DiagnosisClinical Diagnosis The diagnosis of xeroderma pigmentosum (XP) is made clinically. Three major areas are involved:Skin. In a long-term study of 106 individuals with XP examined at the NIH from 1971 to 2009, Bradford et al [2011] reported that the diagnosis can often be made in the first years of life.About 60% of affected children demonstrated acute sun sensitivity (severe sunburn with blistering or persistent erythema on minimal sun exposure). The remaining affected children did not burn easily but developed marked freckle-like pigmentation. These unusual freckles (lentigos), when present on the face before age two years, are typical of XP and rarely seen in children with normal DNA repair mechanisms.Eye. Ophthalmologic abnormalities are usually limited to the anterior, UV-exposed portion of the eyes: conjunctiva, cornea, and lids [Dollfus et al 2003].Photophobia is often present and may be associated with prominent conjunctival injection.Severe keratitis from continued UV exposure of the eye may result in corneal opacification and vascularization.The lids develop increased pigmentation and loss of lashes. Atrophy of the skin of the lids results in ectropion, entropion, or in severe cases, complete loss of the lids.Nervous system. Bradford et al [2011] reported that 25% of affected individuals had characteristic progressive neurologic manifestations that worsen slowly and may manifest later than the skin changes [Rapin et al 2000, Kraemer et al 2007]. These include:Diminished or absent deep tendon stretch reflexes. EMG and nerve conduction velocities may show an axonal (or mixed) neuropathy.Progressive sensorineural hearing loss. Audiometry may reveal early high-tone hearing loss.Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles with thinning of the cortex and thickening of the bones of the skull.Progressive cognitive impairmentCancer. Bradford et al [2011] found that individuals with XP who were younger than age 20 years had an increased risk for the following cancers:Non-melanoma (basal cell and squamous cell) skin cancer at UV-exposed sites. The greater than 10,000-fold increased risk was associated with a median age of onset of nine years, nearly 60 years earlier than in the US general population Cutaneous melanoma. The greater than 2000-fold increased risk was associated with the median age of onset of 22 years, more than 30 years earlier than in the US general population. TestingNo consistent routine clinical laboratory abnormality is observed in individuals with XP. Functional tests on living cells including cellular ultraviolet (UV) hypersensitivity, unscheduled DNA synthesis (UDS), and host-cell reactivation can be used to screen for abnormalities in DNA repair, but are not commonly available [Kraemer & Ruenger 2008, Ruenger et al 2008, Stefanini & Kraemer 2008]. Note: In the XP variant, the clinical findings are the same as in other forms of XP; however, XP variant cells have normal nucleotide excision repair of UV-damaged DNA in contrast to cells from other forms of XP.Click here for additional test options available on a research basis only (pdf). Molecular Genetic TestingGenes. Xeroderma pigmentosum is known to be caused by mutations in XPA, ERCC3, XPC, ERCC2, DDB2, ERCC4, ERCC5, ERCC1, and POLH. In an affected individual both alleles are mutated in any one of the involved genes. (Figure 1).FigureFigure 1. Relationship between genotype and phenotype in the xeroderma pigmentosum-Cockayne syndrome-trichothiodystrophy spectrum
Italicized letters in ovals indicate genes with disease-causing mutations. Rectangles are phenotypes. Because (more...)Table 1. Summary of Molecular Genetic Testing Used in Xeroderma PigmentosumView in own windowComplementation Group ^{1Proportion of XP Attributed to Mutations in This GeneGene SymbolTest MethodMutations DetectedTest AvailabilityA25% 2XPASequence analysisSequence variants 3Clinical BRareERCC3Sequence analysisSequence variants 3ClinicalC25%XPCSequence analysis Sequence variants 3Clinical D15%ERCC2Sequence analysis Sequence variants 3ClinicalERareDDB2Sequence analysisSequence variants 3ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletions 5F6%ERCC4Sequence analysisSequence variants 3ClinicalG6%ERCC5Sequence analysisSequence variants 3ClinicalSee footnote 6Rare 7ERCC1Sequence analysisSequence variants 3ClinicalVariant21%POLHSequence analysisSequence variants 3ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletions 5NA = not applicable1. Before the genes responsible for XP were identified, complementation groups were used to categorize functional defects in affected individuals. In an XP complementation analysis cells from affected individuals were fused in the laboratory to determine whether their defects were different, in which case they would be able to supply all functions necessary to restore a normal cellular phenotype. Complementation is therefore a test of function and allowed categorizing affected individuals as having the same or different defects. Subsequently, each complementation group was found to result from a defect in a different gene. XP complementation groups from Kraemer [2003]. Testing to assign complementation group is currently not commercially available.2. Common in Japan, rare in the US and Europe3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. No deletions or duplications involving POLH or DDB2 have been reported to cause xeroderma pigmentosum. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)6. Previously called group H, a designation that was subsequently withdrawn; see footnote 7.7. Only one person with a mutation in ERCC1 has been reported [Jaspers et al 2007].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis of XP in a proband. In individuals with clinical findings suggestive for XP, such as severe burning on UV exposure or freckle-like pigmentary abnormalities before the age of two years:Begin UV protective measures immediately based on a working clinical diagnosis of XP because molecular confirmation may not be readily available in a timely manner. The steps to pursue a molecular genetic diagnosis are as follows:Perform functional assays of DNA repair. Note: None of these tests is available on a clinical basis in the US (see additional test options). Perform molecular genetic testingSequence analysis of XPA, XPC, ERCC2, ERCC4, ERCC5, ERCC1, ERCC3, POLH, and DDB2. The choice of which genes to analyze can be guided by the clinical features and the relative frequency in the population where the individual was born (see Table 2, Figure 1, and DiGiovanna & Kraemer [2012]). For example, testing first for founder mutations present in some parts of the world (e.g., Japan [Hirai et al 2006] and northern Africa [Tamura et al 2010a]) may be more cost-effective for probands from an area where founder mutations are known. Only a relatively small number of XP disease-causing mutations have been identified to date. Thus, if a new nucleotide variant is found in the sequence of one of the known XP-associated genes, it may be classified as a variant of unknown significance. Additional genetic and functional analyses may need to be performed in a clinical or a research setting to try and determine if the variant is a disease-causing mutation. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersIn addition to XP phenotypes discussed in this GeneReview, mutations in the genes causing XP are associated with the phenotypes trichothiodystrophy (TTD) and cerebrooculofacioskeletal syndrome (COFS) (Figure 1). Trichothiodystrophy (TTD) is an autosomal recessive disorder with a variable phenotype that includes photosensitivity, ichthyosis, brittle hair, intellectual impairment, short stature, microcephaly, dysmyelination of the brain, with characteristic facial features of protruding ears and micrognathia. Approximately 100 cases have been reported in the literature [Faghri et al 2008]. The frequency of pregnancy complications and neonatal abnormalities is increased [Moslehi et al 2010, Tamura et al 2011]. TTD hair shafts have reduced levels of the sulfur-containing amino acids cysteine and cystine, resulting in brittle hair that breaks. TTD hair shafts have a characteristic dark and light transverse banding pattern under polarized light described as a "tiger tail" appearance [Liang et al 2005]. Many individuals with TTD have a cellular defect in nucleotide excision repair. Persons with TTD have a 20-fold increased risk of death before age ten years, primarily from infections [Faghri et al 2008]. Mutations in the nucleotide excision repair genes ERCC3, ERCC2, or GTF2H5 (TTD-A) or in C7orf11 (TTDN1) (of unknown function) cause TTD [Broughton et al 2001, Itin et al 2001, Bootsma et al 2002, Giglia-Mari et al 2004, Liang et al 2005, Kraemer et al 2007] (Figure 1).Cerebrooculofacioskeletal syndrome (COFS syndrome; Pena-Shokeir syndrome, type II) is an autosomal recessive, progressive neurologic disorder marked by microcephaly with intracranial calcifications and growth failure. Ocular findings of microcornea, cataracts, and optic atrophy are present along with congenital joint contractures. Photosensitivity may occur with a concurrent cellular phenotype of UV sensitivity. Individuals with COFS syndrome have mutations in ERCC2, ERCC5, or ERCC6 (which also causes Cockayne syndrome; see Differential Diagnosis) [Meira et al 2000, Graham et al 2001].}

Natural HistoryThe findings in 106 individuals with XP examined at the NIH in a long-term study from 1971 to 2009 by Bradford et al [2011] are summarized below. Citations for any specific findings from earlier studies are provided as well. Xeroderma pigmentosum (XP)Cutaneous. Approximately 60% of individuals with XP have a history of acute sunburn reaction on minimal UV exposure. The other 40% of individuals with XP tan without excessive burning. In all individuals, numerous freckle-like hyperpigmented macules appear on sun-exposed skin. The median onset of the cutaneous symptoms is between ages one and two years [Kraemer et al 1987, Kraemer et al 1994]. These abnormalities are limited to sun-exposed areas.
Continued sun exposure causes the skin to become dry and parchment-like with increased pigmentation; hence the name xeroderma pigmentosum ("dry pigmented skin"). Most individuals with XP develop xerosis (dry skin) and poikiloderma (the constellation of hyper- and hypopigmentation, atrophy, and telangiectasia). Premalignant actinic keratoses develop at an early age. XP is an example of accelerated photo-aging. The appearance of sun-exposed skin in children with XP is similar to that occurring in farmers and sailors after many years of extreme sun exposure.Ocular. Ocular abnormalities are almost as common as the cutaneous abnormalities [Kraemer et al 1987, Kraemer et al 1994]. The posterior portion of the eye (retina) is shielded from UV radiation by the anterior portion (lids, cornea, and conjunctiva). Clinical findings (see Diagnosis) are limited to these anterior, UV-exposed structures and may begin in the first decade of life. The benign conjunctival inflammatory masses that develop can spread to obscure the cornea. Epithelioma, squamous cell carcinoma, and melanoma of UV-exposed portions of the eye are common. The ocular manifestations may be more severe in black individuals [Dollfus et al 2003, Ramkumar et al 2011]. Neurologic. Neurologic abnormalities were reported in approximately 25% of 106 affected individuals. The onset may be early in infancy or, in some individuals, delayed until the second decade or later [Kraemer et al 1987, Rapin et al 2000]. The neurologic abnormalities may be mild (e.g., isolated hyporeflexia) or severe, with microcephaly, progressive intellectual impairment, sensorineural hearing loss beginning with high frequencies, spasticity, ataxia, and/or seizures. During an upper respiratory infection some individuals may develop difficulty swallowing or, rarely, vocal cord paralysis [Ohto et al 2004].
In the past, an individual with XP with any neurologic abnormality was said to have the DeSanctis-Cacchione syndrome. With clarification of the spectrum of XP disease, this term is now reserved for XP with severe neurologic disease with dwarfism and immature sexual development. The complete DeSanctis-Cacchione syndrome has been recognized in very few individuals; however, many individuals with XP have one or more of its neurologic features.
The predominant neuropathologic abnormality found at autopsy in individuals with neurologic symptoms is loss (or absence) of neurons, particularly in the cerebrum and cerebellum. There is evidence for a primary axonal degeneration in peripheral nerves, in some cases with secondary demyelination [Rapin et al 2000].
Reduced nerve conduction velocity may also be present on nerve conduction studies.Cutaneous neoplasia. If aggressive UV avoidance is not begun early, accumulated sunlight-induced DNA damage is likely to result in skin cancer within the first decade of life. Some individuals with XP show exquisitely acute sun sensitivity with severe burning on minimal sun exposure. Many other individuals with XP do not have increased burning on minimal sun exposure, but do tan, freckle, and then develop skin cancers if not protected from sunlight. Individuals with XP younger than age 20 years had a greater than 10,000-fold increased risk of non-melanoma skin cancer (basal cell and squamous cell) at UV-exposed sites and a greater than 2000-fold increased risk of cutaneous melanoma.
Multiple primary cutaneous neoplasms are common. The median age of onset of non-melanoma skin cancer (basal cell or squamous cell carcinoma) was nine years, nearly 60 years earlier than in the US general population; the median age for cutaneous melanoma was 22 years, more than 30 years younger than in the US general population. This large difference in age of onset from that found in the general population illustrates the importance of normal DNA repair in protection from skin cancer. Surprisingly, the persons with XP with the most severe sun sensitivity had a later onset of skin cancer – probably because they used greater sun protection.Other neoplasias. Review of the world literature has revealed a substantial number of people with XP who have oral cavity neoplasms, particularly squamous cell carcinoma of the tip of the tongue, a presumed sun-exposed location [Kraemer et al 1987, Kraemer et al 1994, Butt et al 2010]. Gliomas of the brain and spinal cord, tumors of the lung, uterus, breast, pancreas, stomach, kidney, and testicles, and leukemia have been reported in a few individuals with XP [Kraemer et al 1987, Kraemer et al 1994, DiGiovanna et al 1998]. Because some of the carcinogens in cigarette smoke bind to DNA resulting in damage that is repaired by the NER system, this unrepaired DNA damage may contribute to the development of lung cancer in individuals with XP. Overall, these reports suggest an approximate ten- to 20-fold increase in internal neoplasms in XP [Kraemer et al 1987, Kraemer et al 1994, Bradford et al 2011]. XP/CS complex. A subset of individuals with phenotypic features consistent with both XP and Cockayne syndrome (CS) (the XP/CS complex) have cutaneous features of XP including increased frequency of skin cancers together with the somatic and neurologic features of CS. In contrast to XP, in which neuronal degeneration predominates, dysmyelination typical of CS is observed in XP/CS. Affected individuals have mutations in one of several XP-related genes (ERCC3, ERCC2, or ERCC5) [Rapin et al 2000] (see Figure 1).XP/trichothiodystrophy (TTD) syndrome. Individuals with specific phenotypic features of TTD who have the clinical and cellular phenotype of XP and specific mutations in ERCC2 have been described [Broughton et al 2001] (see Figure 1). See also Genetically Related Disorders. Unlike most people with TTD, individuals with XP/TTD may experience an increased frequency of skin cancers.Xeroderma pigmentosum variant (XP variant). Individuals with XP variant have skin and eye abnormalities identical to other forms of XP (including a high frequency of skin cancer) but do not have a defect in nucleotide excision repair. Individuals with XP variant have a defect in the error-prone polymerase, DNA polymerase eta (Pol η; encoded by POLH). Most individuals with XP variant do not have XP neurologic abnormalities (see Figure 1). Although the onset of clinical abnormalities may be delayed until the third decade in some individuals with XP variant, this finding is not specific to the XP variant [Inui et al 2008].Causes of death. The most common causes of death were skin cancer (34%, n=10); neurologic degeneration (31%, n=9); and internal cancer (17%, n=5). The median age at death (29 years) in persons with XP with neurodegeneration was younger than that in persons with XP without neurodegeneration (37 years) (p=0.02).

Genotype-Phenotype CorrelationsThe study of genotype-phenotype correlations is ongoing. Further information is included in literature-based reviews [Cleaver et al 1999] and a Web-based catalog.Affected individuals. Genotype-phenotype correlations within these disorders are dependent on both the complementation group (i.e., the affected gene) and the specific mutation within the affected gene. For the overall clinical disorders [XP, CS, TTD, COFS, and others (Figure 1)], the complementation group is related to the clinical phenotypes within those broad groups and also to the presence of skin cancer and/or neurologic abnormalities (see Figure 1 and Table 2). However, the genotype-phenotype relationship for these disorders is complex and dependent on the specific gene mutation and its ability to function as part of the multi-step DNA repair/transcription pathway. Since the components of the pathway are interdependent, failure of one component disables the entire pathway, leading to a situation where, for an affected individual, the specific mutation has a major contribution to the resultant phenotype. Because the spectrum of clinical involvement within complementation groups is very broad and dependent on the specific mutation present in an affected individual, the complementation group is not a reliable indicator of prognosis for a specific individual.Phenotypes are given for affected individuals with mutations on both alleles on any one of the indicated genes.Table 2. Genotype-Phenotype Correlations in XP and Related DisordersView in own windowComplementation GroupGeneCutaneous NeoplasiaPhenotypeAXPA+XP with mild-to-severe neurologic abnormalitiesB ^{1ERCC3 +XP/CS-TTD+XP with mild neurologic abnormalitiesCXPC+XP with no neurologic abnormalities 2, 3D 4ERCC2 +XP with no neurologic abnormalities to severe neurologic abnormalities+XP/CS+XP/TTD-TTD-COFSEDDB2+ 5XP with no neurologic abnormalitiesFERCC4 +XP with no neurologic abnormalities or severe late-onset neurologic abnormalities 6GERCC5 +XP with no neurologic abnormalities or severe neurologic abnormalities+XP/CSSee footnote 7ERCC1-COFSVariant 8POLH+XP with no neurologic abnormalitiesXP/CS = xeroderma pigmentosum-Cockayne syndrome complexTTD = trichothiodystrophy (without XP)XP/TTD = trichothiodystrophy with XPCOFS = cerebrooculofacioskeletal syndrome1. The XP-B phenotype was seen in five individuals in four kindreds with the XP/CS complex, two sibs with XP, and two sibs with TTD [Robbins et al 1974, Weeda et al 1997, Oh et al 2006].2. ‘XP neurologic abnormalities’ refers to progressive loss of motor, sensory, and cognitive function thought to result from neuronal loss.3. Most individuals with XP-C have XP without XP neurologic abnormalities [Cleaver et al 1999].4. Individuals with XP-D have XP, XP with neurologic abnormalities, the XP/CS complex, TTD, or XP/TTD [Broughton et al 2001, Lehmann 2001].5. Adults with large numbers of skin cancers have been reported [Oh et al 2011].6. Most individuals are from Japan.7. Previously called group H, a designation that was subsequently withdrawn. Only one person has been reported to have a mutation in ERCC1 [Jaspers et al 2007].8. Individuals with XP variant are clinically identical to other individuals with XP with cutaneous symptoms without neurologic abnormalities.Heterozygotes (carriers) of XP-causing mutations are clinically normal. However, the parents of individuals with XP-C frequently have reduced levels of XPC mRNA [Khan et al 2006]. Investigation of the association between an increased cancer risk and heterozygosity for a mutation causing XP is an active area of research.}

Differential DiagnosisXeroderma pigmentosum (XP), XP with neurologic abnormalities, Cockayne syndrome (CS), the XP/CS complex, trichothiodystrophy (TTD), the XP/TTD complex, cerebrooculofacioskeletal syndrome (COFS), COFS/TTD, CS/TTD complex, and the UV-sensitive syndrome [Horibata et al 2004, Berneburg & Kraemer 2007, Kraemer et al 2007, Kraemer & Ruenger 2008, Ruenger et al 2008, Stefanini & Kraemer 2008] represent ten genetic diseases that exhibit cutaneous photosensitivity caused by defective nucleotide excision repair (NER). They are associated with defects in 13 different genes (see Figure 1).Cockayne syndrome (CS) spectrum includes: CS type I, the "classic" form; CS type II, COFS (a more severe form with symptoms present at birth); CS type III, a milder form; and XP/CS complex.CS type I is characterized by normal prenatal growth with onset of growth and developmental abnormalities in the first two years. By the time the disease has become fully manifest, height, weight, and head circumference are far below the fifth percentile. Progressive impairment of vision, hearing, and central and peripheral nervous system function lead to severe disability. Death typically occurs in the first or second decade.As in XP, cells from individuals with CS are hypersensitive to killing by UV; however, CS cells have normal post-UV unscheduled DNA synthesis (UDS). CS cells also have delayed recovery of RNA synthesis after UV exposure, reflecting their deficiency in transcription-coupled nucleotide excision repair (TC-NER). CS is caused by mutations in either ERCC6 or ERCC8, associated respectively with complementation groups CS-B or CS-A, respectively [Bootsma et al 2002]. XP/CS complex includes facial freckling and early skin cancers typical of XP and some features of CS such as intellectual disability, spasticity, short stature, and hypogonadism, but without skeletal dysplasia. CS is diagnosed in classic cases by clinical findings and the presence of post-UV hypersensitivity of cultured cells to killing and delayed recovery of RNA synthesis, and in "non-classic" cases by assay of DNA repair in skin fibroblasts or lymphoblasts. The XP/CS complex is caused by mutations in ERCC3, ERCC2, or XPG (see Table 2 and Figure 1).Other. In addition to diseases sharing deficient nucleotide excision repair, other diseases exhibiting cutaneous photosensitivity may be considered, especially in cases with a paucity of other clinical findings. These other diseases include the following:Rothmund-Thomson syndrome and the allelic disorder Baller-Gerold syndromeHartnup diseaseThe cutaneous findings of Carney complex may be confused with XP; however, the skin findings in Carney complex are lentigines without evidence of the usually associated signs of skin damage such as atrophy and telangiectasia (i.e., poikiloderma) and are not limited to sun exposed sites.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to XP, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with xeroderma pigmentosum (XP), the following evaluations are recommended [reviewed in Tamura et al 2010b].SkinPerform baseline examination of the skin (including all sun-exposed as well as sun-shielded areas) for evidence of sunlight-induced damage including pigmentary changes, precancerous lesions, and skin cancers For examination of the scalp, use a hair dryer (on a cool setting) to blow the hair aside.Cancers of the lip and adjacent tip of the tongue are often preceded by signs of sun damage, including actinic cheilitis (a type of actinic keratosis or leukoplakia occurring on the lips) and prominent telangiectasia [Butt et al 2010]. Baseline clinical color photographs of the entire skin surface with close-ups (including a ruler) of individual lesions facilitate follow-up and detection of early skin cancers.EyesExamine the lids and anterior UV-exposed portions of the globe for evidence of sun-induced damage including ectropion, entropion, inflammatory masses (pterygia, pinguecula), clouding of the cornea, cancer of the lids, conjunctiva or cornea. Eversion of the lids may be necessary to detect cancers of the mucosal surface.Use the Schirmer test to detect dry eyes. This test involves measurement of the extent of absorption of tears into filter paper placed under eyelids for a few minutes.NeurologicDeep tendon reflex testing and routine audiometry with periodic follow-up audiograms to screen for the presence of XP-associated neurologic abnormalitiesMeasurement of the occipital frontal circumference (OFC), to determine if microcephaly is presentMRI of the brain and nerve conduction velocities, if other neurologic problems are detectedTreatment of Manifestations (Reviewed in Tamura et al [2010b]) Skin. Premalignant lesions (e.g., small actinic keratosis) may be treated by freezing with liquid nitrogen.Larger areas of sun-damaged skin can be treated with field treatments such as topical 5-fluorouracil or imiquimod preparations. Rarely, therapeutic dermatome shaving or dermabrasion has been used to remove the more damaged superficial epidermal layers. This procedure permits repopulation by relatively UV-shielded cells from the follicles and glands.Cutaneous neoplasms are treated in the same manner as in individuals who do not have XP. This involves electrodesiccation/curettage or surgical excision. Skin cancers which are recurrent or in locations at high risk for recurrence are best treated with Mohs micrographic surgery. Because multiple surgical procedures are often necessary, removal of undamaged skin should be minimized. Severe cases have been treated by excision of large portions of the facial surface and grafting with sun-protected skin.Most individuals with XP are not abnormally sensitive to therapeutic x-rays, and individuals with XP have responded normally to full-dose therapeutic x-radiation for treatment of inoperable neoplasms [DiGiovanna et al 1998]. However, cultured cells from a few individuals with XP were found to be hypersensitive to x-radiation [Arlett et al 2006]. When x-radiation therapy is indicated, an initial small dose is advisable to test for clinical hypersensitivity.Oral isotretinoin or acitretin can be effective in preventing new neoplasms in individuals with multiple skin cancers [Kraemer et al 1988]. Because of its toxicity (hepatic, hyperlipidemic, and teratogenic effects; calcification of ligaments and tendons; premature closure of the epiphyses), oral isotretinoin or acitretin should be reserved for individuals with XP who are actively developing large numbers of new tumors. Some individuals may respond to lower doses of isotretinoin or acitretin with less toxicity.A few case reports have described regression of skin cancers with use of imiquimod cream in a few individuals with XP [Giannotti et al 2003, Nagore et al 2003, Roseeuw 2003]; however, no controlled studies have been reported.Eyes. Methylcellulose eye drops or soft contact lenses have been used to keep the cornea moist and to protect against mechanical trauma in individuals with deformed eyelids.Corneal transplantation has restored vision in individuals with severe keratitis with corneal opacity. However, the immunosuppression necessary to prevent rejection of the transplant may increase the risk of skin cancer.Neoplasms of the lids, conjunctiva, and cornea are usually treated surgically.Hearing loss. Hearing aids can be of great help for individuals who have sensorineural hearing loss with learning difficulties in school (see Totonchy et al [2013], Deafness and Hereditary Hearing Loss Overview).Prevention of Primary ManifestationsTreatment of XP depends on early diagnosis and immediate, aggressive avoidance of sun and UV exposure. This involves avoiding or minimizing outdoor exposure at times when UV radiation is present (when the sun is out or during daytime through clouds).Clinical suspicion of XP should prompt immediate sun-protective measures until the diagnosis is confirmed or an alternative explanation is determined.Individuals should be educated to protect all body surfaces from UV radiation by wearing protective clothing including hats, long sleeves, long pants and gloves, broad spectrum, high sun-protective factor (SPF) sunscreens, UV-absorbing glasses, and long hair styles. The eyes should be protected by wearing UV-absorbing glasses with side shields. Some individuals have custom-made hats with UV-absorbing face shields to permit visibility outdoors while protecting the face from UV.Because the cells of individuals with XP are hypersensitive to UVA and UVB (found in sunlight) and UVC (found in some artificial light sources), it is useful to measure UV light in an individual's home, school, or work environment with a light meter so that high levels of environmental UV (such as halogen lamps) can be identified and eliminated if possible. While no standards exist for perfectly safe UV exposure in individuals with XP, the use of UV meters can alert individuals to unexpected sources of high levels of environmental UV.Prevention of Secondary ComplicationsVitamin D is produced in the skin by a reaction involving exposure to UV radiation. Active adults with XP and skin cancers received sufficient vitamin D in their diet in the past to result in normal serum concentrations of the active form (1,25 dihydroxy vitamin D) [Sollitto et al 1997]. However, children protected from sunlight very early in life have had low serum concentration of 25 hydroxy vitamin D; one child became susceptible to bone fractures [Ali et al 2009; Author, personal observation]. Dietary supplementation with oral vitamin D is recommended for persons with low serum concentration of serum vitamin D [Author, personal communication]; see also Reichrath [2007]. Surveillance (Reviewed in Tamura et al [2010b]) Skin. A physician should examine the skin of an affected individual at frequent intervals (every ~3-12 months, depending on the severity of skin disease).Affected individuals or their parents should be educated to look for abnormal pigmented lesions or the appearance of basal cell or squamous cell carcinoma. Individuals should be examined frequently by a family member who has been instructed in recognition of cutaneous neoplasms.A set of color photographs of the entire skin surface with close-ups of lesions (including a ruler) is often useful to both the individual and the physician in detecting new lesions.Eyes should be examined regularly for signs of UV exposure and damage.Neurologic. Routine neurologic examination and audiometry are indicated because of progressive neurologic abnormalities that are present in a minority of individuals with XP and may not be detected in young children. Hearing. Periodic audiograms. Hearing aids can be of great help for individuals who have sensorineural hearing loss with learning difficulties in school. See Totonchy et al [2013].Agents/Circumstances to AvoidExposure to sunlight and artificial sources of UV should be avoided (see Prevention of Primary Manifestations).Artificial sources of UV. Certain light sources (e.g., mercury arc, halogen, and other lamps) can be unrecognized sources of UV. Although such light sources are often shielded, in open areas such as gymnasiums they can be a source of UV if the shield has been breached. UV meters are readily available to enable monitoring of areas to identify unexpected UV sources.Cigarette smoke. Because cells from individuals with XP are also hypersensitive to environmental mutagens, such as benzo(a)pyrene found in cigarette smoke, prudence dictates that individuals with XP should be protected against these agents. One individual with XP who smoked cigarettes for more than ten years died of bronchogenic carcinoma of the lungs at age 35 years [Kraemer et al 1994]. The authors recently cared for another individual with XP who smoked and developed lung cancer in the fifth decade of life. Evaluation of Relatives at RiskClinical evaluation to identify affected sibs of a proband may be difficult, especially in an infant or young child. In this case, sun protection may be recommended for sibs until a definitive laboratory diagnosis is obtained.If the family-specific mutations have been identified, molecular genetic testing for at-risk sibs is possible.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposesTherapies Under InvestigationThe bacterial DNA repair enzyme T4 endonuclease V in a topical liposome-containing preparation has been reported to reduce the frequency of new actinic keratoses and basal cell carcinomas in individuals with XP in one research study [Yarosh et al 2001]. As of 2012, this treatment is not approved by the US Food and Drug Administration. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.OtherUse of cotton swabs to obtain specimens from conjunctival lesions for cytologic examination for malignant cells is being evaluated [Author, personal communication].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Xeroderma Pigmentosum: Genes and DatabasesView in own windowComplementation GroupLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDXP variantPOLH6p21​.1DNA polymerase etaPOLH homepage - Mendelian genesPOLHERCC119q13​.32DNA excision repair protein ERCC-1ERCC1 homepage - Mendelian genesERCC1AXPAXPA9q22​.33DNA repair protein complementing XP-A cellsxpmutations​.org
XPA homepage - Mendelian genesXPABXPBERCC32q14​.3TFIIH basal transcription factor complex helicase XPB subunitCatalogue of Somatic Mutations in Cancer (COSMIC)
xpmutations​.org
ERCC3 homepage - Mendelian genesERCC3CXPCXPC3p25​.1DNA repair protein complementing XP-C cellsxpmutations​.org
XPC homepage - Mendelian genesXPCDXPDERCC219q13​.32TFIIH basal transcription factor complex helicase subunitERCC2 @ LOVDERCC2EXPEDDB211p11​.2DNA damage-binding protein 2DDB2 homepage - Mendelian genesDDB2FXPFERCC416p13​.12DNA repair endonuclease XPFERCC4 homepage - Mendelian genesERCC4GXPGERCC513q33​.1DNA repair protein complementing XP-G cellsERCC5 homepage - Mendelian genesERCC5Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Xeroderma Pigmentosum (View All in OMIM) View in own window 126340EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 2; ERCC2 126380EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 1; ERCC1 133510EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 3; ERCC3 133520EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 4; ERCC4 133530EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 5; ERCC5 278700XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A; XPA 278720XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP C; XPC 278730XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D; XPD 278740XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP E 278750XERODERMA PIGMENTOSUM, VARIANT TYPE; XPV 278760XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP F; XPF 278780XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP G; XPG 600811DNA DAMAGE-BINDING PROTEIN 2; DDB2 603968POLYMERASE, DNA, ETA; POLH 610651XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP B; XPB 611153XPA GENE; XPA 613208XPC GENE; XPCMolecular Genetic PathogenesisAn intact DNA repair system that senses, excises, and repairs UV-induced dipyrimidine photoproducts and other forms of DNA damage is necessary to prevent replication errors and subsequent tumorigenesis (Figure 2).FigureFigure 2. Nucleotide excision repair (NER) pathway
Modified from DiGiovanna & Kraemer [2012] Exposure to UV radiation from sunlight forms cyclobutane dimers or other photoproducts at adjacent pyrimidines, thereby distorting the DNA. Initial lesion recognition in non-transcribed DNA (global genome repair-GGR) is performed by DDB2-encoded protein [Clement et al 2010, Sugasawa 2010]. The XPC-encoded protein binding to the photoproducts is facilitated by the binding of the DDB2-encoded protein. The XPC-encoded protein is complexed with hHR23B and centrin [Sugasawa 2010]. DNA damage in transcribed genes (transcription coupled repair– TCR) is marked by stalled RNA polymerase. The CS encoded proteins (along with others) bind to the damage in the transcribed DNA strand. In both global genome repair and transcription coupled repair the XPA protein probably functions in conjunction with replication protein A (RPA), and TFIIH. The XPB/ERCC3 and XPD/ERCC2 proteins (helicases which are part of the TFIIH complex) partially unwind the DNA in the region of the damage, thereby exposing the lesion for further processing. The XPF/ERCC4 product, in a complex with ERCC1, makes a single-strand nick at the 5' side of the lesion, while the XPG/ERCC5 product makes a similar nick on the 3' side, resulting in the release of a region of approximately 30 nucleotides containing the damage. The resulting gap is filled by DNA polymerase using the other (undamaged) strand as a template in a process involving proliferating cell nuclear antigen. DNA ligase I seals the region, restoring the original undamaged sequence [van Steeg & Kraemer 1999, Bootsma et al 2002].The nucleotide excision repair genes (e.g., XPB/ERCC3 and XPD/ERCC2) that are part of the basal transcription factor TFIIH are essential to life. Mice with knockout of Ercc2 do not survive, whereas Xpa and Xpc knockout mice are viable. XPANormal allelic variants. XPA codes for a 1.4-kb mRNA. It comprises six exons and five introns (reference sequence NM_000380.3).Pathologic allelic variants. A pathologic allele creating a splicing mutation in exon 3 of XPA is estimated to occur in approximately 1% of the Japanese population. Individuals who are homozygous for this allele have severe, progressive neurologic degeneration [Nishigori et al 1994]. A nonsense mutation NM_000380.3:682C>T (p.Arg228X) is common in the Tunisian population and results in mild disease [Messaoud et al 2010].An XPA founder mutation consisting of a splicing mutation in exon 3 of XPA is present as a heterozygous mutation in about 1% of the general population of Japan [Nishigori et al 1994, Hirai et al 2006] representing about one million people. These people are clinically normal. Persons of Japanese heritage who are compound heterozygotes for this XPA mutation and a second XPA mutation have milder disease than those who are homozygous for the founder mutation [Takahashi et al 2010]. Although other common pathologic alleles have been described in population isolates, most pathologic alleles are private. Nonsense mutations have been reported in both alleles in cells from individuals in complementation group XP-A.Mild clinical features were found in an individual with an XPA splicing mutation resulting in 5% of normal residual mRNA [Sidwell et al 2006]. Mutations near the C-terminal coding region of XPA had milder neurologic and cutaneous symptoms and greater residual DNA repair activity in several Japanese persons with XP [Takahashi et al 2010]. Normal gene product. XPA codes for an mRNA corresponding to a 31.3-kd protein of 273 amino acids that functions in maintaining single-stranded regions during repair.Abnormal gene product. XP results from absent or inactivated XPA protein.ERCC3 (XPB)Normal allelic variants. ERCC3 codes for a 2.75-kb mRNA. It comprises 15 exons and 14 introns (reference sequence NM_000122.1).Pathologic allelic variants. Nonsense, frameshift, and splicing defects have been reported [Oh et al 2006]. Patients had severe disease with neurologic involvement or mild disease without neurologic involvement [Oh et al 2007]. See also Table 2.Normal gene product. ERCC3 codes for an 89.3-kd protein of 782 amino acids that functions as a 3'- 5' DNA helicase in unwinding DNA. The ERCC3-encoded protein is part of the TFIIH complex, which is involved in regulation of the basal rate of transcription (RNA synthesis) of active genes, as well as in nucleotide excision repair. Abnormal gene product. XP results from absent or inactivated TFIIH basal transcription factor complex helicase XPB subunit protein.XPCNormal allelic variants. XPC codes for a 3.5-kb mRNA. It comprises 16 exons [Khan et al 2002]. Pathologic allelic variants. Single-base substitution and splice mutations have been found. Nonsense mutations have been reported in both alleles in cells from individuals in complementation group XP-C [Khan et al 2006]. Patients with XPC splice lariat mutations may have severe or mild disease [Khan et al 2004, Khan et al 2009]: those with mild disease have about 3% of normal residual XPC mRNA while those with severe disease have no detectible XPC mRNA. Persons with mutations in XPC typically do not have acute burning on minimal sun exposure [Khan et al 2009]. See also Table 2. A founder mutation in XPC (p.Val548Alafs*572) resulting in severe disease was reported in persons with XP from northern Africa (Algeria, Morocco, and Tunisia) [Mahindra et al 2008, Ben Rekaya et al 2009, Soufir et al 2010, Tamura et al 2010a]. Haplotype analysis suggested that this mutation arose about 50 generations (1250 years) ago [Soufir et al 2010]. The frequency of the African XPC founder mutation is not known.Normal gene product. XPC codes for a 105.9-kd protein of 940 amino acids. The XPC protein is involved with recognition of DNA damage and global genome repair.Abnormal gene product. XP results from absent or inactivated XPC protein.ERCC2 (XPD)Normal allelic variants. ERCC2 codes for a 2.3-kb mRNA. It comprises 22 exons and 21 introns. Reference sequence NM_000400.3.Pathologic allelic variants. Individuals with mutations in ERCC2 exhibit significant allelic heterogeneity. Missense mutations with resulting change in amino acids with some residual activity [Lehmann 2001] are frequently found in cells from individuals with XP-D. ERCC2 mutations in persons with XP result in persistent NER protein accumulation at sites of DNA damage while XPD mutations in persons with TTD result in failure of accumulation of NER proteins at sites of localized DNA damage [Boyle et al 2008]. See also Table 2.Normal gene product. ERCC2 codes for an 86.9-kd protein of 760 amino acids. ERCC2, like the ERCC3 (XPB) protein, is also a DNA helicase (but unwinds DNA in the 5'- 3' direction). ERCC2 is part of basal transcription factor TFIIH that is involved in regulation of the basal rate of transcription (RNA synthesis) of active genes, as well as in NER.Abnormal gene product. XP results from absent or inactivated TFIIH basal transcription factor complex helicase subunit.DDB2 (XPE)Normal allelic variants. DDB2 codes for a 1.8-kb RNA. It comprises ten exons and nine introns.Pathologic allelic variants. Individuals with mutations in the p48 subunit of DDB2 may have large numbers of skin cancer without acute burning on minimal sun exposure [Oh et al 2011]. See also Table 2.Normal gene product. DDB2 codes for a 48-kd protein of 427 amino acids. DDB2 combined with DDB1 forms a heterodimer, which, along with XPC, is involved in the initial recognition of UV-induced DNA damage in non-transcribed portions of the genome.Abnormal gene product. XP results from absent or inactivated DNA damage-binding protein 2.ERCC4 (XPF)Normal allelic variants. ERCC4 codes for a 2.7-kb mRNA. It comprises 11 exons and ten introns.Pathologic allelic variants. Persons with mutations in XPF may have mild disease or adult onset of severe neurologic degeneration [Author, personal observation]. See also Table 2. Normal gene product. ERCC4 codes for a 103.3-kd protein of 905 amino acids that serves as a DNA endonuclease 5' to the lesion.Abnormal gene product. XP results from absent or inactivated DNA repair endonuclease XPF.ERCC5 (XPG)Normal allelic variants. ERCC5 codes for a 4.1-kb mRNA. It comprises 15 exons and 14 introns [Emmert et al 2001].Pathologic allelic variants. Mutations resulting in markedly truncated proteins are found in individuals with XP-G with the XP/CS complex, while individuals with XP-G without neurologic disease have missense mutations that retain some activity [Emmert et al 2002].Normal gene product. ERCC5 codes for a protein of 112 kd that functions as a DNA endonuclease 3' to the lesion.Abnormal gene product. XP results from absent or inactivated DNA repair protein complementing XP-G cells.ERCC1 Normal allelic variants. ERCC1 codes for a 1.2-kb mRNA. It comprises eight exons (reference sequence NM_001983.3).Pathologic allelic variants. One individual was reported by Jaspers et al [2007].Normal gene product. ERCC1 codes for a 110-kd protein of 323 amino acids.Abnormal gene product. XP results from absent or inactivated DNA excision repair protein ERCC-1.POLH (XP-V)Normal allelic variants. POLH codes for a 3.4-kb mRNA. It comprises 11 exons and ten introns.Pathologic allelic variants. Affected Japanese individuals were described by Tanioka et al [2007]. Patients from different countries who had multiple skin cancers but no neurologic involvement were identified with mutations in POLH [Inui et al 2008]. See also Table 2.Normal gene product. POLH (polymerase eta) codes for a 78.4-kd protein of 713 amino acids that functions as an error-prone polymerase [Broughton et al 2002].Abnormal gene product. XP results from absent or inactivated DNA polymerase eta.