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Xeroderma Pigmentosum

Synonym: DeSanctis-Cacchione Syndrome. Includes: DDB2-Related Xeroderma Pigmentosum, ERCC1-Related Xeroderma Pigmentosum, ERCC2-Related Xeroderma Pigmentosum, ERCC3-Related Xeroderma Pigmentosum, ERCC4-Related Xeroderma Pigmentosum, ERCC5-Related Xeroderma Pigmentosum, POLH-Related Xeroderma Pigmentosum, XPA-Related Xeroderma Pigmentosum, XPC-Related Xeroderma Pigmentosum

, MD and , MD.

Author Information
, MD
Dermatology Branch
Center for Cancer Research
National Cancer Institute
Bethesda, Maryland
, MD
Dermatology Branch
Center for Cancer Research
National Cancer Institute
Bethesda, Maryland

Initial Posting: ; Last Update: February 13, 2014.

Summary

Disease characteristics. Xeroderma pigmentosum (XP) is characterized by:

  • Sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure in ~60% of affected individuals, and marked freckle-like pigmentation of the face before age 2 years in most affected individuals);
  • Ocular involvement (photophobia, keratitis, atrophy of the skin of the lids); and
  • Greatly increased risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma).

Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, and progressive cognitive impairment). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

Diagnosis/testing. The diagnosis of XP is made on the basis of clinical findings and family history. The preferred method of laboratory diagnosis is functional testing to screen cells for abnormalities in DNA repair. XP has been classified by complementation group (XP-A, XP-B, XP-C, XP-D, XP-E, XP-F, XP-G) based on research laboratory testing. The XP complementation groups are associated with biallelic mutations in nucleotide excision repair genes: XPA, ERCC1, ERCC3 (XP-B), XPC, ERCC2 (XP-D), DDB2 (XP-E), ERCC4 (XP-F), and ERCC5 (XP-G). In addition XP is associated with mutations in the DNA bypass polymerase POLH.

Management. Treatment of manifestations: Small, premalignant skin lesions such as actinic keratoses can be treated by freezing with liquid nitrogen; larger areas can be treated with field treatments such as topical 5-fluorouracil or imiquimod. Rarely, therapeutic dermatome shaving or dermabrasion has been used; skin neoplasms can be treated (as in persons without XP) with electrodesiccation and curettage, or surgical excision; skin cancers that are recurrent or in locations at high risk for recurrence are best treated with Mohs micrographic surgery. Oral isotretinoin or acitretin can prevent new skin neoplasms but have many side effects. Neoplasms of the eyelids, conjunctiva, and cornea can be treated surgically; corneal transplantation may improve the visual impairment resulting from severe keratitis.

Prevention of primary manifestations: Avoid sun and UV exposure to the skin and eyes.

Prevention of secondary complications: Dietary supplementation with oral vitamin D as needed.

Surveillance: Skin examinations by a physician every 3-12 months; periodic routine eye and neurologic examinations and audiograms.

Agents/circumstances to avoid: Sun and UV exposure, cigarette smoke.

Evaluation of relatives at risk: If the family-specific mutations have been identified, molecular genetic testing of at-risk sibs can permit early diagnosis and rigorous sun protection from an early age.

Genetic counseling. XP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the disease-causing mutations have been identified in the family, carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

Clinical 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 [Sethi et al 2013].
  • Eye. Ophthalmologic abnormalities are usually limited to the anterior, UV-exposed portion of the eyes: conjunctiva, cornea, and lids [Dollfus et al 2003, Brooks et al 2013].
    • 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, Digiovanna & Kraemer 2012, Lai et al 2013, Totonchy et al 2013, Viana et al 2013]. These include the following:
    • 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 impairment

Cancer. 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.

Testing

No 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 [Stefanini & Kraemer 2008, Kraemer & Ruenger 2012, Ruenger et al 2012].

Note: In the XP variant (see Natural History), 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 Testing

Genes. 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 (Table 1). See Molecular Genetic Pathogenesis for more details.

Table 1. Summary of Molecular Genetic Testing Used in Xeroderma Pigmentosum

Complementation Group 1Gene 2Proportion of XP Attributed to Mutations in This Gene: US / Japan 3Test MethodMutations Detected 4
AXPA9% / 55% 5Sequence analysisSequence variants 6
Deletion/duplication analysis 7Unknown, none reported 8
BERCC31% / 0%Sequence analysisSequence variants 6
Deletion/duplication analysis 7Unknown, none reported 8
CXPC43% / 3%Sequence analysis Sequence variants 6
Deletion/duplication analysis 7Exonic or whole-gene deletions
DERCC228% / 5%Sequence analysisSequence variants 6
Deletion/duplication analysis 7Unknown, none reported 8
EDDB23% / 3%Sequence analysisSequence variants 6
Deletion/duplication analysis 7Unknown, none reported 8
FERCC40% / 7% 9Sequence analysisSequence variants 6
Deletion/duplication analysis 7Unknown, none reported 8
GERCC53% / 1%Sequence analysisSequence variants 6
Deletion/duplication analysis 7Unknown, none reported 8
See footnote 10ERCC1Rare 11Sequence analysisSequence variants 6
Deletion/duplication analysis 7Unknown, none reported 8
VariantPOLH7% / 25%Sequence analysisSequence variants 6
Deletion/duplication analysis 7Unknown, none reported 8

1. 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. See Table A. Genes and Databases for chromosome locus and protein name.

3. Frequencies are taken from Bradford et al [2011] for 106 individuals with XP in the US and Moriwaki & Kraemer [2001] for 291 individuals with XP in Japan.

4. See Molecular Genetics for information on allelic variants.

5. Common in Japan, rare in the US and Europe

6. 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. For issues to consider in interpretation of sequence analysis results, click here.

7. 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.

8. No deletions or duplications involving DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA have been reported to cause xeroderma pigmentosum. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by exon-based sequence analysis of genomic DNA.)

9. Patients with mutations in ERCC4 have recently been reported with phenotypes of Fanconi anemia, XP/Cockayne Syndrome complex or with combined XP/CS/FA [Bogliolo et al 2013, Kashiyama et al 2013].

10. Previously called group H, a designation that was subsequently withdrawn

11. Only one person with COFS syndrome and a mutation in ERCC1 has been reported [Jaspers et al 2007]. One patient with an ERCC1 mutation had severe Cockayne syndrome type II and died at age 2.5 years [Kashiyama et al 2013].

Testing Strategy

To confirm/establish the diagnosis of XP in a proband. In individuals with clinical findings suggestive for XP (e.g., severe burning on UV exposure or freckle-like pigmentary abnormalities before age 2 years), begin UV protective measures immediately based on a working clinical diagnosis of XP to reduce exposure while molecular confirmation testing is being performed.

The steps to follow in pursuing a molecular genetic diagnosis:

1.

Perform molecular genetic testing.

  • Sequential single gene testing. 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 1, Table 2, and 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 pathogenic.
  • Multigene panel. An alternate to targeted or sequential single gene testing is a panel in which some or all of the genes leading to XP are sequenced simultaneously. Note: Often mutations identified by such a panel are confirmed by sequence analysis of the involved gene.
2.

Perform functional assays of DNA repair. Note: None of these tests is available on a clinical basis in the US (see additional test options).

Figure 1

Figure

Figure 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...)

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.

Clinical Description

Natural History

The 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 [Sethi et al 2013]. 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, Brooks et al 2013].
  • 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, Lai et al 2013, Viana et al 2013].

    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, ERCC4, 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 Correlations

The 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 syndrome, and others [see 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 Disorders

Complementation GroupGeneCutaneous NeoplasiaPhenotype
AXPA+XP with mild-to-severe neurologic abnormalities
1ERCC3 +XP/CS
-TTD
+XP with mild neurologic abnormalities
CXPC+XP with no neurologic abnormalities 2, 3
4ERCC2 +XP with no neurologic abnormalities to severe neurologic abnormalities
+XP/CS
+XP/TTD
-TTD
-COFS syndrome
EDDB25XP with no neurologic abnormalities
FERCC4 +XP with no neurologic abnormalities or severe late-onset neurologic abnormalities 6; Fanconi anemia (FA) complementation group Q 7; one individual with features of XP, CS, and FA, and two individuals with CS 8
GERCC5 +XP with no neurologic abnormalities or severe neurologic abnormalities
+XP/CS
See footnote 9ERCC1-COFS syndrome
Variant 10POLH+XP with no neurologic abnormalities

XP/CS = xeroderma pigmentosum-Cockayne syndrome complex

TTD = trichothiodystrophy (without XP)

XP/TTD = trichothiodystrophy with XP

COFS = cerebrooculofacioskeletal

1. 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. Bogliolo et al [2013]

8. Kashiyama et al [2013]

9. Previously called group H, a designation that was subsequently withdrawn. Only one person with COFS syndrome has been reported to have a mutation in ERCC1 [Jaspers et al 2007]. One patient with an ERCC1 mutation had severe Cockayne syndrome type II and died at age 2.5 years [Kashiyama et al 2013].

10. 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.

Nomenclature

Xeroderma pigmentosum was first described in Vienna by Moriz Kaposi in the textbook of dermatology he published in 1870 with his father-in-law, Ferdinand Hebra. The disorder was first called xeroderma or parchment skin. See discussion in Kraemer et al [1987] and in DiGiovanna & Kraemer [2012].

Previously, 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.

"Pigmented xerodermoid" is now known to be identical to the XP variant.

Prevalence

Prevalence is estimated at 1:1,000,000 in the United States and in Europe [Kleijer et al 2008].

Certain populations have a higher prevalence:

Differential Diagnosis

Xeroderma pigmentosum (XP), XP with neurologic abnormalities, Cockayne syndrome (CS), the XP/CS complex, trichothiodystrophy (TTD), the XP/TTD complex, cerebrooculofacioskeletal (COFS) syndrome, COFS/TTD, CS/TTD complex, and the UV-sensitive syndrome [Horibata et al 2004, Berneburg & Kraemer 2007, Kraemer et al 2007, Stefanini & Kraemer 2008, Kraemer & Ruenger 2012, Ruenger et al 2012] 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 syndrome (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 with complementation groups CS-B or CS-A, respectively [Bootsma et al 2002], although one person each with CS and biallelic mutations in either ERCC4 or ERCC1 has been described [Kashiyama et al 2013].

XP/CS complex includes facial freckling and early skin cancers typical of XP and some features of CS (e.g., intellectual disability, spasticity, short stature, hypogonadism) but not 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, ERCC4, or ERCC5 (also known as XPG) (see Table 2 and Figure 1) [Kashiyama et al 2013].

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:

  • Hartnup disease, a disorder of amino acid absorption resulting from biallelic mutations in SLC6A19, a non-polar amino acid transporter. Affected individuals may have reduced levels of niacin with resulting pellagra-like symptoms of photosensitivity with dermatitis, diarrhea, and dementia. However, individuals with Hartnup disease are not reported to have increased frequency of skin cancer, as is seen in those with XP.

The cutaneous findings of Carney complex may be confused with those of XP; however, Carney complex is characterized by lentigines without evidence of the usually associated signs of skin damage such as atrophy and telangiectasia (i.e., poikiloderma) and cutaneous findings are not limited to sun-exposed sites.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to XP, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with xeroderma pigmentosum (XP), the following evaluations are recommended [reviewed in Tamura et al 2010b]:

Skin

  • Perform 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.

Eyes

  • Examine 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.

Neurologic

  • Deep tendon reflex testing
  • Routine audiometry with periodic follow-up audiograms to screen for the presence of XP-associated neurologic abnormalities
  • Measurement of the occipital frontal circumference (OFC), to determine if microcephaly is present
  • MRI of the brain and nerve conduction velocities, if other neurologic problems are detected

Medical genetics consultation

Treatment of Manifestations

The treatment of manifestations is 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 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 for 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] and Deafness and Hereditary Hearing Loss Overview).

Prevention of Primary Manifestations

Treatment 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 Complications

Vitamin 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

See Tamura et al [2010b] for review.

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]. Serial audiograms at regular intervals may be useful for assessing the presence or absence of progressive neurologic degeneration, especially in those with a history of acute burning on minimal sun exposure [Totonchy et al 2013].

Agents/Circumstances to Avoid

Exposure 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 Risk

Clinical 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 purposes.

Pregnancy Management

The systemic retinoids isotretinoin and acitretin are used as skin cancer chemopreventive agents in individuals who are actively developing large numbers of skin cancer. Therefore, these drugs may be used by some women who have XP [Kraemer et al 1988]. Systemic retinoids are known to be teratogenic to a developing fetus and pose a high risk for fetal birth defects. Therefore, women who are using systemic retinoids should be appropriately counseled about pregnancy risks and avoidance. These women must use effective contraception and should be monitored with regular pregnancy tests. Systemic retinoids should only be administered by physicians knowledgeable about their risks and benefits.

To access isotretinoin in the US, women and their prescribing providers must be enrolled in the iPLEDGE program to minimize the potential for fetal exposure. Pregnancy avoidance is initiated before therapy, continues during therapy and extends post treatment until the drug is cleared from the body. While both drugs may be effective in preventing skin cancers, acitretin may be slowly eliminated from the body requiring a longer period (3 years) of post-therapy pregnancy avoidance to minimize teratogenic risk.

Therapies Under Investigation

The 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.

Other

Use of cotton swabs to obtain specimens from conjunctival lesions for cytologic examination for malignant cells is being evaluated [Brooks et al 2013].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Xeroderma pigmentosum (XP) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an individual with XP are obligate carriers of one of the two XP-causing gene mutations identified in their child.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • The offspring of an individual with XP are obligate heterozygotes for a disease-causing mutation. These individuals are clinically normal.
  • The offspring of an individual with XP and a clinically normal XP heterozygote will have a 50% chance of having XP. This is a consideration in populations with a founder mutation or with a high rate of consanguinity.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing to identify carriers among family members at risk is possible for mutations in some of the XP-related genes if the mutations have been identified in the family (see Christen-Zaech et al [2009] for discussion).

Carrier testing of reproductive partners of known carriers is possible for mutations in some of the XP-related genes.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in a family member, prenatal testing for pregnancies at increased risk is possible either through a clinical laboratory or a laboratory offering custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Understanding Xeroderma Pigmentosum
    Booklet on XP prepared by the National Institutes of Health for families and others involved in the care of individuals with XP
    National Institutes of Health Clinical Center
    Bethesda MD 20892
  • Xeroderma Pigmentosum Society, Inc (XP Society)
    437 Syndertown Road
    Craryville NY 12521
    Phone: 877-XPS-CURE (877-977-2873); 518-851-2612
    Email: xps@xps.org
  • XP Family Support Group
    8495 Folsom
    #1
    Sacramento CA 95826
    Phone: 916-628-3814
    Email: contact@xpfamilysupport.org
  • XP Support Group
    Instron House
    Coronation Road
    Bucks HP12 3SY
    United Kingdom
    Phone: +44 (0) 1494 456192; +44 (0) 1494 459888
    Email: info@xpsupportgroup.org.uk
  • DNA Repair Interest Group Web site
    This site is primarily for researchers. It contains information about current laboratory research in DNA repair, as well as links to other sites.
    National Institutes of Health (NIH)
    Bethesda MD 20892

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B. OMIM Entries for Xeroderma Pigmentosum (View All in OMIM)

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; XPC

Molecular Genetic Pathogenesis

An 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).

Figure 2

Figure

Figure 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.

XPA

Gene structure. XPA codes for a 1.4-kb mRNA. It comprises six exons and five introns (NM_000380.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. A pathogenic 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.Arg228Ter) 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 individuals are clinically normal.

This founder mutation appeared in the Japanese population approximately 120 generations (about 2400 years) ago [Imoto et al 2013].

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 pathogenic alleles have been described in population isolates, most pathogenic 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)

Gene structure. ERCC3 codes for a 2.75-kb mRNA. It comprises 15 exons and 14 introns (NM_000122.1). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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.

XPC

Gene structure. XPC codes for a 3.5-kb mRNA (NM_004628.4). It comprises 16 exons [Khan et al 2002]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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.Val548AlafsTer572) 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)

Gene structure. ERCC2 codes for a 2.3-kb mRNA. It comprises 22 exons and 21 introns (NM_000400.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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 ERCC2 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.

Patients with mutations in ERCC2 may have phenotype XP, TTD, or XP/TTD [Zhou et al 2013].

A mild phenotype was report in Israel [Falik-Zaccai et al 2012].

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)

Gene structure. DDB2 codes for a 1.8-kb RNA. It comprises ten exons and nine introns (NM_000107.2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Individuals with mutations in the p48 subunit of DDB2 may have large numbers of skin cancers 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 6.7-kb mRNA. It comprises 11 exons and ten introns (NM_005236.2). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Persons with mutations in XPF may have mild disease or adult onset of severe neurologic degeneration [Author, personal observation], or features of FA, CS, XP/CS complex, and XP/CS/FA. See also Table 2 [Bogliolo et al 2013, Kashiyama et al 2013].

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)

Gene structure. ERCC5 codes for a 4.1-kb mRNA (NM_000123.3). It comprises 15 exons and 14 introns [Emmert et al 2001]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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, Moriwaki et al 2012].

One patient with mutation of ERCC5 (XPG) and minimal neurologic involvement developed retinal atrophy and basal ganglia calcification of the XP/CS complex while being followed at the NIH [Brooks et al 2013].

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

Gene structure. ERCC1 codes for a 1.2-kb mRNA. It comprises eight exons (NM_001983.3). For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. One individual with COFS syndrome was reported by Jaspers et al [2007]. One individual with severe CS had a mutation in ERCC1 [Kashiyama et al 2013].

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)

Gene structure. POLH codes for a 8.4-kb mRNA (NM_006502.2). It comprises 11 exons and ten introns. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. Tamura D, DiGiovanna JJ, Kraemer KH. Xeroderma pigmentosum. In: Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I, eds. Treatment of Skin Disease. 3 ed. London, UK: Elsevier; 2010:789-92.
  2. Tamura D, Kraemer KH, DiGiovanna JJ. Xeroderma pigmentosum. In: Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I, eds. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. 4 ed. London, UK: Elsevier; 2014.

Literature Cited

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Chapter Notes

Author Notes

NIH Study 99-C-0099. Examination of Clinical and Laboratory Abnormalities in Patients with Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy is actively recruiting new patients for a study in Bethesda, MD. Click here for more information.

Acknowledgements

This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and National Human Genome Research Institute.

Author History

John J DiGiovanna, MD (2011-present)
Kenneth H Kraemer, MD (2003-present)
Daniel J Wattendorf, MD; National Institutes of Health (2003-2008)

Revision History

  • 13 February 2014 (me) Comprehensive update posted live
  • 14 February 2013 (cd) Revision: changes in testing available for POLH, ERCC3, XPA, XPC, and DDB2
  • 1 November 2012 (cd) Revision: testing for ERCC4 mutations available clinically; Figure 2 added
  • 15 March 2012 (cd) Revision: sequence analysis available clinically for ERCC1 and ERCC3 and no longer available for DDB2
  • 4 August 2011 (me) Comprehensive update posted live
  • 22 April 2008 (me) Comprehensive update posted to live Web site
  • 14 May 2007 (cd) Revision: sequence analysis clinically available for XPA and XPC
  • 1 June 2006 (cd) Revision: confirmation of XPA and XPC mutations identified in a research lab clinically available
  • 15 September 2005 (me) Comprehensive update posted to live Web site
  • 24 February 2004 (kk) Revision: Molecular Genetics
  • 1 October 2003 (kk) Revision: clinical testing no longer available
  • 20 June 2003 (me) Review posted to live Web site
  • 28 April 2003 (kk) Original submission

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