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Xeroderma pigmentosum, group F(XPF)

MedGen UID:
120612
Concept ID:
C0268140
Congenital Abnormality
Synonyms: ERCC4-Related Xeroderma Pigmentosum; XERODERMA PIGMENTOSUM VI; XERODERMA PIGMENTOSUM, COMPLEMENTATION GROUP F; Xeroderma pigmentosum, type 6; XERODERMA PIGMENTOSUM, TYPE F; XP, GROUP F; XPF
SNOMED CT: Xeroderma pigmentosum group F (42530008); Xeroderma pigmentosum, group F (42530008)
 
Gene (location): ERCC4 (16p13.12)
 
Monarch Initiative: MONDO:0010215
OMIM®: 278760

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 sun sensitivity and increased skin sensitivity to UV light, as well as an increased risk of skin cancer associated with a defect in nucleotide excision repair (NER). The XPF form of XP is usually relatively mild compared to other forms. Patients with XPF tend to have later onset of skin cancer. Some patients with XPF may develop neurologic impairment or growth defects, and are then classified as having Cockayne syndrome (summary by Kashiyama et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of xeroderma pigmentosa, see XPA (278700), and of Cockayne syndrome, see CSA (216400).  http://www.omim.org/entry/278760
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.

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.

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.

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.
Keratoacanthoma
MedGen UID:
5954
Concept ID:
C0022572
Neoplastic Process
Keratoacanthoma (KA) is a common benign epithelial tumor that originates from the pilosebaceous glands. In most cases, it is characterized by rapid evolution, followed by spontaneous resolution over 4 to 6 months. KA usually presents as a solitary flesh-coloured nodule with a central keratin plug on the sun-exposed skin of elderly individuals.
Seborrheic keratosis
MedGen UID:
5957
Concept ID:
C0022603
Neoplastic Process
Seborrheic keratoses are common benign epidermal lesion that can develop on any part of the body.
Neoplasm of the skin
MedGen UID:
19993
Concept ID:
C0037286
Neoplastic Process
A tumor (abnormal growth of tissue) of the skin.
Skin basal cell carcinoma
MedGen UID:
1648304
Concept ID:
C4721806
Neoplastic Process
The presence of a basal cell carcinoma of the skin.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Decreased body weight
MedGen UID:
1806755
Concept ID:
C5574742
Finding
Abnormally low body weight.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
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).
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Dementia
MedGen UID:
99229
Concept ID:
C0497327
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
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.
Morphological central nervous system abnormality
MedGen UID:
892343
Concept ID:
C4021765
Anatomical Abnormality
A structural abnormality of the central nervous system.
Aplasia/Hypoplasia involving the central nervous system
MedGen UID:
871188
Concept ID:
C4025665
Finding
Absence or underdevelopment of tissue in the central nervous system.
Brain atrophy
MedGen UID:
1643639
Concept ID:
C4551584
Disease or Syndrome
Partial or complete wasting (loss) of brain tissue that was once present.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Flexion contracture
MedGen UID:
83069
Concept ID:
C0333068
Anatomical Abnormality
A flexion contracture is a bent (flexed) joint that cannot be straightened actively or passively. It is thus a chronic loss of joint motion due to structural changes in muscle, tendons, ligaments, or skin that prevents normal movement of joints.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Freckling
MedGen UID:
5272
Concept ID:
C0016689
Finding
The presence of an increased number of freckles, small circular spots on the skin that are darker than the surrounding skin because of deposits of melanin.
Erythema
MedGen UID:
11999
Concept ID:
C0041834
Disease or Syndrome
Redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin.
Papule
MedGen UID:
507324
Concept ID:
C0332563
Finding
A circumscribed, solid elevation of skin with no visible fluid, varying in size from a pinhead to less than 10mm in diameter at the widest point.
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.
Numerous pigmented freckles
MedGen UID:
369801
Concept ID:
C1968565
Finding
Astigmatism
MedGen UID:
2473
Concept ID:
C0004106
Disease or Syndrome
Astigmatism (from the Greek 'a' meaning absence and 'stigma' meaning point) is a condition in which the parallel rays of light entering the eye through the refractive media are not focused on a single point. Both corneal and noncorneal factors contribute to refractive astigmatism. Corneal astigmatism is mainly the result of an aspheric anterior surface of the cornea, which can be measured readily by means of a keratometer; in a small fraction of cases (approximately 1 in 10) the effect is neutralized by the back surface. The curvature of the back surface of the cornea is not considered in most studies, because it is more difficult to measure; moreover, in the case of severe corneal astigmatism, there is evidence that both surfaces have the same configuration. Noncorneal factors are errors in the curvature of the 2 surfaces of the crystalline lens, irregularity in the refractive index of the lens, and an eccentric lens position. Since the cornea is the dominant component of the eye's refracting system, a highly astigmatic cornea is likely to result in a similarly astigmatic ocular refraction (summary by Clementi et al., 1998).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.
Defective DNA repair after ultraviolet radiation damage
MedGen UID:
368469
Concept ID:
C1968564
Finding
Deficient excision of UV-induced pyrimidine dimers in DNA
MedGen UID:
871166
Concept ID:
C4025640
Finding

Recent clinical studies

Etiology

Crossley MP, Song C, Bocek MJ, Choi JH, Kousouros JN, Sathirachinda A, Lin C, Brickner JR, Bai G, Lans H, Vermeulen W, Abu-Remaileh M, Cimprich KA
Nature 2023 Jan;613(7942):187-194. Epub 2022 Dec 21 doi: 10.1038/s41586-022-05545-9. PMID: 36544021Free PMC Article
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
Dehé PM, Gaillard PHL
Nat Rev Mol Cell Biol 2017 May;18(5):315-330. Epub 2017 Mar 22 doi: 10.1038/nrm.2016.177. PMID: 28327556
Tofuku Y, Nobeyama Y, Kamide R, Moriwaki S, Nakagawa H
J Dermatol 2015 Sep;42(9):897-9. Epub 2015 May 25 doi: 10.1111/1346-8138.12942. PMID: 26010807
Wojcik EJ, Buckley RS, Richard J, Liu L, Huckaba TM, Kim S
Gene 2013 Dec 1;531(2):133-49. Epub 2013 Aug 14 doi: 10.1016/j.gene.2013.08.004. PMID: 23954229Free PMC Article

Diagnosis

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
Carré G, Marelli C, Anheim M, Geny C, Renaud M, Rezvani HR, Koenig M, Guissart C, Tranchant C
J Neurol Sci 2017 May 15;376:198-201. Epub 2017 Mar 16 doi: 10.1016/j.jns.2017.03.021. PMID: 28431612
Dehé PM, Gaillard PHL
Nat Rev Mol Cell Biol 2017 May;18(5):315-330. Epub 2017 Mar 22 doi: 10.1038/nrm.2016.177. PMID: 28327556
Manandhar M, Boulware KS, Wood RD
Gene 2015 Sep 15;569(2):153-61. Epub 2015 Jun 12 doi: 10.1016/j.gene.2015.06.026. PMID: 26074087Free PMC Article
Tofuku Y, Nobeyama Y, Kamide R, Moriwaki S, Nakagawa H
J Dermatol 2015 Sep;42(9):897-9. Epub 2015 May 25 doi: 10.1111/1346-8138.12942. PMID: 26010807

Therapy

Ganzinelli M, Linardou H, Alvisi MF, Caiola E, Lo Russo G, Cecere FL, Bettini AC, Psyrri A, Milella M, Rulli E, Fabbri A, De Maglie M, Romanelli P, Murray S, Broggini M, Marabese M, Garassino MC
ESMO Open 2021 Feb;6(1):100034. Epub 2021 Jan 7 doi: 10.1016/j.esmoop.2020.100034. PMID: 33422766Free PMC Article
Liu Y, Liu K, Zhao X, Sun Y, Ma N, Tang L, Yang H, Gao X, Yan L, Yuan M, Wang B, Zhang X, Jia J
Biosci Rep 2019 May 31;39(5) Epub 2019 May 23 doi: 10.1042/BSR20181785. PMID: 31040199Free PMC Article
Mirecka A, Paszkowska-Szczur K, Scott RJ, Górski B, van de Wetering T, Wokołorczyk D, Gromowski T, Serrano-Fernandez P, Cybulski C, Kashyap A, Gupta S, Gołąb A, Słojewski M, Sikorski A, Lubiński J, Dębniak T
Gene 2014 Aug 10;546(2):156-61. Epub 2014 Jun 13 doi: 10.1016/j.gene.2014.06.026. PMID: 24933002
Wojcik EJ, Buckley RS, Richard J, Liu L, Huckaba TM, Kim S
Gene 2013 Dec 1;531(2):133-49. Epub 2013 Aug 14 doi: 10.1016/j.gene.2013.08.004. PMID: 23954229Free PMC Article
Kondo S, Mamada A, Miyamoto C, Keong CH, Satoh Y, Fujiwara Y
Photodermatol 1989 Apr;6(2):89-95. PMID: 2664729

Prognosis

Felix FA, da Silva LP, Lopes MLDS, Sobral APV, Freitas RA, de Souza LB, Barboza CAG
Arch Oral Biol 2021 Jan;121:104987. Epub 2020 Nov 11 doi: 10.1016/j.archoralbio.2020.104987. PMID: 33202356
Marín M, Ramírez MJ, Carmona MA, Jia N, Ogi T, Bogliolo M, Surrallés J
Genes (Basel) 2019 Jan 17;10(1) doi: 10.3390/genes10010060. PMID: 30658521Free PMC Article
Zhang JS, Zhang C, Yan XY, Yuan ZF, Duan ZY, Gao H
Asian Pac J Cancer Prev 2013;14(3):1847-50. doi: 10.7314/apjcp.2013.14.3.1847. PMID: 23679285
Kirschner K, Melton DW
Anticancer Res 2010 Sep;30(9):3223-32. PMID: 20944091
Matsumura Y, Nishigori C, Yagi T, Imamura S, Takebe H
Hum Mol Genet 1998 Jun;7(6):969-74. doi: 10.1093/hmg/7.6.969. PMID: 9580660

Clinical prediction guides

Crossley MP, Song C, Bocek MJ, Choi JH, Kousouros JN, Sathirachinda A, Lin C, Brickner JR, Bai G, Lans H, Vermeulen W, Abu-Remaileh M, Cimprich KA
Nature 2023 Jan;613(7942):187-194. Epub 2022 Dec 21 doi: 10.1038/s41586-022-05545-9. PMID: 36544021Free PMC Article
Liu Y, Liu K, Zhao X, Sun Y, Ma N, Tang L, Yang H, Gao X, Yan L, Yuan M, Wang B, Zhang X, Jia J
Biosci Rep 2019 May 31;39(5) Epub 2019 May 23 doi: 10.1042/BSR20181785. PMID: 31040199Free PMC Article
Kirschner K, Melton DW
Anticancer Res 2010 Sep;30(9):3223-32. PMID: 20944091
McCabe KM, Olson SB, Moses RE
J Cell Physiol 2009 Sep;220(3):569-73. doi: 10.1002/jcp.21811. PMID: 19452447Free PMC Article
Matsumura Y, Nishigori C, Yagi T, Imamura S, Takebe H
Hum Mol Genet 1998 Jun;7(6):969-74. doi: 10.1093/hmg/7.6.969. PMID: 9580660

Recent systematic reviews

Mohammadreza Niktabar S, Alireza Dastgheib S, Heiranizadeh N, Kargar S, Raee-Ezzabadi A, Jarahzadeh MH, Mohsen Miresmaeili S, Zare-Shehneh M, Neamatzadeh H
Klin Onkol 2020 Spring;33(3):184-194. doi: 10.14735/amko2020184. PMID: 32683874
Liu Y, Liu K, Zhao X, Sun Y, Ma N, Tang L, Yang H, Gao X, Yan L, Yuan M, Wang B, Zhang X, Jia J
Biosci Rep 2019 May 31;39(5) Epub 2019 May 23 doi: 10.1042/BSR20181785. PMID: 31040199Free PMC Article

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