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.
 |
|
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of XP is made clinically based on skin, eye, and neurologic manifestations. Because clinical history and findings on examination of the skin and eyes are often not sufficient to make the diagnosis, a detailed family history with attention to consanguinity may aid in diagnosis. Functional tests on living cells can be used to screen for abnormalities in DNA repair. Cells from individuals with XP with defective nucleotide excision repair (NER) are hypersensitive to killing by UV in comparison to normal cells; cells from individuals with XP variant may have normal or near-normal post-UV cell survival. Unscheduled DNA synthesis is abnormal in XP cells and normal in XP variant cells. Host-cell reactivation is abnormal in all forms of NER-deficient XP and is used on a research basis to determine XP complementation groups. Xeroderma pigmentosum is known to be associated with mutations in XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), ERCC1, and POLH (XP-V). Mutations in XPA and XPC account for approximately 50% of XP. Molecular genetic testing for a specific XP-causing gene mutation is possible after cells from an individual are assigned to a known complementation group using host-cell reactivation or other studies in a research laboratory. Molecular genetic testing of the XPA and XPC genes is clinically available. Molecular genetic testing for the remaining genes is available on a research basis only.
Management. Treatment of manifestations: Treat small, premalignant skin lesions such as actinic keratoses with topical 5-fluorouracil or freeze with liquid nitrogen; treat larger areas with dermatome shaving or dermabrasion to remove damaged superficial epidermal layers; treat skin neoplasms with electrodesiccation and curettage, surgical excision, or chemosurgery; use high-dose oral isotretinoin to prevent new neoplasms; treat neoplasms of the eyelids, conjunctiva, and cornea surgically; corneal transplantation for those with severe keratitis and corneal opacity. Prevention of primary manifestations: Avoid sun and UV exposure with UV-blocking protective clothing, high sun-protective factor (SPF) sunscreens, UV-absorbing glasses with side shields, and long hair styles. Surveillance: skin examinations by a physician every 3-6 months for cutaneous neoplasms; periodic routine neurologic examination. Agents/circumstances to avoid: sun and UV exposure, cigarette smoke. Prevention of secondary manifestations: vitamin D supplementation to prevent deficiency from sun avoidance. Testing of relatives at risk: Sun protection may be recommended for sibs until a definitive laboratory diagnosis is obtained. Other: When x-radiation therapy is indicated, an initial small dose may be used to test for clinical hypersensitivity, although most persons with XP have a normal response to therapeutic x-radiation.
Genetic counseling. XP is inherited in an autosomal recessive manner. The parents of an individual with XP are obligate carriers of a mutation in one of the nine genes associated with XP. Heterozygotes (carriers) are asymptomatic. 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. No laboratories offering molecular genetic testing for prenatal diagnosis of XP are listed in the GeneTests Laboratory Directory; however, prenatal testing may be available through laboratories offering custom prenatal testing for families in which the disease-causing mutations have been identified.
The diagnosis of xeroderma pigmentosum (XP) is made clinically. Three major areas are involved:
Skin. The diagnosis can often be made in the first year of life because half of affected children demonstrate acute sun sensitivity: severe sunburn with blistering or persistent erythema on minimal sun exposure. Marked freckling of the face of a child before age two years is typical of XP and rarely seen in normal children. Most individuals with XP develop xerosis (dry skin) and poikiloderma (the constellation of hyper- and hypopigmentation, atrophy, and telangiectasia).
Eye. Ophthalmologic abnormalities are usually limited to the anterior, UV-exposed portion of the eyes: conjunctiva, cornea, and lids. Photophobia is often present and may be associated with prominent conjunctival injection. Continued UV exposure of the eye may result in severe keratitis leading to 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. Thirty percent of affected individuals have characteristic neurologic manifestations that worsen slowly and may manifest later than the skin changes. These include the following:
Acquired microcephaly. CT and MRI of the brain may show enlarged ventricles and thinning of the cortex.
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.
Progressive cognitive impairment
Cancer. Individuals with XP who are younger than age 20 years have a greater than 1000-fold increased risk of cancer at UV-exposed sites including the skin and eyes. The median age of onset of non-melanoma skin cancer is before age ten years.
No consistent routine clinical laboratory abnormality is observed in individuals with XP. Functional tests on living cells can be used to screen for abnormalities in DNA repair.
In XP variant, the clinical appearance is the same as in other forms of XP. However, in contrast to cells from other forms of XP, cells from XP variant have normal nucleotide excision repair (NER) of UV-damaged DNA.
Cellular ultraviolet (UV) hypersensitivity. A post-UV exposure cellular survival curve reflects the ability of the DNA repair enzymes of a cell to repair UV-induced damage. Cellular UV hypersensitivity can be measured from skin fibroblasts [van Steeg & Kraemer 1999, Bootsma et al 2002, Kraemer 2003a]:
XP cells. Cells from individuals with XP with defective nucleotide excision repair (NER) are hypersensitive to killing by UV in comparison to normal individuals.
XP variant cells. Cells from individuals with the variant form of XP (XP variant) may have normal or near-normal post-UV cell survival. However, post-UV cell killing of XP variant cells (but not of normal cells) is potentiated by addition of caffeine to the culture medium.
Unscheduled DNA synthesis (UDS). One of the most commonly used tests of NER is UDS [Bootsma et al 2002, Kraemer 2003a]. UDS measures the combined action of endonuclease, exonuclease, and polymerase in the NER system. Cells are treated with UV and then incubated in medium containing radioactive thymidine. The cells are then fixed and overlaid with x-ray-sensitive autoradiographic emulsion. An alternative assay uses scintillation counting to measure UV-induced incorporation of radioactive thymidine in non-dividing cells:
Normal cells. UV radiation of normal fibroblasts results in a large increase in radiographic signal over all non-S phase nuclei.
XP cells. UDS is abnormal. UV radiation of NER-defective (XP) fibroblasts results in minimal signal over non-S phase nuclei.
XP variant cells. UDS is normal.
Host-cell reactivation. DNA viruses or plasmids do not have the ability to repair damage to their DNA and thus depend on host cellular repair systems [Emmert et al 2002]. Damaged DNA viruses or plasmids are expected to have greater growth or expression on cells with normal DNA repair capacity than on cells with reduced DNA repair capacity. A plasmid DNA repair assay utilizes a non-replicating plasmid that contains a reporter gene, such as luciferase. Host-cell reactivation involves transfection of a UV-damaged plasmid into the human host cell. The plasmid is repaired by the cell's enzymes. The activity of the reporter gene depends on the capacity of the DNA repair enzymes of the cell:
XP cells. Host-cell reactivation is abnormal in all forms of NER-deficient XP. Expression of a UV-treated marker gene such as luciferase is lower in DNA repair-deficient XP cells than in repair-proficient normal cells.
XP complementation groups. Host-cell reactivation is currently also used on a research basis to determine the XP complementation group by co-transfecting a UV-treated plasmid plus plasmids expressing wild-type XP cDNA of different complementation groups.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
GeneReviewsdesignates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. Xeroderma pigmentosum is known to be associated with mutations in XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), ERCC1, and POLH (XP-V).
Clinical testing
Sequence analysis. Sequence analysis is clinically available for XPA and XPC mutations.
Research testing
Targeted mutation analysis. More than 90% of Japanese individuals with XPA-related XP (XP-A) have the same single-base substitution mutation in this gene [Nishigori et al 1994]. Molecular genetic testing using PCR products specific to this mutation has been developed for rapid diagnosis of XP-A homozygotes and heterozygotes as well as for prenatal diagnosis [Kore-eda et al 1992].
Direct DNA. Molecular genetic testing for a specific XP-causing gene mutation is possible after cells from an individual are assigned to a known complementation group using host-cell reactivation or other studies.
| Complementation Group 1 | Test Method | Mutations Detected | Proportion of XP Attributed to Mutations in This Gene | Mutation Detection Frequency by Test Method | Test Availability |
|---|---|---|---|---|---|
| A | Sequence analysis | XPA sequence variants | 25% 2 | Unknown | Clinical
 |
| B | Direct DNA 3 | ERCC3 mutations | Rare | Research only | |
| C | Sequence analysis | XPC sequence variants | 25% | Clinical | |
| D | Direct DNA 3 | ERCC2 mutations | 15% | Research only | |
| E | DDB2 mutations | Rare | |||
| F | ERCC4 mutations | 6% | |||
| G | ERCC5 mutations | 6% | |||
| H | ERCC1 4 | Rare | |||
| Variant | POLH mutations | 21% |
1. From Kraemer [2003b]
2. Common in Japan, rare in the US and Europe
3. The use of targeted mutation analysis, mutation scanning, sequence analysis, or other means of molecular genetic testing to detect a genetic alteration associated with a specific disorder
4. Jaspers et al [2007] reported one individual.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Confirmation of the diagnosis in a proband. The preferred method for diagnosis of XP is functional assay of the ability of living cells from the proband to repair DNA damage. Examples of such tests:
Post-UV cell survival
Post-UV host cell reactivation
Post-UV unscheduled DNA synthesis
Note: None of the above tests is currently available on a clinical basis.
Molecular genetic testing currently available is limited to clinical confirmation of mutations in XPA or XPC previously identified in a research laboratory. Individuals for whom this testing would be appropriate include the following:
Newborn sibs of an affected individual (in order to institute appropriate interventions as soon after birth as possible)
Unaffected adult sibs of an affected individual (in order to determine carrier status for genetic counseling purposes)
For laboratories offering clinical confirmation of mutations previously identified in a research laboratory, see
.
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.
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.
). In the general population, allelic variants in XPA, XPC, ERCC2, and ERCC5 are associated with an increased risk of skin and lung cancer and altered response to certain chemotherapeutic agents.
Trichothiodystrophy (TTD). TTD is an autosomal recessive disorder with a variable phenotype that may include photosensitivity, ichthyosis, brittle hair, intellectual impairment, short stature, microcephaly, characteristic facial features of protruding ears and micrognathia, and decreased fertility. Approximately 100 cases have been reported in the literature. Sulfur deficiency reduces levels of cysteine and cystine in the protein, resulting in brittle hair that splits and demonstrates under polarized light a characteristic dark and light transverse banding pattern described as a "tiger tail" appearance [Liang et al 2005]. Many individuals with TTD have a cellular defect in NER. Mutations in ERCC3, ERCC2, or TTDA cause TTD [Broughton et al 2001, Itin et al 2001, Bootsma et al 2002, Giglia-Mari et al 2004, Liang et al 2005].
Cerebrooculofacioskeletal syndrome (COFS syndrome; Pena-Shokeir syndrome, type II). COFS syndrome 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 joint contractures. Photosensitivity may occur with a concurrent cellular phenotype of UV sensitivity. Individuals with COFS syndrome have mutations in ERCC2 and ERCC5 as well as in ERCC6 (CSB), which also causes Cockayne syndrome (see Differential Diagnosis) [Meira et al 2000, Graham et al 2001].
Lung and skin cancer. Recent investigations of individuals with one normal allele and one common normal allelic variant of one of four XP genes (XPA, XPC, ERCC2, or ERCC5) have reported an increased risk of skin cancer, lung cancer, or altered response to chemotherapeutic agents that are inactivated by efficient NER [Park et al 2001, Shen et al 2001, Chen et al 2002, Hou et al 2002, Park et al 2002, Qiao et al 2002, Gao et al 2003, Jeon et al 2003, Liang et al 2003, Misra et al 2003, Marin et al 2004, Blankenburg et al 2005]. Meta-analyses of many studies of normal allelic variants of genes involved in NER were performed by Hu et al (2004), Kiyohara & Yoshimasu (2007), and Manuguerra et al (2006). Benhamou & Sarasin (2005) reviewed this active area of research.
Functional studies are limited, but allelic variants in a gene(s) have demonstrated altered NER [Khan et al 2002, Qiao et al 2002].
Xeroderma pigmentosum (XP)
Cutaneous. Approximately 50% of individuals with XP have a history of acute sunburn reaction on minimal UV exposure. The other 50% of individuals with XP tan normally without excessive burning. In all individuals, numerous freckle-like hyperpigmented macules appear on sun-exposed skin. The median age of onset of the cutaneous symptoms is between 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"). 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. Benign conjunctival inflammatory masses or papillomas of the lids may be present. Inflammatory masses on the conjunctiva 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.
Neurologic. Neurologic abnormalities have been reported in approximately 30% of affected individuals [Kraemer et al 1987, Rapin et al 2000]. The onset may be early in infancy or, in some individuals, delayed until the second decade or later. 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, 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.
Cutaneous neoplasia. If aggressive UV avoidance is not introduced early, accumulated sunlight-induced DNA damage is likely to result in skin cancer in the first decade of life. Some individuals with XP show exquisite acute sun sensitivity with severe burning on minimal sun exposure. However, many individuals with XP have no symptoms of increased sunburning on minimal sun exposure but tan, freckle, and then develop skin cancers if not protected from sunlight. Affected individuals younger than age 20 years have a greater than 1000-fold increased risk of cutaneous basal cell carcinoma, squamous cell carcinoma, or melanoma [Kraemer et al 1987, Kraemer et al 1994]. Multiple primary cutaneous neoplasms are common. The median age of onset of non-melanoma skin cancer reported in individuals with XP is eight years. This 50-year difference in age of onset from that found in the general population illustrates the importance of DNA repair in protection from skin cancer in normal individuals.
Other neoplasias. Review of the world literature has revealed a substantial number of cases of oral cavity neoplasms, particularly squamous cell carcinoma of the tip of the tongue, a presumed sun-exposed location.
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.
).
).
). 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.Genotype-phenotype correlation is ongoing. Further information is included in literature-based reviews [Cleaver et al 1999] and a Web-based catalog.
and Table 2). Genotype-phenotype correlations based on specific alleles are currently an active area of study.
| Complementation Group | Gene | Cutaneous Neoplasia | Phenotype |
|---|---|---|---|
| A | XPA | + | XP with mild-to-severe neurologic abnormalities |
| B 1 | ERCC3 | + | XP/CS |
| - | TTD | ||
| + | XP with mild neurologic abnormalities | ||
| C | XPC | + | XP with no neurologic abnormalities 2 |
| D 3 | ERCC2 | + | XP with no neurologic abnormalities to severe neurologic abnormalities |
| + | XP/CS | ||
| + | XP/TTD | ||
| - | TTD | ||
| - | COFS | ||
| E | DDB2 | + 4 | XP with no neurologic abnormalities |
| F | ERCC4 | + | XP with no neurologic abnormalities or severe late-onset neurologic abnormalities 5 |
| G | ERCC5 | + | XP with no neurologic abnormalities or severe neurologic abnormalities |
| + | XP/CS | ||
| H | ERCC1 | - | COFS |
| Variant 6 | POLH | + | XP with no neurologic abnormalities |
XP/CS = xeroderma pigmentosum-Cockayne syndrome complex
TTD = trichothiodystrophy (without XP)
XP/TTD = trichothiodystrophy with XP
COFS = cerebrooculofacioskeletal syndrome
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. Most individuals with XP-C have XP without neurologic abnormalities [Cleaver et al 1999].
3. Individuals with XP-D have XP, XP with neurologic abnormalities, the XP/CS complex, TTD, or XP/TTD [Broughton et al 2001, Lehmann 2001].
4. Skin symptoms are generally mild.
5. Most individuals are from Japan.
6. Individuals with XP variant are clinically identical to other individuals with XP with cutaneous symptoms without neurologic abnormalities.
Heterozygotes (carriers) are clinically normal. However, the parents of individuals with XP-C frequently have reduced levels of XPC mRNA [Khan et al 2004].
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].
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 is estimated at 1:1,000,000 in the United States.
Certain populations have a higher prevalence. For example, in Japan, the prevalence is estimated as 1:22,000 [Hirai et al 2006]. Prevalence is increased in North Africa (Tunisia, Algeria, Morocco, Libya, and Egypt) and the Middle East (Turkey, Israel, and Syria), especially in communities in which consanguinity is common.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
).
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.
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.
XP-CS includes facial freckling and early skin cancers typical of XP and some features of CS such as mental retardation, 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 to recovery of RNA synthesis, and in "non-classic" cases by assay of DNA repair in skin fibroblasts or lymphoblasts.
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 (CSB) or ERCC8 (CSA), associated respectively with complementation groups CSB or CSA [Bootsma et al 2002].
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 syndrome
Hartnup disease
The cutaneous findings of Carney complex may be confused with XP; however, the skin findings in Carney complex are lentigines (not poikiloderma) and affected individuals are not sun sensitive.
To establish the extent of disease in an individual diagnosed with xeroderma pigmentosum (XP), the following evaluations are recommended:
Skin. 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 of 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.
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
Examination of the lids and anterior UV-exposed portions of the globe for evidence of sun-induced damage including ectropion, entropion, inflammatory masses (pterygia, punguecula), 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 and routine audiometry 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
Skin. Premalignant lesions, such as small actinic keratoses, may be treated with topical 5-fluorouracil or by freezing with liquid nitrogen.
Larger areas of sun-damaged skin can be treated with therapeutic dermatome shaving or dermabrasion 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 and curettage, surgical excision, or chemosurgery. 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.
High-dose oral isotretinoin is 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 should be reserved for individuals with XP who have had multiple skin cancers. Some individuals may respond to lower doses of isotretinoin 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.
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, 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.
Vitamin D is produced in the skin by a reaction involving exposure to UV radiation. Individuals with XP generally 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 1,25 dihydroxy vitamin D; one child became susceptible to bone fractures [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).
Skin. A physician should examine the skin of an affected individual at frequent intervals (every ~3-6 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 aids can be of great help for individuals who have sensorineural hearing loss with learning difficulties in school.
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 should be protected against these agents. One individual 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.
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.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes
A bacterial DNA repair enzyme, denV T4 endonuclease 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 2007, this treatment is not yet 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.
Use of cotton swabs to obtain specimens from conjunctival lesions for cytologic examination for malignant cells is being evaluated [Author, personal communication].
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Xeroderma pigmentosum (XP) is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an individual with XP are obligate carriers of an XP-causing gene mutation.
The parents have mutations in the same XP-causing gene; the two mutations may be the same or different.
Heterozygotes (carriers) are asymptomatic. However, the parents of individuals with XPC frequently have reduced levels of XPC mRNA [Khan et al 2006].
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.
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 effect 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 testing for family members at risk for mutations in XPA or XPC is available on a clinical basis once the mutations have been identified in the family.
Carrier testing using molecular genetic techniques for the other genes causing XP is not offered because it is not clinically available.
See Testing Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment
Family planning
The optimal time for determination of genetic risk 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 or at risk of being carriers.
DNA banking. 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. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100% or molecular genetic testing is available on a research basis only. See
for a list of laboratories offering DNA banking.
No laboratories offering molecular genetic testing for prenatal diagnosis of XP are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutations have been identified. For laboratories offering custom prenatal testing, see
.
Preimplantation genetic diagnosis (PGD). Preimplantation genetic diagnosis may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Complementation Group | Locus Name | Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|---|---|
| XP variant | POLH | 6p21.1-p12 | DNA polymerase eta | POLH | ||
| A | XPA | XPA | 9q22.3 | DNA repair protein complementing XP-A cells | XPA | |
| B | XPB | ERCC3 | 2q21 | TFIIH basal transcription factor complex helicase XPB subunit | Catalogue of Somatic Mutations in Cancer (COSMIC) | ERCC3 |
| C | XPC | XPC | 3p25 | DNA repair protein complementing XP-C cells | XPC | |
| D | XPD | ERCC2 | 19q13.2-q13.3 | TFIIH basal transcription factor complex helicase subunit | ERCC2 @ LOVD | ERCC2 |
| E | XPE | DDB2 | 11p12-p11 | DNA damage-binding protein 2 | DDB2 | |
| F | XPF | ERCC4 | 16p13.3-p13.13 | DNA repair endonuclease XPF | ERCC4 | |
| G | XPG | ERCC5 | 13q33 | DNA repair protein complementing XP-G cells | ERCC5 | |
| H | XPH | ERCC1 | 19q13.2-q13.3 | DNA excision repair protein ERCC-1 | ERCC1 |
| 126340 | EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 2; ERCC2 |
| 126380 | EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 1; ERCC1 |
| 133510 | EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 3; ERCC3 |
| 133520 | EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 4; ERCC4 |
| 133530 | EXCISION-REPAIR, COMPLEMENTING DEFECTIVE, IN CHINESE HAMSTER, 5; ERCC5 |
| 278700 | XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP A; XPA |
| 278720 | XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP C; XPC |
| 278730 | XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D; XPD |
| 278740 | XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP E |
| 278750 | XERODERMA PIGMENTOSUM, VARIANT TYPE; XPV |
| 278760 | XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP F; XPF |
| 278780 | XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP G; XPG |
| 600811 | DNA DAMAGE-BINDING PROTEIN 2; DDB2 |
| 603968 | POLYMERASE, DNA, ETA; POLH |
| 610651 | XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP B; XPB |
| 611153 | XPA GENE; XPA |
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.
Exposure to UV radiation from sunlight forms cyclobutane dimers or other photoproducts at adjacent pyrimidines, thereby distorting the DNA. The XPC-encoded protein and other unidentified gene products bind to the damaged DNA, marking it for further processing. The XPC-encoded protein may function in conjunction with the DDB2 (XPE)-encoded protein in lesion recognition. The XPA protein probably functions in conjunction with replication protein A (RPA), TFIIH, and ERCC1. The ERCC3 (XPB) and ERCC2 (XPD) proteins partially unwind the DNA in the region of the damage, thereby exposing the lesion for further processing. These proteins are part of the TFIIH basal transcription factor and appear to prefer to repair damage in actively transcribing genes before inactive genes. The ERCC4 (XPF) gene product, in a complex with ERCC1, makes a single-strand nick at the 5' side of the lesion, while the ERCC5 (XPG) gene 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 (PCNA). DNA ligase I seals the region, restoring the original undamaged sequence [van Steeg & Kraemer 1999, Bootsma et al 2002].
The NER genes (e.g., ERCC3 and ERCC2) that are part of the basal transcription factor TFIIH are essential to life. Mice with knockout of ERCC2 do not survive. On the other hand, XPA and XPC knockout mice are viable.
XPA
Normal allelic variants: The XPA gene codes for a 1.4-kb mRNA. It contains six exons and five introns.
Pathologic allelic variants: A pathologic allele creating a splicing mutation in exon 3 of the XPA gene is common in Japan. It has been estimated to occur in approximately 1% of the Japanese population, representing approximately 1 million persons [Hirai et al 2006].
Other common pathologic alleles have been described in population isolates; however, 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].
Normal gene product: XPA codes for an mRNA corresponding to a protein of 31.3-kd protein of 273 amino acids that functions in maintaining single stranded regions during repair.
ERCC3 (XPB)
Normal allelic variants: The ERCC3 gene codes for a 2.75-kb mRNA. It contains 15 exons and 14 introns.
Pathologic allelic variants: Analysis of the DNA of XP-B cells showed mutations within the ERCC3 gene [Oh et al 2006]. See also Table A: locus-specific databases and HGMD.
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.
XPC
Normal allelic variants: The XPC gene codes for a 3.5-kb mRNA. It contains 16 exons and 15 introns [Khan et al 2002].
Pathologic allelic variants: Single-base substitution and splice mutations have been found in individuals with XP-C. Nonsense mutations have been reported in both alleles in cells from individuals in complementation group XP-C [Khan et al 2006]. See also Table A: locus-specific databases and HGMD.
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.
ERCC2 (XPD)
Normal allelic variants: The ERCC2 gene codes for a 2.3-kb mRNA. It contains 22 exons and 21 introns.
Pathologic allelic variants: Individuals with mutations in the ERCC2 gene 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. See also Table A: locus-specific databases and HGMD.
Normal gene product: The ERCC2 gene 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.
DDB2 (XPE)
Normal allelic variants: The DDB2 gene codes for a 1.8-kb RNA. It contains ten exons and nine introns.
Pathologic allelic variants: While two individuals with XP-E have mutations in the p48 subunit of the DDB2 gene, no mutations have been found by molecular analysis in other individuals with XP-E. See also Table A: locus-specific databases and HGMD.
Normal gene product: The DDB2 gene 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.
ERCC4 (XPF)
Normal allelic variants: The ERCC4 gene codes for a 2.7-kb mRNA. It contains 11 exons and ten introns.
Pathologic allelic variants: See Table A: locus-specific databases and HGMD.
Normal gene product: The ERCC4 gene codes for a 103.3-kd protein of 905 amino acids that serves as a DNA endonuclease 5' to the lesion.
ERCC5 (XPG)
Normal allelic variants: The ERCC5 gene codes for a 4.1-kb mRNA. It contains 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: The ERCC5 gene codes for a protein of 112 kd that functions as a DNA endonuclease 3' to the lesion.
ERCC1 (XPH)
Normal allelic variants: The ERCC1 gene codes for a 1.2-kb mRNA. It contains eight exons.
Pathologic allelic variants: One individual was reported by Jaspers et al (2007).
Normal gene product: The ERCC1 gene codes for a 110-kd protein of 323 amino acids.
POLH (XP-V, POL/ETA)
Normal allelic variants: The POLH gene codes for a 3.4-kb mRNA. It contains 11 exons and ten introns.
Pathologic allelic variants: See Table A: locus-specific databases and HGMD. Japanese individuals were described by Tanioka et al (2007).
Normal gene product: The POLH gene (polymerase eta) codes for a 78.4-kd protein of 713 amino acids that functions as an error-prone polymerase [Broughton et al 2002].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
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.
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.
Kenneth H Kraemer, MD (2003-present)
Daniel J Wattendorf, MD; National Institutes of Health (2003-2008)
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
