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Xeroderma pigmentosum, group D(XPD)

MedGen UID:
75656
Concept ID:
C0268138
Disease or Syndrome
Synonyms: ERCC2-Related Xeroderma Pigmentosum; XERODERMA PIGMENTOSUM IV; XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP D; XP, GROUP D; XP, GROUP H; XP4 XERODERMA PIGMENTOSUM VIII; XPD
SNOMED CT: Xeroderma pigmentosum, group D (68637004); Xeroderma pigmentosum group D (68637004)
 
Gene (location): ERCC2 (19q13.32)
 
Monarch Initiative: MONDO:0010212
OMIM®: 278730

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 rare autosomal recessive disorder characterized by acute photosensitivity and a predisposition to skin cancer on sun-exposed areas of the body. The primary defect in XP involves nucleotide excision repair (NER) (summary by Flejter et al., 1992).  http://www.omim.org/entry/278730
From MedlinePlus Genetics
Individuals with xeroderma pigmentosum may experience early menopause.

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. 

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.
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).
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.
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.
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.
Keratoconjunctivitis sicca
MedGen UID:
9620
Concept ID:
C0022575
Disease or Syndrome
Dryness of the eye related to deficiency of the tear film components (aqueous, mucin, or lipid), lid surface abnormalities, or epithelial abnormalities. Keratoconjunctivitis sicca often results in a scratchy or sandy sensation (foreign body sensation) in the eyes, and may also be associated with itching, inability to produce tears, photosensitivity, redness, pain, and difficulty in moving the eyelids.
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.
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.
Microphthalmia
MedGen UID:
10033
Concept ID:
C0026010
Congenital Abnormality
Microphthalmia is an eye abnormality that arises before birth. In this condition, one or both eyeballs are abnormally small. In some affected individuals, the eyeball may appear to be completely missing; however, even in these cases some remaining eye tissue is generally present. Such severe microphthalmia should be distinguished from another condition called anophthalmia, in which no eyeball forms at all. However, the terms anophthalmia and severe microphthalmia are often used interchangeably. Microphthalmia may or may not result in significant vision loss.\n\nPeople with microphthalmia may also have a condition called coloboma. Colobomas are missing pieces of tissue in structures that form the eye. They may appear as notches or gaps in the colored part of the eye called the iris; the retina, which is the specialized light-sensitive tissue that lines the back of the eye; the blood vessel layer under the retina called the choroid; or in the optic nerves, which carry information from the eyes to the brain. Colobomas may be present in one or both eyes and, depending on their size and location, can affect a person's vision.\n\nPeople with microphthalmia may also have other eye abnormalities, including clouding of the lens of the eye (cataract) and a narrowed opening of the eye (narrowed palpebral fissure). Additionally, affected individuals may have an abnormality called microcornea, in which the clear front covering of the eye (cornea) is small and abnormally curved.\n\nBetween one-third and one-half of affected individuals have microphthalmia as part of a syndrome that affects other organs and tissues in the body. These forms of the condition are described as syndromic. When microphthalmia occurs by itself, it is described as nonsyndromic or isolated.
Corneal neovascularization
MedGen UID:
43103
Concept ID:
C0085109
Disease or Syndrome
Ingrowth of new blood vessels into the cornea.
Cataract
MedGen UID:
39462
Concept ID:
C0086543
Disease or Syndrome
A cataract is an opacity or clouding that develops in the crystalline lens of the eye or in its capsule.
Defective DNA repair after ultraviolet radiation damage
MedGen UID:
368469
Concept ID:
C1968564
Finding

Professional guidelines

PubMed

Chang WS, Yueh TC, Tsai CW, Ji HX, Wu CN, Wang SC, Lai YL, Hsu SW, Hsieh MH, Hsiao CL, Hung YW, Shih TC, Bau DT
Anticancer Res 2016 Apr;36(4):1657-63. PMID: 27069143
Ji HX, Chang WS, Tsai CW, Wang JY, Huang NK, Lee AS, Shen MY, Chen WY, Chiang YC, Shih TC, Hsu CM, Bau DT
Anticancer Res 2015 Sep;35(9):4975-81. PMID: 26254397
Gnoni A, Russo A, Silvestris N, Maiello E, Vacca A, Marech I, Numico G, Paradiso A, Lorusso V, Azzariti A
Curr Drug Metab 2011 Dec;12(10):918-31. doi: 10.2174/138920011798062300. PMID: 21787270

Recent clinical studies

Etiology

Theil AF, Häckes D, Lans H
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Ferri D, Orioli D, Botta E
Clin Genet 2020 Jan;97(1):12-24. Epub 2019 Apr 22 doi: 10.1111/cge.13545. PMID: 30919937
Yang R, Zhang C, Malik A, Shen ZD, Hu J, Wu YH
World J Gastroenterol 2014 Nov 28;20(44):16765-73. doi: 10.3748/wjg.v20.i44.16765. PMID: 25469049Free PMC Article
Zhu H, Cao S, Liu Y, Ding X, Wu Q, Ma H
J Cancer Res Ther 2013 Apr-Jun;9(2):187-92. doi: 10.4103/0973-1482.113345. PMID: 23771356
Suzumura H, Arisaka O
Adv Exp Med Biol 2010;685:210-4. doi: 10.1007/978-1-4419-6448-9_19. PMID: 20687508

Diagnosis

Kamran SC, Zhou Y, Otani K, Drumm M, Otani Y, Wu S, Wu CL, Feldman AS, Wszolek M, Lee RJ, Saylor PJ, Lennerz J, Van Allen E, Willers H, Hong TS, Liu Y, Davicioni E, Gibb EA, Shipley WU, Mouw KW, Efstathiou JA, Miyamoto DT
Clin Cancer Res 2023 Dec 15;29(24):5116-5127. doi: 10.1158/1078-0432.CCR-23-0792. PMID: 37870965Free PMC Article
Riechelmann RP, Donadio MDS, Jesus VHF, de Carvalho NA, Santiago KM, Barros MJ, Lopes L, Oliveira Dos Santos G, Nirvana Formiga M, Carraro DM, Torrezan GT
Endocr Relat Cancer 2023 Jun 1;30(6) Epub 2023 May 11 doi: 10.1530/ERC-22-0258. PMID: 36947458
Pietzak EJ, Whiting K, Srinivasan P, Bandlamudi C, Khurram A, Joseph V, Walasek A, Bochner E, Clinton T, Almassi N, Truong H, de Jesus Escano MR, Wiseman M, Mandelker D, Kemel Y, Zhang L, Walsh MF, Cadoo KA, Coleman JA, Al-Ahmadie H, Rosenberg JE, Iyer GV, Solit DB, Ostrovnaya I, Offit K, Robson ME, Stadler ZK, Berger MF, Bajorin DF, Carlo M, Bochner BH
Clin Cancer Res 2022 Oct 3;28(19):4267-4277. doi: 10.1158/1078-0432.CCR-22-1006. PMID: 35833951Free PMC Article
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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

Therapy

Kamran SC, Zhou Y, Otani K, Drumm M, Otani Y, Wu S, Wu CL, Feldman AS, Wszolek M, Lee RJ, Saylor PJ, Lennerz J, Van Allen E, Willers H, Hong TS, Liu Y, Davicioni E, Gibb EA, Shipley WU, Mouw KW, Efstathiou JA, Miyamoto DT
Clin Cancer Res 2023 Dec 15;29(24):5116-5127. doi: 10.1158/1078-0432.CCR-23-0792. PMID: 37870965Free PMC Article
Galsky MD, Daneshmand S, Izadmehr S, Gonzalez-Kozlova E, Chan KG, Lewis S, Achkar BE, Dorff TB, Cetnar JP, Neil BO, D'Souza A, Mamtani R, Kyriakopoulos C, Jun T, Gogerly-Moragoda M, Brody R, Xie H, Nie K, Kelly G, Horowitz A, Kinoshita Y, Ellis E, Nose Y, Ioannou G, Cabal R, Del Valle DM, Haines GK, Wang L, Mouw KW, Samstein RM, Mehrazin R, Bhardwaj N, Yu M, Zhao Q, Kim-Schulze S, Sebra R, Zhu J, Gnjatic S, Sfakianos J, Pal SK
Nat Med 2023 Nov;29(11):2825-2834. Epub 2023 Oct 2 doi: 10.1038/s41591-023-02568-1. PMID: 37783966Free PMC Article
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Ding H, Wen Z, Sun G
Med Sci Monit 2018 Nov 9;24:8015-8021. doi: 10.12659/MSM.910944. PMID: 30409962Free PMC Article
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Prognosis

Galsky MD, Daneshmand S, Izadmehr S, Gonzalez-Kozlova E, Chan KG, Lewis S, Achkar BE, Dorff TB, Cetnar JP, Neil BO, D'Souza A, Mamtani R, Kyriakopoulos C, Jun T, Gogerly-Moragoda M, Brody R, Xie H, Nie K, Kelly G, Horowitz A, Kinoshita Y, Ellis E, Nose Y, Ioannou G, Cabal R, Del Valle DM, Haines GK, Wang L, Mouw KW, Samstein RM, Mehrazin R, Bhardwaj N, Yu M, Zhao Q, Kim-Schulze S, Sebra R, Zhu J, Gnjatic S, Sfakianos J, Pal SK
Nat Med 2023 Nov;29(11):2825-2834. Epub 2023 Oct 2 doi: 10.1038/s41591-023-02568-1. PMID: 37783966Free PMC Article
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J Transl Med 2023 Feb 2;21(1):69. doi: 10.1186/s12967-023-03936-8. PMID: 36732815Free PMC Article
Gil-Jimenez A, van Dorp J, Contreras-Sanz A, van der Vos K, Vis DJ, Braaf L, Broeks A, Kerkhoven R, van Kessel KEM, Ribal MJ, Alcaraz A, Wessels LFA, Seiler R, Wright JL, Mengual L, Boormans J, van Rhijn BWG, Black PC, van der Heijden MS
Eur Urol 2023 Apr;83(4):313-317. Epub 2022 Aug 11 doi: 10.1016/j.eururo.2022.07.023. PMID: 35965206
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
Chang WS, Yueh TC, Tsai CW, Ji HX, Wu CN, Wang SC, Lai YL, Hsu SW, Hsieh MH, Hsiao CL, Hung YW, Shih TC, Bau DT
Anticancer Res 2016 Apr;36(4):1657-63. PMID: 27069143

Clinical prediction guides

Galsky MD, Daneshmand S, Izadmehr S, Gonzalez-Kozlova E, Chan KG, Lewis S, Achkar BE, Dorff TB, Cetnar JP, Neil BO, D'Souza A, Mamtani R, Kyriakopoulos C, Jun T, Gogerly-Moragoda M, Brody R, Xie H, Nie K, Kelly G, Horowitz A, Kinoshita Y, Ellis E, Nose Y, Ioannou G, Cabal R, Del Valle DM, Haines GK, Wang L, Mouw KW, Samstein RM, Mehrazin R, Bhardwaj N, Yu M, Zhao Q, Kim-Schulze S, Sebra R, Zhu J, Gnjatic S, Sfakianos J, Pal SK
Nat Med 2023 Nov;29(11):2825-2834. Epub 2023 Oct 2 doi: 10.1038/s41591-023-02568-1. PMID: 37783966Free PMC Article
Jeon H, Byun J, Kang H, Kim K, Lee E, Kim JH, Hong CK, Song SW, Kim YH, Chong S, Kim JH, Nam SJ, Park JE, Lee S
J Transl Med 2023 Feb 2;21(1):69. doi: 10.1186/s12967-023-03936-8. PMID: 36732815Free PMC Article
Xiao F, Pu J, Wen Q, Huang Q, Zhang Q, Huang B, Huang S, Lan A, Zhang Y, Li J, Zhao D, Shen J, Wu H, He Y, Li H, Yang X
Oncotarget 2017 Jul 18;8(29):48488-48506. doi: 10.18632/oncotarget.17290. PMID: 28489582Free PMC Article
Chang WS, Yueh TC, Tsai CW, Ji HX, Wu CN, Wang SC, Lai YL, Hsu SW, Hsieh MH, Hsiao CL, Hung YW, Shih TC, Bau DT
Anticancer Res 2016 Apr;36(4):1657-63. PMID: 27069143
Zhu H, Cao S, Liu Y, Ding X, Wu Q, Ma H
J Cancer Res Ther 2013 Apr-Jun;9(2):187-92. doi: 10.4103/0973-1482.113345. PMID: 23771356

Recent systematic reviews

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