share the same complementation group.

●Nucleotide excision repair – The most common forms of UV-induced DNA damage are cyclobutane pyrimidine dimers and 6-4 photoproducts, and both DNA lesions are repaired by nucleotide excision repair (NER). The NER pathway is initiated through either global genome nucleotide excision repair (GG-NER) or transcription-coupled nucleotide excision repair (TC-NER).

•GG-NER involves the function of two XP-associated proteins (XPC and XPE) that continuously probe DNA and recognize bulky adducts based on DNA helical distortion.

•Alternatively, TC-NER is initiated by the stalling of ribonucleic acid (RNA) polymerase II during transcription due to a DNA lesion, leading to recruitment of the proteins associated with Cockayne syndrome types A and B to the site of DNA damage.

Both the GG-NER and TC-NER pathways then converge on the same repair mechanism with the recruitment of the transcription factor II H complex. The transcription factor II H complex contains two helicase subunits (XPB and XPD) that unwind DNA in opposite directions to expose the damaged DNA strand. XPA is involved in confirming the presence of a DNA lesion and recruiting downstream repair factors.

The endonucleases that remove the damaged patch of DNA are the heterodimer XPF-ERCC1 that cleaves 5' of the lesion and XPG that cleaves 3', releasing a single-stranded oligonucleotide containing the DNA adduct. These endonucleases create a 20 to 30 nucleotide gap in one strand of the DNA double helix that is filled in by the replication machinery: a DNA polymerase for templated DNA synthesis and DNA ligases to restore the integrity of the DNA phosphodiester backbone.

●DNA translesion synthesis – Uniquely, XPV is not an NER protein but a DNA polymerase involved in DNA damage tolerance via translesion synthesis (TLS). XPV can replicate DNA across a UV-induced lesion, allowing replication to continue without repair, albeit often at the price of creating a mutation.

●Genotype/phenotype correlations – The broad clinical heterogeneity of XP can be attributed to the function of the affected gene (complementation group) in the NER pathway, additional functions of the gene product in other DNA repair pathways, and the effect of the mutation on gene function or expression [3,11]. The largest impact on disease severity is determined by whether the affected protein functions in GG-NER, TC-NER, or TLS [3].

•Variants in genes associated with GG-NER (XPC and XPE) typically result in milder phenotypes and normal sunburn reaction. However, GG-NER defects are associated with high mutation rates and increased cancer risk.

•Variants in genes associated with TC-NER (XPA, XPB, XPD, XPF, and XPG) are often associated with more severe phenotypes, with systemic symptoms including neurodegeneration. Unrepaired oxidative DNA damage within neurons, leading to cell death and progressive cerebral atrophy, is the mechanism of neurologic degeneration [12-14].

•Some NER proteins have additional functions in other DNA repair pathways. Thus, defective proteins result in symptoms overlapping with those of other genome instability disorders (eg, Fanconi anemia or Cockayne syndrome) (table 1) [8,13].

•TLS (XPV) variants are associated with a milder phenotype, normal sunburn reaction, but increased risk of skin cancer later in life.

CLINICAL MANIFESTATIONS — All patients with XP experience photosensitivity and increased rates of skin cancer. The degree of photosensitivity and neurologic compromise vary by complementation group and the severity of the pathogenic variant (eg, missense variant versus stop codon).

Early skin findings — With the exception of complementation groups XPE and XPV, the skin manifestations associated with XP typically appear in early childhood and worsen over time.

●Lentigines and freckles – Children with XPC present initially with lentigines and freckles in sun-exposed areas, typically by age two (picture 1) [15].

●Sunburn – Sunburns may be severe, prolonged, and blistering, even with minimal sun exposure [16]. Complementation groups with exaggerated sunburn reactions include XPA, XPB, XPD, XPF, and XPG [3]. In contrast, patients with XPC, XPE, and XPV have more normal reactions to sun exposure, which delays XP diagnosis. They may not come to medical attention until early adulthood, often with a high skin cancer burden [15]. (See 'Skin cancer' below.)

●Pigmentary changes – Over time, the skin develops progressive mottling with hyper- and hypopigmentation and scaling papules.

●Premature aging – Patients with XP show signs of premature aging of the skin with increasing number of lentigines on the skin and lips, telangiectasias, poikiloderma, xerosis, skin atrophy, and wrinkling (picture 2A-C).

●Actinic keratoses and nonmelanoma skin cancers – Actinic keratoses and nonmelanoma skin cancers may develop in the first decade of life [15]. (See 'Skin cancer' below.)

Skin cancer — Skin cancer is a leading source of morbidity and mortality in XP. The most common cutaneous malignancies are nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma (picture 3). Patients with XP have >10,000 times higher risk of nonmelanoma skin cancer and >2000 times higher risk of melanoma compared with the general population. Patients with XP develop their first nonmelanoma skin cancer and melanoma at a median age of 9 and 22 years, respectively, decades earlier than individuals without XP [11]. Skin cancers occur exclusively on exposed areas of the body.

Oral cancers — Patients with XP may develop tongue cancer at a very young age [17,18]. Tongue tip and dorsal tongue (presumably sun-exposed areas) are the most common sites. Cancers of the gingiva and palate as well as oral angiosarcoma and fibrosarcoma have also been reported in patients with XP [19,20]. Intraoral pyogenic granulomas are also more common in patients with XP than in individuals without XP and may mimic oral malignancies [21]. (See "Pyogenic granuloma (lobular capillary hemangioma)".)

Ocular findings — Ultraviolet (UV) injury causes ocular abnormalities in over 90 percent of patients with XP [22]. These include photophobia (most common), conjunctival injection, corneal neovascularization and scarring, ectropion, conjunctival melanosis, and ocular surface cancers [22,23]. Patients with XPC have the most severe ocular disease [3].

Neurologic findings — Up to approximately 40 percent of patients with XP, depending on type, experience neurodegeneration with progressive cognitive decline, sensorineural hearing loss, peripheral neuropathy, ataxia, and loss of speech [11,24,25]. High-frequency hearing loss and loss of deep tendon reflexes are the first signs of neurologic deterioration and begin at approximately two years of age in the most severe cases [9].

Neurologic manifestations are most common in XPA and XPD. They are also seen in XPB, XPF, and XPG [12,13] but not in XPC, XPE, or XPV [26]. Although patients with XPC do not have progressive neurodegeneration, hearing loss has been reported [3,24,26].

Associated internal malignancies — Patients with certain XP types have a 10 to 35 times higher risk of developing internal malignancies compared with the general population [27-30]. Moreover, malignancies occur in these patients at a much younger age. Patients with XPC are at the highest risk. Hematologic cancers (eg, myelodysplastic syndrome, acute lymphoblastic leukemia, acute myeloid leukemia, lymphoma) and central nervous system malignancies (eg, glioblastoma, medulloblastoma, astrocytoma, schwannoma) are most common [30,31]. Other associated cancers include thyroid, gynecologic (ovarian, uterine), breast, esophageal, gastric, prostate, and renal cancers [11,30,32]. Colorectal and lung cancers have also been reported in patients with XPG and XPD, respectively [33,34]. Early-onset thyroid nodules have been noted in patients with XP [35]. While risk of malignant transformation is low, surveillance for thyroid abnormalities is warranted in patients with XP.

Reproductive concerns — Female patients with XP are more likely to experience premature menopause [36]. In a study of female patients with XP who were followed at the National Institutes of Health, menarche occurred at a median age of 12, consistent with norms in the general population, but menopause was experienced at a median age of 29.5 years. Of the 60 females in the study, 21 gave birth to a total of 32 children. Further investigation is needed to determine the full impact of XP on reproductive health in males and females.

DIAGNOSIS

Clinical suspicion — The rarity of XP coupled with the variable clinical presentation often results in a delayed diagnosis or even investigation for child abuse. XP should be suspected in children presenting with one or more of the following [37,38]:

●Severe sun sensitivity on minimal exposure

●Early skin freckling (before the age of two years)

●Skin cancer during childhood

●Ocular symptoms (eg, photophobia with marked conjunctival injection, keratitis, corneal neovascularization and scarring)

●Neurologic symptoms (eg, loss of deep tendon reflexes, hearing loss)

XP should also be suspected in young adult patients with multiple skin cancers in the absence of increased sun sensitivity. Patients with XPE and XPV may in fact not come to medical attention until early adulthood, often with a high skin cancer burden.

Unscheduled DNA synthesis — The measurement of unscheduled DNA synthesis (UDS) following ultraviolet (UV) irradiation of live cells (historically dermal fibroblasts) from patients suspected to have XP is the pathognomonic diagnostic test for XP [39,40]. DNA synthesis outside of the S phase of the cell cycle (ie, UDS) that occurs in those cells following UV irradiation is, by definition, nucleotide excision repair (NER). With the exception of XPV, this assay is agnostic to the complementation group but provides information about the impact of inherited pathogenic variants on a patient's NER capacity. UV-induced UDS can range from undetectable to normal and roughly correlates with disease severity. Unlike the other complementation groups, XPV has normal levels of UDS and NER because XPV is involved in UV-induced DNA damage tolerance rather than repair.

Measuring UDS requires establishing primary cell cultures, typically from a skin biopsy, which is not routinely available in Clinical Laboratory Improvement Amendments (CLIA)-certified diagnostic laboratories.

Genetic testing — Genetic testing is more widely available than UDS for the diagnosis of XP. Options include serial single-gene testing, multigene panels, or complete genomic testing. Targeted, multigene panels that test for several XP variants have higher sensitivity than single gene tests and are therefore preferred. The finding of biallelic pathogenic variants in one of the genes involved in XP confirms the diagnosis [37].

The detection of novel variants not previously reported requires further testing, usually performed in research settings, to determine their impact on NER capacity.

In cases where the clinical suspicion is high but targeted testing is negative, whole exome sequencing can be performed. Whole exome sequencing can detect other genetic diseases with clinical presentations similar to XP. (See 'Differential diagnosis' below.)

Prenatal testing — Prenatal genetic testing through chorionic villus sampling or amniocentesis can be offered to families with known XP pathogenic variants [41].

DIFFERENTIAL DIAGNOSIS

●Genome instability disorders associated with photosensitivity – Genome instability disorders related to XP include, among others, Cockayne syndrome, trichothiodystrophy, and ultraviolet (UV)-sensitive syndrome (table 2). They share features with XP, including increased photosensitivity, but are not associated with an increased risk of malignancy.

•Cockayne syndrome – Cockayne syndrome is a rare genetic disorder caused by biallelic variants in the CSA and CSB genes [42]. Patients with Cockayne syndrome have characteristic bird-like facies; global developmental delay; and a spectrum of progressive, neurologic abnormalities [43,44]. An XP-Cockayne syndrome overlap syndrome has been described [45]. (See "Neuropathies associated with hereditary disorders", section on 'Cockayne syndrome'.)

•Trichothiodystrophy – Trichothiodystrophy is a rare, genetically heterogeneous, autosomal recessive disorder. Photosensitive trichothiodystrophy (types 1, 2, and 3) is caused by biallelic variants in ERCC2, ERCC3, and GTF2H5. Patients with trichothiodystrophy present with neurologic and developmental abnormalities, brittle hair (picture 4), and ichthyosiform skin changes [46,47]. Hairs show alternating birefringence ("tiger tail" appearance) when viewed with polarized light (picture 5). (See "Autosomal recessive congenital ichthyoses", section on 'Trichothiodystrophy'.)

•UV-sensitive syndrome – UV-sensitive syndrome is an autosomal recessive disorder of nucleotide excision repair (NER) caused by variants in the ERCC6, ERCC8, or UVSSA genes [48]. UV-sensitive syndrome is associated with mild photosensitivity, cutaneous hyperpigmentation, and freckling starting very early in life [49]. There is no known increased risk of cutaneous or internal malignancy or neurologic defects [50].

●Other inherited disorders associated with photosensitivity – Other rare, autosomal recessive disorders associated with photosensitivity may be differentiated from XP based on the clinical and genetic findings.

•Erythropoietic protoporphyria – Erythropoietic protoporphyria (MIM #177000) is an autosomal recessive disorder caused by variants in FECH, resulting in reduced synthesis of ferrochelatase, an enzyme in the heme biosynthetic pathway [51]. Erythropoietic protoporphyria is characterized by the acute onset of nonblistering, painful erythema in sun-exposed areas. Anemia is present in approximately one-half of all patients. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

•Bloom syndrome – Bloom syndrome (MIM #210900) is a rare, autosomal recessive, chromosomal instability disorder caused by pathogenic variants in the BLM gene. Patients with Bloom syndrome are sun sensitive and develop facial erythema, telangiectasias, and atrophy of the central face in a butterfly distribution. UV-induced erythema and blistering can develop on any exposed body sites. Additional features include high-pitched voice; short stature; and long, narrow face with a prominent nose. Immunoglobulin deficiencies and malignancies, especially hematologic, are also common [52]. (See "Bloom syndrome".)

•Rothmund-Thomson syndrome – Rothmund-Thomson syndrome is an autosomal recessive disorder caused by variants in ANAPC1 (MIM #618625) or RECQL4 (MIM #268400). Rothmund-Thomson syndrome is characterized by facial erythema and blistering that develop in the first few months of life and progress to reticulate pigment changes, telangiectasias, and atrophy (poikiloderma) (picture 6) [53]. Other features include sparse hair, eyelashes, and eyebrows; skeletal/dental defects; cataracts; and increased cancer risk, especially osteosarcoma.

•Hartnup disease – Hartnup disease (MIM #234500) is an autosomal recessive disorder caused by variants in SLC6A19, resulting in decreased neutral amino acid absorption from the kidneys and intestinal tract [54]. Patients with Hartnup disease present with pellagra-like, scaling, pink patches in sun-exposed sites; cerebellar ataxia; and mild intellectual impairment.

MANAGEMENT — Patients with XP are best managed by a multidisciplinary team including dermatologists, ophthalmologists, audiologists, oral surgeons, geneticists, 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.

Prevention and early detection of skin cancer — Implementation of strict ultraviolet (UV) protection and early detection and treatment of skin cancers and premalignant lesions are the mainstays of management of patients with XP.

Photoprotection strategies — Individuals with XP and their parents or caregivers should be educated about the importance of strict sun protection for the prevention of skin cancer and other cutaneous manifestations of XP. However, studies have shown that adherence to photoprotection is variable, and poor adherence may be a significant issue among patients with XP [55]. An international study investigating the psychologic correlates of photoprotection in 156 adult patients with XP found that face photoprotection was suboptimal in at least one-third of the patients [56].

●Sun avoidance and sun protection – Sun exposure should be avoided. During daylight hours, protective garments, wide-brimmed hats attached to UV-protective face shields, sunglasses, and gloves are recommended. All skin should be covered with clothing made of UV-resistant fabric (see "Selection of sunscreen and sun-protective measures", section on 'Photoprotective clothing'). Layering of clothing enhances protection.

Broad-spectrum sunscreen with a sun protection factor (SPF) of 30 or higher should be applied every two hours to sun-exposed areas. (See "Selection of sunscreen and sun-protective measures".)

●Creating ultraviolet-safe environments – UV-safe environments can be created by applying UV-resistant film to windows in the car, home, and school. Incandescent light bulbs with low wattage or light-emitting diode (LED) lights are safest. Fluorescent and halogen lights can be a source of UV exposure and should be shielded [57]. Handheld UV meters can help determine UV exposure risk and are useful for families to assess the safety of unfamiliar environments and when it is safe to go outdoors without head-to-toe barrier protection. Levels of under 2 to 3 microW/cm² are recommended, although safe levels are unknown.

●Risk of vitamin D deficiency – Patients with XP are at risk for vitamin D deficiency; supplementation is usually needed.

Chemoprevention — In patients with XP, chemoprevention strategies aimed at reducing the development of actinic keratoses and cutaneous squamous cell carcinomas may be considered based on patients' characteristics and preferences. (See "Cutaneous squamous cell carcinoma: Primary and secondary prevention", section on 'Chemoprevention'.)

●Topical agents – Both topical fluorouracil and imiquimod have been evaluated for the prevention of keratinocyte carcinomas in patients with multiple actinic keratoses and field cancerization [58,59]. However, evidence on their efficacy in patients with XP is limited to a few case reports.

•Topical fluorouracil – In two patients with XP, pulsed dosing of topical fluorouracil every three months decreased the rates of new squamous cell carcinoma and basal cell carcinoma [60]. The primary side effect of topical fluorouracil is skin irritation at the sites of use.

•Imiquimod – In a series of 15 patients with XP (8 with XPV) treated with imiquimod 5% applied to one cheek five times per week for six weeks, none developed a skin cancer on the treated area during a two-year follow-up time [61]. Adverse effects included local inflammation, ulceration, and crusting.

●Systemic agents – Systemic agents that have been investigated for the prevention of keratinocyte carcinomas include oral retinoids and nicotinamide. The latter has not been tested in patients with XP.

•High-dose oral isotretinoin – In a study of five patients with XP, high-dose oral isotretinoin 2 mg/kg per day for two years substantially decreased the number of new skin cancer development (from 121 in the two-year interval before starting treatment to 25 in the two years during treatment) [62]. However, a rebound in skin cancer frequency was noted after treatment discontinuation [63]. Adverse effects of high-dose isotretinoin limit its prolonged use. There is no evidence supporting the use of lower-dose regimens.

•Nicotinamide – Nicotinamide (vitamin B3) is an oral supplement that may prevent actinic keratoses and nonmelanoma skin cancers. In a trial randomizing high-risk individuals to either nicotinamide 500 mg twice daily or placebo, those receiving nicotinamide had a 23 percent reduction in the incidence of new nonmelanoma skin cancer and a 14 percent reduction in actinic keratoses at 12 months [64]. However, a subsequent study in transplant patients, also at increased risk of cutaneous malignancies in sun-exposed areas, failed to identify a significant reduction in nonmelanoma skin cancer at 12 months [65]. No serious side effects were noted in either study.

Skin cancer surveillance — Close clinical follow-up for early detection and treatment of skin cancer and premalignant lesions is indicated for all patients with XP. Most patients are seen for skin examinations at least twice yearly and more often if they have a history of skin cancer.

Treatment of skin cancer and precursor lesions

Actinic keratosis — Prompt and frequent treatment of actinic keratoses is important to prevent progression to squamous cell carcinoma [66,67]. Patients with XP are best treated with field-directed therapies, which include:

●Topical fluorouracil – Topical fluorouracil is the first-line field treatment for patients with XP [63,68]. A 1:1 combination of topical calcipotriene with fluorouracil shortens the treatment duration without decreasing efficacy. (See "Treatment of actinic keratosis", section on 'Topical fluorouracil' and "Treatment of actinic keratosis", section on 'Topical fluorouracil plus calcipotriol'.)

●Imiquimod – Imiquimod is a topical immune response modifier approved for the treatment of actinic keratosis and superficial basal cell carcinoma. Imiquimod can be used as an alternative to topical fluorouracil for the treatment of multiple actinic keratoses. (See "Treatment of actinic keratosis", section on 'Imiquimod'.)

●Photodynamic therapy – Photodynamic therapy involves the pretreatment of skin with a photosensitizing agent, which is preferentially absorbed by premalignant or malignant cells, followed by irradiation with a specific wavelength of light or exposure to daylight. This results in the death of the target cells. Photodynamic therapy has been described as a treatment for both actinic keratoses and small basal cell carcinomas in patients with XP [69-72]. (See "Treatment of actinic keratosis", section on 'Photodynamic therapy' and "Photodynamic therapy".)

●Other modalities – Other effective modalities used to destroy actinic keratoses include cryotherapy with liquid nitrogen, trichloroacetic acid chemical peel, and ablative fractionated laser. (See "Treatment of actinic keratosis", section on 'Liquid nitrogen cryosurgery' and "Treatment of actinic keratosis", section on 'Field ablation treatments'.)

Nonmelanoma skin cancers

Surgery — Conventional wide local excision or Mohs micrographic surgery are the treatments of choice for skin cancers in patients with XP. Mohs micrographic surgery offers the highest cure rate with the lowest risk of recurrence and is preferred for cosmetically sensitive body sites or recurrent lesions [73]. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma" and "Treatment of basal cell carcinomas at high risk for recurrence".)

Nonsurgical therapies — Other therapies used to treat nonmelanoma skin cancer in patients with XP include cryosurgery, photodynamic therapy, imiquimod [61,74-77], and topical fluorouracil. While these therapies may be inferior to surgical excision, there may be clinical scenarios in which skin-sparing options are reasonable alternatives. Imiquimod has been used successfully in patients with XP to treat basal cell carcinomas. Local skin inflammation and irritation are common, but ulceration, facial swelling, and rare systemic symptoms (eg, fever and malaise) have been reported. (See "Treatment and prognosis of basal cell carcinoma at low risk of recurrence" and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)

Systemic therapies — Systemic therapies have been used in a few patients with XP with inoperable or metastatic nonmelanoma skin cancers. These treatments are discussed in detail separately. (See "Systemic treatment of advanced basal cell and cutaneous squamous cell carcinomas not amenable to local therapies".)

●Hedgehog pathway inhibitors – In single case reports, the hedgehog pathway inhibitor vismodegib has been employed to manage multiple or unresectable basal cell carcinomas in patients with XP [78,79].

●Immune checkpoint inhibitors – There are a few reports of the use of pembrolizumab, an anti-programmed cell death ligand 1 (PD-L1) checkpoint inhibitor, for the treatment of advanced skin cancers in patients with XP [80-82]. In one report, treatment with pembrolizumab and ipilimumab for advanced cutaneous squamous cell carcinoma and melanoma in three patients also decreased the rates of new cutaneous malignancies [83]. However, these agents have significant adverse effects that may limit their use in patients with XP. (See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors" and "Toxicities associated with immune checkpoint inhibitors".)

Melanoma — The staging system and management of melanoma in patients with XP is the same as for children and adults without XP. (See "Melanoma in children", section on 'Management' and "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites" and "Overview of the management of advanced cutaneous melanoma".)

Management of extracutaneous manifestations

Ocular management — Patients should be followed up every three to six months with ophthalmology, and examinations should include assessment for eyelid and ocular surface tumors. UV-protective glasses or soft UV-protective contact lenses are recommended [16]. Methylcellulose eye drops may be used to protect against eye dryness. Corneal transplant or keratoplasty may improve vision in patients with severe keratitis. The use of keratoprosthesis or artificial cornea may be preferred to avoid immunosuppression, which can further increase the risk of skin cancers.

Ocular tumors are usually treated with excision or cryotherapy. Other modalities include combination of surgery and topical chemotherapy with mitomycin C [84], subconjunctival injections of interferon (IFN)-alpha-2b and topical mitomycin C [85], topical IFN-alpha-2b, and fluorouracil eyedrops [86].

Neurologic management — There are no targeted treatments for the neurologic manifestations of XP. Treatments are primarily supportive and include speech, physical, and occupational therapy. Vision and hearing screening should be conducted at regular intervals starting early in life.

INVESTIGATIONAL TREATMENTS

Gene therapy — Genetic techniques to improve DNA repair are the most promising approaches to the treatment of XP [87,88]. A retrovirus-based strategy to transduce the wild-type XPC gene into human XPC keratinocytes was used in an in vitro study using XPC keratinocytes without adverse effects (eg, oncogenic activation) [89]. The transcription activator-like effector nuclease (TALEN) technology was used to correct the frequent c.1643_1644delTG XPC mutation in XP cells [90].

Topical agents

T4 endonuclease — Topical T4 endonuclease is a DNA repair enzyme that has been reported to decrease the rates of new basal cell carcinoma and precancerous actinic keratoses in patients with XP when applied topically to sun-exposed skin [91]. However, this agent has not been further investigated and is not available.

Photolyase — Several studies suggest that sunscreen containing photolyase may be effective in preventing actinic keratoses in patients at high risk [92,93]. Photolyases are enzymes expressed in bacteria, fungi, plants, and some animals (but not in placental mammals, including humans). Photolyases chemically reverse ultraviolet (UV)-induced DNA damage upon activation by visible light. Topical photolyases are approved as a medical device in Europe and are available over the counter in the United States.

Agents targeting aging and senescence — Animal models of XP recapitulate the cancer-prone phenotype but also suggest that there are aspects of accelerated aging (eg, the neurodegeneration and accelerated photoaging of the skin) [94,95]. There has been an effort to develop therapeutics that target fundamental mechanisms of aging [96]. These include agents that remove cells harboring DNA damage (ie, senescent cells), suppress inflammation or oxidative stress, improve metabolism, and replenish key metabolites that erode with aging [97]. These therapeutics significantly improve tissue homeostasis in mouse models [98,99]. However, whether these agents may mitigate disease progression in patients with XP has not been investigated.

PROGNOSIS — Patients with XP have a decreased life expectancy due to fatal skin malignancies, internal malignancies, and neurodegeneration. The reported mean lifespan is 29 and 37 years for those with and without neurodegeneration, respectively [11]. Patients with XP experience additional non-ultraviolet (UV)-induced causes of morbidity and mortality. Nearly 20 percent of patients with XP succumb to internal malignancies, including tumors of the central nervous system, head and neck cancers, and lung cancer [11,32].

GENETIC COUNSELING — Genetic counseling is recommended for all families of patients with XP. For parents considering additional children, the risk of having another affected child is 25 percent, and the risk of a child being an asymptomatic carrier is 50 percent. Siblings should be tested to increase early diagnosis and implementation of ultraviolet (UV) protective measures.

RESOURCES AND SUPPORT GROUPS — Several online resources and patient organizations can provide information and support for patients with XP and their families/caregivers.

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

●The XP Family Support Group is a United States group that provides information and resources, including ultraviolet (UV)-protecting hoods, gloves, and UV meters, to newly diagnosed families. They host a biannual family retreat and medical conference.

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

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

●Action for XP (formerly The Teddington Trust) is a United Kingdom charity that provides advice and support to patients with XP and their families.

●Guy's and St. Thomas' Hospitals National Health Service Foundation Trust in the United Kingdom provides the only comprehensive evaluation and care center for patients with XP in the world, providing access to clinicians in all disciplines impacted by XP and Cockayne syndrome.

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" and "Society guideline links: Photosensitivity disorders (photodermatoses)".)

SUMMARY AND RECOMMENDATIONS

●Definition and molecular pathogenesis – Xeroderma pigmentosum (XP) is an autosomal recessive disorder of DNA repair caused by inherited mutations in one of eight possible genes related to the repair or tolerance of ultraviolet (UV)-induced DNA damage and other helix-distorting DNA adducts. (See 'Molecular genetics and pathogenesis' above.)

●Clinical manifestations – Clinical manifestations of XP include exaggerated, early sunburn reactions and progressive lentiginosis on exposed areas elicited by minimal UV exposure. Premature photoaging of the skin, telangiectasias, poikiloderma, xerosis, skin atrophy, and wrinkling are observed in childhood or teen years. Skin cancers occur early in life and are the leading cause of mortality. In some cases, depending on the complementation group and impact of specific mutations on the gene product function, intellectual impairment, progressive neurodegenerative disease, and/or the development of other malignancies may occur. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of XP is suspected in individuals presenting with one or more of the following (see 'Clinical suspicion' above):

•Severe sun sensitivity on minimal exposure

•Early skin freckling (before the age of two years)

•Skin cancer during childhood

•Numerous skin cancers in early adulthood

•Severe photophobia with marked conjunctival injection and other ocular symptoms (eg, keratitis, corneal neovascularization and scarring)

•Neurologic symptoms (eg, loss of deep tendon reflexes, hearing loss)

The definitive diagnosis of XP is made with genetic testing. (See 'Genetic testing' above.)

●Management – Strict sun protection and avoidance, close clinical follow-up, and appropriate and early management of any premalignant and malignant skin lesions are the mainstays of treatment for patients with XP.

•Photoprotection – Patients with XP require complete, strict photoprotection (including avoiding all outdoor and indoor UV light sources); protective clothing; eye protection/sunglasses; and application of broad-spectrum sunscreen to any exposed areas. Due to the increased risk for vitamin D deficiency associated with strict photoprotection, we suggest vitamin D supplementation for most patients with XP (Grade 2C). (See "Vitamin D insufficiency and deficiency in children and adolescents".)

•Surveillance for skin cancer – Regular skin and eye examination for early detection and treatment of skin cancer and premalignant lesions is recommended for all patients with XP. (See 'Photoprotection strategies' above and 'Skin cancer surveillance' above.)

•Treatment of actinic keratosis – Actinic keratoses are best treated with field-directed therapies, including topical fluorouracil, imiquimod, and photodynamic therapy. (See 'Actinic keratosis' above and "Treatment of actinic keratosis".)

•Treatment of nonmelanoma skin cancers – Wide local excision and Mohs surgery are first-line treatments for nonmelanoma skin cancers. Alternative therapies, including cryosurgery, imiquimod, and topical fluorouracil, may be used for low-risk or superficial tumors. (See 'Nonmelanoma skin cancers' above.)

•Treatment of melanoma – The treatment of melanoma in patients with XP is the same as for children and adults without XP. (See "Melanoma in children", section on 'Management' and "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites" and "Overview of the management of advanced cutaneous melanoma".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Lawrence F Eichenfield, MD, and Catherine Gupta Warner, MD, who contributed to an earlier version of this topic review.