Last updated:
2/7/2025
Years published: 1987, 1988, 1989, 1995, 1997, 1998, 1999, 2003, 2017, 2021, 2025
NORD gratefully acknowledges Stephanie Lin, NORD Editorial Intern from the University of Connecticut, Debby Tamura MS, RN, APNG, Research Nurse (retired), and Kenneth H. Kraemer, MD, Chief DNA Repair Section (emeritus), Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, for assistance in the preparation of this report.
Summary
Xeroderma pigmentosum (XP) is a rare inherited multisystem disorder characterized by a heightened sensitivity to the DNA damaging effects of ultraviolet radiation (UV). The main source of UV is the sun. The major signs and symptoms of XP can be seen in sun-exposed areas of the body. The effects are greatest on the skin and the tissues of the eyes including eyelids, the surface of the eyes and the surrounding tissues. The tip of the tongue and lips may also be damaged. In addition, approximately 25% of people with XP develop abnormalities of the nervous system manifesting as progressive neurodegeneration including hearing loss. People with XP have a 10,000-fold increased risk for developing skin cancer including basal cell carcinoma, squamous cell carcinoma and melanoma. They also have a 2,000-fold increased risk for cancer of the eye surface and surrounding ocular tissues. Many of these symptoms appear early in life, typically before age 10 years.
XP is managed by preventative techniques (i.e., avoiding the sun, using sunscreen, wearing protective clothing) and regular screening for changes in the skin, vision and neurological status. Many complications can be treated with medication and/or surgery, but some cancers and neurological problems can be life threatening.
XP is an autosomal recessive genetic condition caused by changes (variants) in nine different DNA Repair genes. Eight of the genes make up the nucleotide excision repair pathway (NER) that identities and repairs UV induced DNA damage. The ninth gene acts to bypass unrepaired DNA damage.
Introduction
XP was first described in Vienna, Austria in 1870. In a dermatology textbook, Moriz Kaposi described a new disorder called xeroderma, which translates to “parchment skin.”
Individuals with XP are particularly sensitive to the DNA damaging effects of UV. Sources of UV include the sun, unshielded florescent light bulbs, mercury vapor lights and halogen light bulbs. Symptoms may differ from person to person, but typically impact the skin, eyes and nervous system. People with XP may develop premature menopause, multiple thyroid nodules or thyroid cancer, central nervous system cancers or leukemia.
Cutaneous (Skin) Effects
Approximately half of people with XP develop blistering burns on sun exposed skin after minimal sun exposure (sometimes less than 10 minutes in the sun). These burns evolve over several days and may take greater than a week to heal. Sometimes these burns are so severe, child abuse is suspected. The other 50% of people with XP do not burn, but tan after sun exposure. However, both types of sun reactions result in the early onset of multiple, widespread freckling (lentigos) of the skin.
Lentigos are a patchy freckling of the skin that often appear before the age of two years in people with XP. This early onset of freckling is not common in the general population. The lentigos can be visible on all sun exposed skin but are often seen first on the face. Lentigos are a sign of unrepaired UV damage in the skin. Repeated sun exposure also results in dry, parchment-like skin (xerosis) and a mixture of both hyper (increased) and hypo (decreased) skin pigmentation (poikiloderma), thinning of skin tissue (skin atrophy) and a widening of the small blood vessels, which produces red lines and patterns on the skin (telangiectasia). In people who do not have XP, poikiloderma is typically seen in older adults with many years of sun exposure who work outdoors, such as farmers or sailors.
For people with XP, continuous repeated sun exposure has severe effects, resulting in the early development of precancerous skin lesions such as actinic keratosis and skin cancers (see below).
Ocular (Eye) Effects
The eyelids and the surface of the eyes exposed to sunlight will usually be affected within the first decade of life.
Light sensitivity or pain upon seeing light (photophobia) is common and is often noted in infancy or early childhood. The covering of the white portion of the eye (conjunctiva) may show sunlight induced inflammation. People with XP also develop dry eye. Symptoms of dry eye include a feeling of ‘something being in the eye’, constant irritation and redness of the eye. Dry eye can result in chronic inflammation and keratitis. Keratitis, or inflammation of the cornea (the clear outer portion of the eye) may also occur in response to sunlight. In severe cases, keratitis can result in lack of transparency (corneal opacification) and an increase in blood vessel density (vascularization). These combined effects may obscure vision, leading to blindness. With repeated sun exposure, the lids of the eyes may degenerate (atrophy) and eyelashes may fall out, leaving the eyes unprotected and contributing to vision loss.
Cancers of the eyelids, tissues surrounding the eyes, cornea and white part of the eye (sclera) can occur very early in life. Surgeries to remove ocular cancers can lead to lid abnormalities resulting in difficulty completely closing the eyes and vision loss. When cancers in or near the eye are large or invasive, the globe of the eye may need to be removed to prevent spread to the brain.
Neurologic (Nerve) Effects
Approximately 25% of people with XP develop progressive neurodegeneration. The degeneration can vary in time of onset and rate of progression. Symptoms of neurodegeneration include acquired microcephaly (a condition marked by small head size and structural changes in the brain), diminishing (or absent) deep tendon reflexes, progressive high-frequency sensorineural hearing loss (deafness caused by damage to the nerves of the inner ear), progressive cognitive impairment, spasticity (tightness/rigidity of the skeletal muscles), ataxia (poor muscle control and coordination), seizures, difficulty swallowing and/or vocal cord paralysis.
These issues are thought to arise due to the loss of nerve cells in the brain. On imaging such as MRI or CT scans, the brains of people with XP with neurologic degeneration show tissue atrophy with marked dilation of the ventricles (fluid filled spaces in the middle of the brain). It is thought that accumulating unrepaired DNA damage in the brain cells results in their death, however, the source of this damage has not been identified.
Neoplasms (Cancer)
Individuals with XP have a much greater chance of developing certain cancers. The risk of acquiring non-melanoma skin cancers (e.g., basal cell carcinoma and squamous cell carcinoma) is 10,000 times greater than in the general population in patients under 20 years of age. The median age of first non-melanoma cancer for people with XP is 9 years old, which is 50 years earlier than in the general population. For melanoma skin cancer, the risk is 2,000 times greater for those with XP. The median age of onset is 22 years, which is 30 years earlier than in the general population.
Oral cavity neoplasms, specifically squamous cell carcinoma of the tip of the tongue (a non-pigmented sun exposed area), is common especially in dark skinned people with XP who live in very sunny and warm climates. Increased frequency of internal cancers have been reported in individuals with XP including glioblastoma of the brain, astrocytoma of the spinal cord, and cancer of the lung at an early age in patients who smoke, and rarely, leukemia (cancer of the white blood cells). Cancers of the thyroid, uterus, breast, pancreas, stomach, kidney and testicles have also been reported.
Premature Ovarian Insufficiency (Early Menopause)
Females with XP may have early onset of premature ovarian insufficiency (menopause). A study at the National Institutes of Health found that females with XP begin to menstruate (menarche) at the normal age range of 9-17 years. However, they have a higher incidence of premature ovarian insufficiency. The median age of menopause for females with XP in the study was 29 years. This is well below the age for menopause (50 + 4 years) in the general population. It is unclear why premature ovarian insufficiency occurs in females with XP especially those who have variants in the XPC gene. Symptoms of premature ovarian sufficiency may include irregular menses, hot flashes and vaginal dryness. It is important to monitor for premature ovarian insufficiency in females with XP. If symptoms develop, they may need to seek medical care.
Thyroid Nodules and Cancer
A study at the NIH identified an increased incidence of benign thyroid nodules in over half of the people with XP. Although benign thyroid nodules are relatively common in older people in the general population, people with XP in the study were younger, with a median age of 20 years at the time of diagnosis. In addition, two patients in the study were identified with thyroid cancer following thyroidectomy for suspicious findings detected by ultrasound exam. Most people identified with thyroid nodules in the study had variants in the XP-C or XP-E (DDB2) genes. Ultrasound monitoring for suspicious changes in the thyroid gland of people with XP should be considered.
Variants in nine DNA repair genes are associated with XP. Eight of these genes are nucleotide excision repair (NER) genes XPA, XPC, DDB2 (XP-E), ERCC1, ERCC2 (XP-D), ERCC3 (XP-G), ERCC4 (XP-F) and ERCC5 (XP-B). The proteins resulting from normal expression of these genes are involved in DNA repair and recognize damaged DNA, remove the damage and fill in the resulting gap. A ninth gene, POLH (XP variant) acts to bypass unrepaired DNA damage.
XP is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
When a person inherits two disease-causing XP gene variants, they are unable to properly repair DNA damage from UV and will show signs of the condition. All people with XP have an increased risk of developing skin cancer. In addition, people with XP who have variants in the XPA, XPD, XPF or XPG genes may have extreme sun sensitivity and progressive neurodegeneration, although some do not, depending on the specific variant in the gene.
XP affects males and females in equal numbers. Some gene variants associated with XP are more common in certain parts of the world (founder mutations); in these locations there is a higher prevalence of XP. In the United States and Europe, prevalence of XP is about 1 in 1,000,000. In Japan, XP is much more common, affecting 1 in 22,000 people. Areas of North Africa (e.g., Tunisia, Algeria, Morocco, Libya, Egypt) and the Middle East (e.g., Turkey, Israel, Syria) also show a greatly increased prevalence of XP.
A diagnosis of XP is typically first suspected based on clinical symptoms. Many people with XP do not have a family history of the condition.
Molecular genetic testing for variants in the XP genes is available to confirm the diagnosis.
Prevention
Rigorous sun (UV) protection is necessary beginning as soon as the diagnosis is suspected to prevent continued DNA damage and disease progression. Individuals with XP should avoid exposing the skin and eyes to ultraviolet (UV) radiation. This can be done by wearing protective clothing such as hats, hoods with UV blocking face shields, long sleeves, pants and gloves. High sun-protective factor (SPF) sunscreens, UV-blocking glasses with side-shields and long hair can also provide protection.
The surroundings (e.g., home, school and work) should be tested for levels of UV using a UV light meter. The meter can help identify areas of increased UV and sources of damaging UV (e.g., from halogen and unshielded florescent light bulbs and mercury vapor lamps). These sources of UV should be eliminated from the environment. Since UV can pass through glass, windows in homes, schools, workplaces and cars should be treated with UV blocking film.
Vitamin D is an essential vitamin, which helps maintain healthy bones. Vitamin D is manufactured by the interaction of UV with the skin. Since people with XP avoid UV, oral dietary supplements may be taken to avoid complications of inadequate vitamin D levels.
Certain carcinogens in cigarette smoke damage DNA in ways similar to UV so exposure to cigarette smoke (including second-hand smoke) should be avoided. People with XP who smoke cigarettes have developed lung cancer at an early age.
Skin Care
The skin (including the scalp, lips, tongue and eyelids) should be examined by a dermatologist or other knowledgeable health care provider every 6-12 months (or more often if necessary) to detect precancerous and cancerous lesions. Prompt removal of skin cancers is necessary to prevent further growth or spread of the lesions. Affected individuals and guardians of children should be instructed in skin examination techniques to aid in the early detection of possible skin cancers. Full body photographic images including close-ups may be useful for following patients to detect newly appearing skin lesions or changes in pre-existing lesions.
Individuals should also undergo routine eye exams with an ophthalmologist. The eyelids should be examined for ectropion (drooping and sagging), entropion (inward rotation, which may cause eye irritation) and pterygia/pinguecula (benign growths on the surface of the eyes). The cornea, which covers the eye, should be assessed for clouding and the eyes should be tested for dryness; in the Schirmer test, a filter paper is placed under the eyelids to measure absorption of tears. A dilated eye exam is important to assess for any changes in the retina (back of the eye).
Basic neurologic examinations including measuring the occipital frontal circumference (to determine the presence of microcephaly) and assessing for the presence of deep tendon reflexes should be part of the routine care of an XP patient. Hearing exams should be done on a regular basis to assess for early onset hearing loss, which is an indicator of XP with neurologic disease. If hearing loss is detected, hearing aids can be very beneficial in correcting the deficits. If neurologic problems are identified, more in-depth exams by a neurologist are indicated. In addition, MRI can assess for changes that are commonly seen in the brain of a person with XP who has neurodegeneration. People with XP who develop neurologic disease can have a peripheral neuropathy, which may be assessed by testing nerve conduction velocity (speed of electrical transmission) through the nerves of the arms and legs.
Treatment of Skin Cancers
Small, premalignant skin lesions, (e.g., actinic keratosis) can be treated by freezing with liquid nitrogen. For larger areas of damaged skin, topical creams such as 5-fluorouracil or imiquimod may be applied. Surgical procedures such as dermatome shaving and dermabrasion have been used for larger areas of skin. Small skin cancers on the trunk and extremities can be treated with electrodessication and curettage, or surgical excision. Deeply invasive skin cancers or skin cancers on the face and areas that require tissue-sparing techniques can be treated with Mohs micrographic surgery. In severe cases, large portions of skin may be re-grafted (or replaced) with sun-protected skin.
People with XP have normal responses to X-rays. X-ray therapy can be used to treat inoperable or larger neoplasms or as adjuvant therapy to surgery. Multiple basal cell carcinomas can be treated with oral vismodegib, a sonic hedgehog pathway inhibitor. Recently, new chemotherapy agents called checkpoint inhibitors have been used to treat large skin tumors and metastatic cancers. They have been successful in treating the tumors; however serious side effects can be seen as in the general population.
The oral retinoids isotretinoin or acitretin can be used to prevent new skin neoplasms but have many side effects including liver toxicity, elevated levels of cholesterol, calcification of the ligaments and tendons, and premature closure of the growing bone shafts. These retinoid drugs are known to cause birth defects and are contraindicated in pregnant women or women who are trying to become pregnant.
Treatment of XP Eye Abnormalities
Lubricating eye drops used frequently keep the cornea moist and protects against the inflammatory effects of dry eye so it is best to start with simpler treatments first.
Neoplasms of eyelids, conjunctiva and cornea can be treated with surgery. In some people, corneal transplantation has been attempted to correct UV induced ocular damage and corneal clouding. However, the transplants may not be successful due to invasion by blood vessels and immune rejection. Unfortunately, immunosuppressive drugs used to prevent immune rejection may lead to additional skin cancers. Topical chemotherapy agents can be used to treat tumors on the conjunctiva and sclera of the eye.
Treatment of XP Neurologic Abnormalities
Neurologic abnormalities are associated with increased high frequency sensory-neural hearing loss. The hearing loss gets worse over time (progressive) and can be treated with hearing aids. Recently, cochlear implants have been used by some people with XP. Cognitive delays can be seen in childhood and special education classes, physical and occupational therapies along with UV safe accommodations at school are very helpful for children with XP. As they get older, people with XP who have neurologic disease also have increasing ataxia, difficulty swallowing (dysphagia) and difficulty speaking (dysarthria) as the condition progresses. They may require wheelchairs, feeding tubes and long-term nursing care.
Treatment of Premature Ovarian Insufficiency
Hormone replacement with low doses of estrogen and progesterone can be used to reduce the symptoms of premature ovarian insufficiency. Females with XP who have premature ovarian insufficiency should be monitored for reduced loss of bone density and fracture risk. Discussions of the impact of premature ovarian insufficiency on childbearing (including the possibility of egg freezing) may be considered.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com.
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Tamura D, Ono R, DiGiovanna JJ, Kraemer KH. Management of Xeroderma Pigmentosum. In Nishgori, C., and Sugasawa, K. (Eds) DNA Repair Disorders, Springer Science and Business Media, Singapore. 2019.
Tamura D, Kraemer KH, DiGiovanna JJ. Xeroderma Pigmentosum (Chapter 257). In: Treatment of Skin Disease, Fifth Ed. Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I (Eds). Elsevier. 2018. pp. 873-877.
JOURNAL ARTICLES
Sagun JP, Khan SG, Imoto K, et al. Different germline variants in the XPA gene are associated with severe, intermediate, or mild neurodegeneration in xeroderma pigmentosum patients. PLoS Genet. 2024;20(12):e1011265. Published 2024 Dec 2. doi:10.1371/journal.pgen.1011265
Fernandez ER, Tamura D, Khan SG, et al. Retrospective study of efficacy and adverse events of immune checkpoint inhibitors in 22 xeroderma pigmentosum patients with metastatic or unresectable cancers. Front Oncol. 2023;13:1282823. Published 2023 Oct 25. doi:10.3389/fonc.2023.1282823
Kouatcheu SD, Marko J, Tamura D, Khan SG, Lee CR, DiGiovanna JJ, Kraemer K H. Thyroid nodules in xeroderma pigmentosum patients: a feature of premature aging. J Endocrinol Invest. 2021 Jul;44(7):1475-1482.
Lehmann A, Fassi H. Molecular analysis directs the prognosis, management and treatment of patients with xeroderma pigmentosum. DNA Repair (Amst). 2020;Sep;93:102907.
Oetjen K A, Levoska MA, Tamura D, Ito S, Douglas D, Khan SG, Calvo KR, Kraemer K H, and DiGiovanna JJ. Predisposition to hematologic malignancies in patients with xeroderma pigmentosum. Haematologica. 2020 Apr; 105(4): e144–e146.
Merideth M, Tamura D, Angra, D, Khan SG, Ferrell J, Alisa M, Goldstein AM, DiGiovanna, JJ, Kraemer KH. Reproductive health in xeroderma pigmentosum: features of premature aging. Obstetrics & Gynecology 2019;00:1–6. DOI: 10.1097/AOG.0000000000003490
Hirai Y, Noda A, Kodama Y, et al. Increased risk of skin cancer in Japanese heterozygotes of xeroderma pigmentosum group A. J Hum Genet. 2018;63(11):1181-1184. doi:10.1038/s10038-018-0495-y
Salomon G. Maza A. Boulinguez C. Paul D. Lamant L. Tournier E. Mazereeuw-Hautier J. and Meyer N. Efficacy of anti-programmed cell death-1 immunotherapy for skin carcinomas and melanoma metastases in a patient with xeroderma pigmentosum; Br J Dermatol 2018; 178:100.
Tamura D, DiGiovanna JJ, Khan SG, Kraemer KH. Living with xeroderma pigmentosum: Comprehensive photoprotection for highly photosensitive patients. Photodermatology, Photoimmunology and Photomedicine 2014;30 (2-3):146-152.
Brooks BP, Thompson AH, Bishop RJ, et al. Ocular manifestations of xeroderma pigmentosum: long-term follow-up highlights the role of DNA repair in protection from sun damage. Ophthalmology. 2013;120(7):1324-1336. doi:10.1016/j.ophtha.2012.12.044
Lai J-P, Liu T-C, Alimchandani M, Liu Q, Aung PP, Matsuda K, Lee C-C R, Tsokos M, Hewitt S, Rushing EJ, Tamura D, Levens DL, DiGiovanna JJ, Fine HA, Patronas N, Khan SG, Kleiner DE, Oberholtzer JC, Quezado MM and Kraemer KH. The influence of DNA repair on neurologic degeneration, cachexia, skin cancer and internal neoplasms: autopsy report of four xeroderma pigmentosum patients (XP-A, XP-C and XP-D) Acta Neuropathologica Communications 2013: 1:4 DOI: 10.1186/2051-5960-1-4.
Totonchy MB, Tamura D, Pantell M S, Zalewski C, Bradford, PT, Merchant SN, Nadol J, Khan S G., Schiffmann R, Pierson TM, Wiggs E, Griffith AJ., DiGiovanna JJ, Kraemer K H and Brewer CC. Auditory analysis of xeroderma pigmentosum, 1971-2012: Hearing function, sun sensitivity and DNA repair predict neurologic degeneration. Brain 2013;136 (Pt 1):194-208.
Digiovanna JJ and Kraemer KH. Shining light on xeroderma pigmentosum. J Invest Dermatol. 2012 Mar;132(3 Pt 2):785-96. doi: 10.1038/jid.2011.426. Epub 2012 Jan 5.
Bradford PT, Goldstein AM, Tamura D, Khan SG, Ueda T, Boyle J, Oh K-S, Imoto K, Inui H, Moriwaki S-I, Emmert S, Pike K M, Raziuddin A, Plona TM, DiGiovanna JJ, Tucker MA, and Kraemer KH. Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterizes the role of DNA repair. J. Medical Genetics 2011;48:168-176.
Christen-Zaech S, Imoto K, Khan SG, Oh K-S, Tamura D, DiGiovanna JJ, Boyle J, Patronas NJ, Schiffmann R, Kraemer KH and Paller AS. Unexpected occurrence of xeroderma pigmentosum in an uncle and nephew. Arch Dermatol. 2009 Nov; 145(11): 1285–1291.
Zghal M, et al. A whole family affected by xeroderma pigmentosum: clinical and genetic particularities. Ann Dermatol Venereol. 2003;130:31-36.
Wesiberg NK, Varghese M. Therapeutic response of a brother and sister with xeroderma pigmentosum to imiquimod 5% cream. Dermatol Surg. 2002;28:513-23.
Nelson BR, et al. The role of dermabrasion and chemical peels in the treatment of patients with xeroderma pigmentosum. J Am Acad Dermatol. 1995;32:623-26.
Kondoh M, et al. Siblings with xeroderma pigmentosum complementation group A with different skin cancer development: importance of sun protection at an early age. J Am Acad Dermatol.1994;31:993-96.
INTERNET
Kraemer KH, DiGiovanna JJ, Tamura D. Xeroderma Pigmentosum. 2003 Jun 20 [Updated 2022 Mar 24]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1397/ Accessed Jan 29, 2025.
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