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Xeroderma pigmentosum group A(XPA)

MedGen UID:
82775
Concept ID:
C0268135
Disease or Syndrome
Synonyms: Xeroderma pigmentosum, complementation group A; Xeroderma pigmentosum, type 1; XP, group A; XPA
SNOMED CT: Xeroderma pigmentosum group A (43477006); Xeroderma pigmentosum, group A (43477006)
 
Gene (location): XPA (9q22.33)
 
Monarch Initiative: MONDO:0010210
OMIM®: 278700

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 a genetically heterogeneous autosomal recessive disorder characterized by increased sensitivity to sunlight with the development of carcinomas at an early age. Some patients develop neurologic symptoms or a more severe clinical phenotype known as de Sanctis-Cacchione syndrome (278800) (Satokata et al., 1992). See also XPB (610651), XPC (278720), XPD (278730), XPE (278740), XPF (278760), XPG (278780), and variant XP (XPV; 278750).  http://www.omim.org/entry/278700
From MedlinePlus Genetics
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.

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.

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.

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.

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. 

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.

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. 

Individuals with xeroderma pigmentosum may experience early menopause.

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.  https://medlineplus.gov/genetics/condition/xeroderma-pigmentosum

Clinical features

From HPO
Melanoma
MedGen UID:
9944
Concept ID:
C0025202
Neoplastic Process
Melanoma 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.\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\nMost 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\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.
Squamous cell carcinoma of the skin
MedGen UID:
107512
Concept ID:
C0553723
Neoplastic Process
Squamous cell carcinoma of the skin is a malignant tumor of squamous epithelium.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).
Mental deterioration
MedGen UID:
66713
Concept ID:
C0234985
Mental or Behavioral Dysfunction
Loss of previously present mental abilities, generally in adults.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Distal sensory impairment
MedGen UID:
335722
Concept ID:
C1847584
Finding
An abnormal reduction in sensation in the distal portions of the extremities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
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.
Telangiectasia
MedGen UID:
21088
Concept ID:
C0039446
Finding
Telangiectasias refer to small dilated blood vessels located near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. Telangiectasia are located especially on the tongue, lips, palate, fingers, face, conjunctiva, trunk, nail beds, and fingertips.
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.
Verrucous nevus
MedGen UID:
83927
Concept ID:
C0362030
Disease or Syndrome
A type of epidermal nevus (which represent Blaschkoid hamartomas of the skin that result from mosaic post-zygotic mutations) that appears as skin-colored-to-brown, sharply demarcated, papillomatous papules that coalesce into plaques. The majority of these nevi are either present at birth or occur within the first year of life.
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.
Erythematous papule
MedGen UID:
834002
Concept ID:
C0747241
Finding
A circumscribed, solid elevation of skin with no visible fluid that is reddish (erythematous) in color.
Hypermelanotic macule
MedGen UID:
375013
Concept ID:
C1842774
Finding
A hyperpigmented circumscribed area of change in normal skin color without elevation or depression of any size.
Defective DNA repair after ultraviolet radiation damage
MedGen UID:
368469
Concept ID:
C1968564
Finding

Professional guidelines

PubMed

Moriwaki S, Yamashita Y, Nakamura S, Fujita D, Kohyama J, Takigawa M, Ohmichi M
J Dermatol 2012 Jun;39(6):516-9. Epub 2011 Dec 14 doi: 10.1111/j.1346-8138.2011.01425.x. PMID: 22168765

Recent clinical studies

Etiology

Kim J, Li CL, Chen X, Cui Y, Golebiowski FM, Wang H, Hanaoka F, Sugasawa K, Yang W
Nature 2023 May;617(7959):170-175. Epub 2023 Apr 19 doi: 10.1038/s41586-023-05959-z. PMID: 37076618Free PMC Article
Krasikova YS, Lavrik OI, Rechkunova NI
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Muscle Nerve 2020 Oct;62(4):534-540. Epub 2020 Aug 10 doi: 10.1002/mus.27028. PMID: 32696477
Borszéková Pulzová L, Ward TA, Chovanec M
Int J Mol Sci 2020 Mar 22;21(6) doi: 10.3390/ijms21062182. PMID: 32235701Free PMC Article
Hartwig A
Met Ions Life Sci 2013;11:491-507. doi: 10.1007/978-94-007-5179-8_15. PMID: 23430782

Diagnosis

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Musich PR, Li Z, Zou Y
Adv Exp Med Biol 2017;996:41-54. doi: 10.1007/978-3-319-56017-5_4. PMID: 29124689Free PMC Article
Amr K, Messaoud O, El Darouti M, Abdelhak S, El-Kamah G
Gene 2014 Jan 1;533(1):52-6. Epub 2013 Oct 14 doi: 10.1016/j.gene.2013.09.125. PMID: 24135642
Hartwig A
Met Ions Life Sci 2013;11:491-507. doi: 10.1007/978-94-007-5179-8_15. PMID: 23430782
Moriwaki S, Yamashita Y, Nakamura S, Fujita D, Kohyama J, Takigawa M, Ohmichi M
J Dermatol 2012 Jun;39(6):516-9. Epub 2011 Dec 14 doi: 10.1111/j.1346-8138.2011.01425.x. PMID: 22168765

Therapy

Almushawwah S, Almutairi MH, Alamri AM, Semlali A
Genes (Basel) 2023 Jun 27;14(7) doi: 10.3390/genes14071349. PMID: 37510255Free PMC Article
Sonohara Y, Takatsuka R, Masutani C, Iwai S, Kuraoka I
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Sugasawa K
Enzymes 2019;45:99-138. Epub 2019 Jul 8 doi: 10.1016/bs.enz.2019.06.004. PMID: 31627884
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Adv Exp Med Biol 2017;996:41-54. doi: 10.1007/978-3-319-56017-5_4. PMID: 29124689Free PMC Article
Hartwig A
Met Ions Life Sci 2013;11:491-507. doi: 10.1007/978-94-007-5179-8_15. PMID: 23430782

Prognosis

Yu J, Yan C, Paul T, Brewer L, Tsutakawa SE, Tsai CL, Hamdan SM, Tainer JA, Ivanov I
Nat Commun 2024 Oct 1;15(1):8511. doi: 10.1038/s41467-024-52860-y. PMID: 39353945Free PMC Article
Borszéková Pulzová L, Ward TA, Chovanec M
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Zhang J, Cheng R, Yu X, Sun Z, Li M, Yao Z
Photodermatol Photoimmunol Photomed 2017 Jan;33(1):58-63. doi: 10.1111/phpp.12283. PMID: 27982466
Nakano E, Masaki T, Kanda F, Ono R, Takeuchi S, Moriwaki S, Nishigori C
Exp Dermatol 2016 Aug;25 Suppl 3:28-33. doi: 10.1111/exd.13082. PMID: 27539899
Honecker F, Mayer F, Stoop H, Oosterhuis JW, Koch S, Bokemeyer C, Looijenga LH
Lab Invest 2003 Oct;83(10):1489-95. doi: 10.1097/01.lab.0000090221.95883.41. PMID: 14563950

Clinical prediction guides

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Carcinogenesis 2022 Feb 11;43(1):52-59. doi: 10.1093/carcin/bgab087. PMID: 34546339
Wang H, Lautrup S, Caponio D, Zhang J, Fang EF
Int J Mol Sci 2021 Jun 23;22(13) doi: 10.3390/ijms22136748. PMID: 34201700Free PMC Article
Tsuji Y, Ueda T, Sekiguchi K, Nishiyama M, Kanda F, Nishigori C, Toda T, Matsumoto R
Muscle Nerve 2020 Oct;62(4):534-540. Epub 2020 Aug 10 doi: 10.1002/mus.27028. PMID: 32696477
Borszéková Pulzová L, Ward TA, Chovanec M
Int J Mol Sci 2020 Mar 22;21(6) doi: 10.3390/ijms21062182. PMID: 32235701Free PMC Article

Recent systematic reviews

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Ding D, Zhang Y, Yu H, Guo Y, Jiang L, He X, Ma W, Zheng W
Int J Cancer 2012 Jul 15;131(2):488-96. Epub 2011 Oct 20 doi: 10.1002/ijc.26391. PMID: 21866550

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