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Xeroderma pigmentosum variant type(XPV)

MedGen UID:
376352
Concept ID:
C1848410
Disease or Syndrome
Synonyms: Photosensitivity with defective DNA synthesis; POLH-Related Xeroderma Pigmentosum; Xeroderma pigmentosum with normal DNA repair rates
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): POLH (6p21.1)
 
Monarch Initiative: MONDO:0010214
OMIM®: 278750
Orphanet: ORPHA90342

Disease characteristics

Excerpted from the GeneReview: Xeroderma Pigmentosum
Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). 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). [from GeneReviews]
Authors:
Kenneth H Kraemer  |  John J DiGiovanna  |  Deborah Tamura   view full author information

Additional descriptions

From OMIM
Xeroderma pigmentosum is an autosomal recessive disorder characterized by increased sensitivity to sunlight and defects in DNA repair. For a general overview of the disorder, see XPA (278700). Some patients with xeroderma pigmentosum have been found to have normal DNA excision repair, but defective postreplication repair (Lehman et al., 1975). This XP 'variant' class is characterized by a defect in conversion of newly synthesized DNA from low to high molecular weight after UV irradiation (Masutani et al., 1999). So-called 'pigmentary xerodermoid' is apparently identical to the XP variant, which is characterized by loss of a gene product that permits normal cells to replicate DNA without interruption at UV-damaged sites (Cleaver et al., 1980).  http://www.omim.org/entry/278750
From MedlinePlus Genetics
Xeroderma pigmentosum, commonly known as XP, is an inherited condition characterized by an extreme sensitivity to ultraviolet radiation (UVR), which is present in sunlight and may also be found in some types of artificial lighting. This condition mostly affects the eyes and areas of skin exposed to the sun. Xeroderma pigmentosum is associated with an increased risk of UVR-induced cancers. People with this condition often experience premature aging. Some affected individuals also have problems involving the nervous system.

Researchers have identified at least eight genetic forms of xeroderma pigmentosum: complementation group A (XP-A) through complementation group G (XP-G), plus a variant type (XP-V). The types are distinguished by their genetic cause. All of the types increase the risk of skin cancer, although some are more likely than others to be associated with neurological abnormalities.

The signs of xeroderma pigmentosum usually appear in infancy or early childhood. About half of affected children develop a severe sunburn after spending just a few minutes in the sun. The sunburn causes redness and blistering that can last for weeks. However, some children with xeroderma pigmentosum can tan normally. 

By age 2, almost all children with xeroderma pigmentosum develop freckling of the skin in sun-exposed areas (such as the face, arms, and lips); this type of freckling rarely occurs in young children without the disorder. In affected individuals, exposure to sunlight often causes dry skin (xeroderma) and changes in skin coloring (pigmentation). This combination of features gives the condition its name.

People with xeroderma pigmentosum are 10,000 times more likely to develop non-melanoma skin cancer and up to 2,000 times more likely to  develop melanoma skin cancer compared to individuals without this condition. The types of skin cancer that can develop include basal cell carcinoma, squamous cell carcinoma, and melanoma. Most commonly, the first skin cancer appears in affected individuals before age 10. 

Without protection from the sun and other sources of UVR, most people with xeroderma pigmentosum develop multiple skin cancers during their lifetime. These cancers occur most often on  portions of the body that are exposed to the sun, including the face, the lips, the eyelids, the surface of the eyes, the scalp, and the tip of the tongue. Studies suggest that people with xeroderma pigmentosum may also have an increased risk of some internal cancers, including brain tumors, thyroid cancer, and blood cancers. Additionally, affected individuals who smoke cigarettes have a significantly increased risk of lung cancer.

The eyes of people with xeroderma pigmentosum may be painfully sensitive to UVR (photophobia). If the eyes are not protected from UVR, they may become bloodshot and irritated, and the clear front covering of the eyes (the cornea) may become cloudy. In some people, the eyelashes fall out and the eyelids may be thin and turn abnormally inward or outward. In addition to an increased risk of cancer on the surface of the eye, xeroderma pigmentosum is associated with noncancerous growths on the eye. Many of these eye abnormalities can impair vision.

About 30 percent of people with xeroderma pigmentosum develop progressive neurological abnormalities in addition to problems involving the skin and eyes. These abnormalities can include hearing loss, poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty swallowing and talking, and seizures. When these neurological problems occur, they tend to worsen with time.

Individuals with xeroderma pigmentosum may experience early menopause.  https://medlineplus.gov/genetics/condition/xeroderma-pigmentosum

Clinical features

From HPO
Squamous cell carcinoma
MedGen UID:
2874
Concept ID:
C0007137
Neoplastic Process
The presence of squamous cell carcinoma of the skin.
Malignant melanoma of skin
MedGen UID:
57486
Concept ID:
C0151779
Neoplastic Process
Most melanomas affect only the outermost layer of skin (the epidermis). If a melanoma becomes thicker and involves multiple layers of skin, it can spread to other parts of the body (metastasize).\n\nMelanoma may develop from an existing mole or other normal skin growth that becomes cancerous (malignant); however, many melanomas are new growths. Melanomas often have ragged edges and an irregular shape. They can range from a few millimeters to several centimeters across. They can also be a variety of colors: brown, black, red, pink, blue, or white.\n\nA large number of moles or other pigmented skin growths on the body, generally more than 25, is associated with an increased risk of developing melanoma. Melanoma is also a common feature of genetic syndromes affecting the skin such as xeroderma pigmentosum. Additionally, individuals who have previously had melanoma are nearly nine times more likely than the general population to develop melanoma again. It is estimated that about 90 percent of individuals with melanoma survive at least 5 years after being diagnosed.\n\nMelanoma is a type of skin cancer that begins in pigment-producing cells called melanocytes. This cancer typically occurs in areas that are only occasionally sun-exposed; tumors are most commonly found on the back in men and on the legs in women. Melanoma usually occurs on the skin (cutaneous melanoma), but in about 5 percent of cases it develops in melanocytes in other tissues, including the eyes (uveal melanoma) or mucous membranes that line the body's cavities, such as the moist lining of the mouth (mucosal melanoma). Melanoma can develop at any age, but it most frequently occurs in people in their fifties to seventies and is becoming more common in teenagers and young adults.
Skin basal cell carcinoma
MedGen UID:
1648304
Concept ID:
C4721806
Neoplastic Process
The presence of a basal cell carcinoma of the skin.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Photophobia
MedGen UID:
43220
Concept ID:
C0085636
Sign or Symptom
Excessive sensitivity to light with the sensation of discomfort or pain in the eyes due to exposure to bright light.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Conjunctivitis
MedGen UID:
1093
Concept ID:
C0009763
Disease or Syndrome
Inflammation of the conjunctiva.
Keratitis
MedGen UID:
44013
Concept ID:
C0022568
Disease or Syndrome
Inflammation of the cornea.
Ectropion
MedGen UID:
4448
Concept ID:
C0013592
Disease or Syndrome
An outward turning (eversion) or rotation of the eyelid margin.
Entropion
MedGen UID:
41813
Concept ID:
C0014390
Disease or Syndrome
An abnormal inversion (turning inward) of the eyelid (usually the lower) towards the globe. Entropion is usually acquired as a result of involutional or cicatricial processes but may occasionally be congenital.
Dermal atrophy
MedGen UID:
101793
Concept ID:
C0151514
Disease or Syndrome
Partial or complete wasting (atrophy) of the skin.
Cutaneous photosensitivity
MedGen UID:
87601
Concept ID:
C0349506
Pathologic Function
An increased sensitivity of the skin to light. Photosensitivity may result in a rash upon exposure to the sun (which is known as photodermatosis). Photosensitivity can be diagnosed by phototests in which light is shone on small areas of skin.
Poikiloderma
MedGen UID:
97905
Concept ID:
C0392777
Disease or Syndrome
Poikiloderma refers to a patch of skin with (1) reticulated hypopigmentation and hyperpigmentation, (2) wrinkling secondary to epidermal atrophy, and (3) telangiectasias.
Freckles in sun-exposed areas
MedGen UID:
348494
Concept ID:
C1859923
Finding
Cutaneous telangiectasia
MedGen UID:
1845965
Concept ID:
C5848131
Finding
Dilated blood vessels on the skin.

Term Hierarchy

Professional guidelines

PubMed

Xue MH, Li GY, Wu XJ, Zhang CX, Zhang CF, Zhu KX
Int J Clin Exp Pathol 2015;8(5):5563-9. Epub 2015 May 1 PMID: 26191265Free PMC Article
Artac M, Bozcuk H, Pehlivan S, Akcan S, Pehlivan M, Sever T, Ozdogan M, Savas B
J Cancer Res Clin Oncol 2010 Jun;136(6):803-9. Epub 2009 Nov 12 doi: 10.1007/s00432-009-0720-3. PMID: 19908066
Gu J, Zhao H, Dinney CP, Zhu Y, Leibovici D, Bermejo CE, Grossman HB, Wu X
Clin Cancer Res 2005 Feb 15;11(4):1408-15. doi: 10.1158/1078-0432.CCR-04-1101. PMID: 15746040

Suggested Reading

Recent clinical studies

Etiology

Soares IFZ, Christofolini DM, Silva LG, Feder D, de Siqueira Carvalho AA
Mol Genet Genomic Med 2020 Nov;8(11):e1491. Epub 2020 Sep 16 doi: 10.1002/mgg3.1491. PMID: 32935933Free PMC Article
Borroni RG, Diegoli M, Grasso M, Concardi M, Agozzino M, Vignini M, Arbustini E
G Ital Dermatol Venereol 2020 Jun;155(3):349-354. doi: 10.23736/S0392-0488.16.05158-0. PMID: 32635709
Ono R, Masaki T, Takeuchi S, Shimizu A, Tanioka M, Kambe N, Matsue H, Kamide R, Nishigori C
Photodermatol Photoimmunol Photomed 2013 Jun;29(3):132-9. doi: 10.1111/phpp.12038. PMID: 23651273

Diagnosis

Borroni RG, Diegoli M, Grasso M, Concardi M, Agozzino M, Vignini M, Arbustini E
G Ital Dermatol Venereol 2020 Jun;155(3):349-354. doi: 10.23736/S0392-0488.16.05158-0. PMID: 32635709
Nakano E, Takeuchi S, Ono R, Tsujimoto M, Masaki T, Nishigori C
J Invest Dermatol 2018 Feb;138(2):467-470. Epub 2017 Oct 10 doi: 10.1016/j.jid.2017.08.046. PMID: 29024689
Ono R, Masaki T, Takeuchi S, Shimizu A, Tanioka M, Kambe N, Matsue H, Kamide R, Nishigori C
Photodermatol Photoimmunol Photomed 2013 Jun;29(3):132-9. doi: 10.1111/phpp.12038. PMID: 23651273
Tanioka M, Masaki T, Ono R, Nagano T, Otoshi-Honda E, Matsumura Y, Takigawa M, Inui H, Miyachi Y, Moriwaki S, Nishigori C
J Invest Dermatol 2007 Jul;127(7):1745-51. Epub 2007 Mar 8 doi: 10.1038/sj.jid.5700759. PMID: 17344931

Therapy

Nakano E, Takeuchi S, Ono R, Tsujimoto M, Masaki T, Nishigori C
J Invest Dermatol 2018 Feb;138(2):467-470. Epub 2017 Oct 10 doi: 10.1016/j.jid.2017.08.046. PMID: 29024689
Tayeb T, Laure B, Sury F, Lorette G, Goga D
J Craniomaxillofac Surg 2011 Oct;39(7):496-8. Epub 2010 Aug 21 doi: 10.1016/j.jcms.2010.03.026. PMID: 20728371

Prognosis

Ono R, Masaki T, Takeuchi S, Shimizu A, Tanioka M, Kambe N, Matsue H, Kamide R, Nishigori C
Photodermatol Photoimmunol Photomed 2013 Jun;29(3):132-9. doi: 10.1111/phpp.12038. PMID: 23651273

Clinical prediction guides

Soares IFZ, Christofolini DM, Silva LG, Feder D, de Siqueira Carvalho AA
Mol Genet Genomic Med 2020 Nov;8(11):e1491. Epub 2020 Sep 16 doi: 10.1002/mgg3.1491. PMID: 32935933Free PMC Article
Borroni RG, Diegoli M, Grasso M, Concardi M, Agozzino M, Vignini M, Arbustini E
G Ital Dermatol Venereol 2020 Jun;155(3):349-354. doi: 10.23736/S0392-0488.16.05158-0. PMID: 32635709

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