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.

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.

Xeroderma pigmentosum is caused by variants (also called mutations) in at least nine genes: DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, and XPC. These genesare involved in repairing damaged DNA. DNA can be damaged by UVR and by toxic chemicals, such as those found in cigarette smoke. Normal cells are usually able to fix DNA damage before it causes problems. However, in people with xeroderma pigmentosum, DNA damage is not repaired normally. As damage builds up in DNA, cells malfunction and eventually become cancerous or die.

Many of the genes related to xeroderma pigmentosum are part of a DNA-repair process known as nucleotide excision repair (NER). The proteins produced from these genes play a variety of roles in this process. They recognize DNA damage, unwind regions of DNA where the damage has occurred, snip out (excise) the abnormal sections, and replace the damaged areas with the correct DNA. Changes in NER-related genes prevent cells from carrying out one or more of these steps. The DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, and XPC genes are all involved in the NER process. The POLHgene also plays a role in protecting cells from UVR-induced DNA damage by bypassing the DNA damage, although it is not involved in NER.

More than half of all cases of xeroderma pigmentosum in the United States are caused by variants in the XPC, ERCC2, and POLHgenes. Variants in the other genes generally account for a smaller percentage of cases.

The major features of xeroderma pigmentosum result from a buildup of unrepaired DNA damage. When UVR damages genes that control cell growth and division, cells can either die or grow too fast and in an uncontrolled way. Unregulated cell growth can lead to the development of cancerous tumors. The neurological abnormalities are also thought to result from a builup of DNA damage, although the brain is not exposed to UVR. Researchers suspect that other factors damage DNA in nerve cells. It is unclear why some people with xeroderma pigmentosum develop neurological abnormalities and others do not.

Normal Function

The ERCC2 gene provides instructions for making a protein called XPD. This protein is an essential part (subunit) of a group of proteins known as the general transcription factor 2 H (TFIIH) complex. The TFIIH complex has two major functions: it is involved in a process called gene transcription, and it helps repair damaged DNA.

Gene transcription is the first step in protein production. By controlling gene transcription, the TFIIH complex helps regulate the activity of many different genes. The XPD protein appears to stabilize the TFIIH complex. Studies suggest that the XPD protein works together with XPB, another protein in the TFIIH complex that is produced from the ERCC3 gene, to start (initiate) gene transcription.

The TFIIH complex also plays an important role in repairing damaged DNA. DNA can be damaged by ultraviolet (UV) rays from sunlight and by toxic chemicals, such as those found in cigarette smoke. DNA damage occurs frequently, but normal cells are usually able to fix it before it can cause problems.

One of the major mechanisms that cells use to fix DNA is known as nucleotide excision repair (NER). The TFIIH complex is part of this repair mechanism. The XPD protein acts as a helicase, which is an enzyme that attaches (binds) to particular regions of DNA and temporarily unwinds the two spiral strands. Once the damaged region has been exposed, other proteins snip out (excise) the abnormal section and replace the damaged area with the correct DNA.

Health Conditions Related to Genetic Changes

Trichothiodystrophy

Many variants (also called mutations) in the ERCC2 gene have been found to cause trichothiodystrophy. This condition affects many parts of the body. The hallmark of trichothiodystrophy is hair that is sparse and easily broken. Affected children may develop severe hip degeneration.

Variants in this gene are the most common cause of the photosensitive form of the condition, which is characterized by an extreme sensitivity to UV rays from sunlight.

Studies suggest that the ERCC2 gene variants responsible for trichothiodystrophy reduce the amount of functional TFIIH complex in cells. Without enough of this complex, cells cannot effectively repair DNA damage caused by UV radiation. These problems with DNA repair cause people with the photosensitive form of trichothiodystrophy to be extremely sensitive to sunlight. Other features of the condition, such as slow growth, intellectual disability, and brittle hair, probably result from problems with the transcription of genes needed for normal development before and after birth.

Unlike another condition called xeroderma pigmentosum (described below), trichothiodystrophy is not associated with an increased risk of skin cancer. Researchers are working to determine why some variants in the ERCC2 gene affect a person's cancer risk and others do not.

Xeroderma pigmentosum

More than two dozen variants in the ERCC2 gene have been identified in people with xeroderma pigmentosum. This condition is characterized by an extreme sensitivity to UV rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun.

Variants in the ERCC2 gene are the second most common cause of xeroderma pigmentosum in the United States. The ERCC2 gene variants responsible for xeroderma pigmentosum prevent the TFIIH complex from repairing damaged DNA effectively. As damage builds up in DNA, cells malfunction and eventually become cancerous or die. These problems with DNA repair cause people with xeroderma pigmentosum to be extremely sensitive to UV rays. When UV rays damage genes that control cell growth and division, cells can grow too fast and in an uncontrolled way. As a result, people with xeroderma pigmentosum have a greatly increased risk of developing cancer. These cancers occur most frequently in areas of the body that are exposed to the sun, such as the skin and eyes.

When xeroderma pigmentosum is caused by ERCC2 gene variants, it is often associated with progressive neurological abnormalities. These nervous system problems include hearing loss, poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty swallowing and talking, and seizures. The neurological abnormalities are thought to result from a buildup of DNA damage, although the brain is not exposed to UV rays. Researchers suspect that other factors damage DNA in nerve cells. It is unclear why some people with xeroderma pigmentosum develop neurological abnormalities and others do not.

Other disorders

Rarely, variants in the ERCC2 gene can cause features of both xeroderma pigmentosum and trichothiodystrophy in the same individual. This condition is known as xeroderma pigmentosum/trichothiodystrophy (XP/TTD) complex. ERCC2 gene variants have also been identified in a few individuals with signs and symptoms of both xeroderma pigmentosum and another condition related to defective DNA repair called Cockayne syndrome. This combination of features is known as xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex.

Researchers are uncertain how variants in this single gene can cause several different disorders with a wide variety of signs and symptoms. Studies suggest that different ERCC2 gene variants affect the stability and function of the TFIIH complex in different ways. Variants also have varied effects on the interaction between the XPD protein and other proteins that make up the TFIIH complex. These variants may account for the different features of xeroderma pigmentosum, trichothiodystrophy, and XP/TTD and XP/CS complexes.

Other Names for This Gene

• basic transcription factor 2 80 kDa subunit
• BTF2 p80
• COFS2
• CXPD
• DNA excision repair protein ERCC-2
• DNA repair protein complementing XP-D cells
• EM9
• ERCC2_HUMAN
• excision repair cross-complementation group 2
• excision repair cross-complementing rodent repair deficiency, complementation group 2
• MAG
• MGC102762
• MGC126218
• MGC126219
• TFIIH
• TFIIH 80 kDa subunit
• TFIIH basal transcription factor complex 80 kDa subunit
• TFIIH basal transcription factor complex helicase subunit
• TFIIH p80
• TTD
• xeroderma pigmentosum complementary group D
• xeroderma pigmentosum group D-complementing protein

Genomic Location

Normal Function

The ERCC3 gene provides instructions for making a protein called XPB. This protein is an essential part (subunit) of a group of proteins known as the general transcription factor 2 H (TFIIH) complex. The TFIIH complex has two major functions: it is involved in a process called gene transcription, and it helps repair damaged DNA.

Gene transcription is the first step in protein production. By controlling gene transcription, the TFIIH complex helps regulate the activity of many different genes. Studies suggest that the XPB protein works together with XPD, another protein in the TFIIH complex that is produced from the ERCC2 gene, to start (initiate) gene transcription.

The TFIIH complex also plays an important role in repairing damaged DNA. DNA can be damaged by ultraviolet (UV) rays from sunlight and by toxic chemicals, such as those found in cigarette smoke. DNA damage occurs frequently, but normal cells are usually able to fix it before it can cause problems.

One of the major mechanisms that cells use to fix DNA is known as nucleotide excision repair (NER). As part of this repair mechanism, the TFIIH complex unwinds the section of double-stranded DNA that surrounds the damage. Studies suggest that the XPB protein may act as a wedge, holding open the two strands of DNA so other proteins can snip out (excise) the abnormal section and replace the damaged area with the correct DNA.

Health Conditions Related to Genetic Changes

Trichothiodystrophy

At least one variant (also called a mutation) in the ERCC3 gene appears to be a rare cause of trichothiodystrophy. This condition affects many parts of the body. The hallmark of trichothiodystrophy is hair that is sparse and easily broken. The ERCC3 gene variant causes the photosensitive form of the condition, which is characterized by an extreme sensitivity to UV rays from sunlight.

The ERCC3 gene variant known to cause trichothiodystrophy changes one protein building block (amino acid) in the XPB protein; specifically, it replaces the amino acid threonine with the amino acid proline at protein position 119 (written as Thr119Pro or T119P). This variant probably makes the TFIIH complex unstable and reduces its ability to repair DNA damage caused by UV radiation. These problems with DNA repair cause people with the photosensitive form of trichothiodystrophy to be extremely sensitive to sunlight. Other features of the condition, such as slow growth, intellectual disability, and brittle hair, likely result from problems with the transcription of genes needed for normal development before and after birth.

Unlike xeroderma pigmentosum (described below), trichothiodystrophy is not associated with an increased risk of skin cancer. Researchers are working to determine why some variants in the ERCC3 gene affect a person's cancer risk and others do not.

Xeroderma pigmentosum

At least one variant in the ERCC3 gene also appears to be a rare cause of xeroderma pigmentosum. This condition is characterized by an extreme sensitivity to UV rays from sunlight. This condition mostly affects the eyes and areas of skin exposed to the sun.

The ERCC3 gene variant that causes xeroderma pigmentosum changes one amino acid in the XPB protein. Specifically, the variant replaces the amino acid phenylalanine with the amino acid serine at protein position 99 (written as Phe99Ser or F99S). This variant greatly reduces the ability of the TFIIH complex to repair damaged DNA. As damage builds up in DNA, cells malfunction and eventually become cancerous or die.

Problems with DNA repair cause people with xeroderma pigmentosum to be extremely sensitive to UV rays. When UV rays damage genes that control cell growth and division, cells can grow too fast and in an uncontrolled way. As a result, people with xeroderma pigmentosum have a greatly increased risk of developing cancer. These cancers occur most frequently in areas of the body that are exposed to the sun, such as the skin and eyes.

In addition to sun sensitivity, xeroderma pigmentosum is sometimes associated with progressive neurological abnormalities. In affected individuals with the Phe99Ser variant, neurological abnormalities have been relatively mild and have included hearing loss and poor coordination. Studies suggest that the neurological abnormalities associated with this condition result from a buildup of DNA damage, although the brain is not exposed to UV rays. Researchers suspect that other factors damage DNA in nerve cells. It is unclear why some people with xeroderma pigmentosum develop neurological abnormalities and others do not.

Other disorders

Several variants in the ERCC3 gene can cause features of both xeroderma pigmentosum and another condition related to defective DNA repair called Cockayne syndrome. When this combination of features occurs in the same individual, it is known as xeroderma pigmentosum/Cockayne syndrome (XP/CS) complex. People with XP/CS complex may have extreme sun sensitivity, an increased risk of skin cancer, short stature, hearing loss, poor coordination, and intellectual disability.

Researchers are uncertain how variants in this single gene can cause several different disorders with a wide variety of signs and symptoms. Studies suggest that different ERCC3 gene variants affect the stability and function of the TFIIH complex in different ways. These variations may account for the different features of xeroderma pigmentosum, trichothiodystrophy, and XP/CS complex.

Other Names for This Gene

• basic transcription factor 2 89 kDa subunit
• BTF2
• BTF2 p89
• DNA excision repair protein ERCC-3
• DNA repair protein complementing XP-B cells
• ERCC3_HUMAN
• excision repair cross-complementation group 3
• excision repair cross-complementing rodent repair deficiency, complementation group 3
• excision repair cross-complementing rodent repair deficiency, complementation group 3 (xeroderma pigmentosum group B complementing)
• GTF2H
• RAD25
• TFIIH 89 kDa subunit
• TFIIH basal transcription factor complex 89 kDa subunit
• TFIIH basal transcription factor complex helicase XPB subunit
• TFIIH p89
• xeroderma pigmentosum group B-complementing protein
• xeroderma pigmentosum, complementation group B

Genomic Location

Normal Function

The POLH gene provides instructions for making a protein called DNA polymerase eta. DNA polymerases are a group of enzymes that "read" sequences of DNA and use them as templates to produce new DNA. These enzymes are important for copying (replicating) cells' genetic material in preparation for cell division. DNA polymerases also play critical roles in DNA repair.

The major function of DNA polymerase eta is to replicate DNA that has been damaged, particularly by ultraviolet (UV) rays from sunlight. Most other DNA polymerases are unable to replicate DNA with this type of damage. When they reach a segment of damaged DNA, they get stuck and the replication process stalls. However, when DNA polymerase eta encounters damaged DNA, it skips over the abnormal segment and continues copying. This activity, which is known as translesion synthesis, allows cells to tolerate some abnormalities created by UV exposure. Without this tolerance, unrepaired DNA damage would block DNA replication and cause the cell to die. Therefore, DNA polymerase eta plays an essential role in protecting cells from some of the effects of DNA damage.

DNA polymerase eta is a relatively "error-prone" polymerase. When it bypasses damaged DNA, it often inserts an incorrect DNA building block (nucleotide). This type of error results in a variant (also called a mutation) in the replicated DNA.

Health Conditions Related to Genetic Changes

Xeroderma pigmentosum

Several variants in the POLH gene have been found to cause a condition called xeroderma pigmentosum. In particular, POLH gene variants cause the variant type of xeroderma pigmentosum (XP-V). Like the other forms of xeroderma pigmentosum, XP-V is characterized by an increased sensitivity to UV rays from sunlight. However, this form of the disorder is typically not associated with neurological abnormalities, such as delayed development and hearing loss.

Most POLH gene variants prevent the production of any detectable DNA polymerase eta. A loss of this enzyme prevents cells from replicating damaged DNA effectively. Without this mechanism for tolerating DNA damage, errors resulting from exposure to UV rays accumulate in genes that control cell growth and division. These errors cause cells to grow too fast and in an uncontrolled way. As a result, people with XP-V have an increased risk of developing skin cancer in areas where the skin is exposed to sunlight.

Other Names for This Gene

• FLJ16395
• FLJ21978
• POLH_HUMAN
• polymerase (DNA directed), eta
• polymerase (DNA) eta
• RAD30
• RAD30 homolog A
• RAD30A
• xeroderma pigmentosum variant type protein
• XP-V
• XPV

Genomic Location

Normal Function

The XPA gene provides instructions for making a protein that is involved in repairing damaged DNA. DNA can be damaged by ultraviolet (UV) rays from sunlight and by toxic chemicals, radiation, and unstable molecules called free radicals.

DNA damage occurs frequently, but normal cells are usually able to fix it before it can cause problems. One of the major mechanisms that cells use to fix DNA is known as nucleotide excision repair (NER). As part of this repair mechanism, the XPA protein helps verify DNA damage and stabilize the DNA as it is repaired. The XPA protein attaches (binds) to areas of damaged DNA, where it interacts with many other proteins as part of a large complex. Proteins in this complex unwind the section of DNA where the damage has occurred, snip out (excise) the abnormal section, and replace the damaged area with the correct DNA.

Health Conditions Related to Genetic Changes

Xeroderma pigmentosum

Many variants (also called mutations) in the XPA gene have been found to cause xeroderma pigmentosum. People with this condition have an extreme sensitivity to UV rays from sunlight. As a result, affected individuals have a high risk of sunlight-induced cancer and premature aging.

XPA gene variants are responsible for a very severe form of xeroderma pigmentosum that is more common in the Japanese population than in other populations. Most Japanese people with xeroderma pigmentosum have the same XPA gene variant, which is written as IVS3AS, G>C. This variant prevents cells from producing any functional XPA protein. Other XPA gene variants, which have been reported in Japan and elsewhere, result in the production of a nonfunctional version of the XPA protein or greatly reduce the amount of this protein that is made in cells.

A partial or total loss of the XPA protein prevents cells from repairing DNA damage normally. As damage builds up in DNA, cells malfunction and eventually become cancerous or die. These problems with DNA repair cause people with xeroderma pigmentosum to be extremely sensitive to UV rays. When UV rays damage genes that control cell growth and division, cells can grow too fast and in an uncontrolled way. This uncontrolled cell growth can lead to cancer. In people with xeroderma pigmentosum, these cancers occur most frequently in areas of the body that are exposed to the sun, such as the skin and eyes.

When xeroderma pigmentosum is caused by XPA gene variants, it is often associated with progressive neurological abnormalities. These nervous system problems include hearing loss, poor coordination, difficulty walking, movement problems, loss of intellectual function, difficulty swallowing and talking, and seizures. The neurological abnormalities are thought to result from a buildup of DNA damage, although the brain is not exposed to UV rays. Researchers suspect that other factors damage DNA in nerve cells. It is unclear why some people with xeroderma pigmentosum develop neurological abnormalities and others do not.

Other Names for This Gene

• xeroderma pigmentosum, complementation group A
• XP1
• XPA_HUMAN
• XPAC

Genomic Location

Normal Function

The XPC gene provides instructions for making a protein that is involved in repairing damaged DNA. DNA can be damaged by ultraviolet (UV) rays from sunlight and by toxic chemicals, radiation, and unstable molecules called free radicals.

DNA damage occurs frequently, but normal cells are usually able to fix it before it can cause problems. One of the major mechanisms that cells use to fix DNA is known as nucleotide excision repair (NER). The XPC protein starts this repair process by detecting DNA damage. Then a group (complex) of other proteins unwind the section of DNA where the damage has occurred, snip out (excise) the abnormal section, and replace the damaged area with the correct DNA.

Studies suggest that the XPC protein may have additional roles in DNA repair and in other cell activities. Less is known about these proposed functions of the XPC protein.

Health Conditions Related to Genetic Changes

Xeroderma pigmentosum

Many variants (also called mutations) in the XPC gene have been found to cause xeroderma pigmentosum. People with this condition have an extreme sensitivity to UV rays from sunlight. As a result, affected individuals have a high risk of sunlight-induced cancer and premature aging.

Variants in the XPC gene are the most common cause of this disorder in the United States and Europe. Most XPC gene variants prevent the production of any XPC protein. A loss of this protein keeps cells from repairing DNA damage normally. As damage builds up in DNA, cells malfunction and eventually become cancerous or die.

These problems with DNA repair cause people with xeroderma pigmentosum to be extremely sensitive to UV rays. When UV rays damage genes that control cell growth and division, cells can grow too fast and in an uncontrolled way. This uncontrolled cell growth can lead to cancer. In people with xeroderma pigmentosum, cancers occur most frequently in areas of the body that are exposed to the sun, such as the skin and eyes.

Individuals with xeroderma pigmentosum caused by variants in the XPC gene may have an increased risk of early menopause compared to the general population. Unlike some of the other forms of xeroderma pigmentosum, when the disorder is caused by variants in the XPC gene it is generally not associated with neurological abnormalities (such as delayed development and hearing loss). It is unclear why some people with xeroderma pigmentosum develop neurological abnormalities and others do not.

Other Names for This Gene

• RAD4
• Xeroderma pigmentosum group C-complementing protein
• xeroderma pigmentosum, complementation group C
• XP3
• XPC_HUMAN
• XPCC

Genomic Location

• Skin and eyes extra sensitive to ultraviolet radiation
• Severe sunburn with blistering
• Patches of dark or light colored skin (hyper- or hypopigmentation)
• Dry skin and eyes
• Corneal clouding
• Corneal swelling
• Microcephaly
• Hearing loss
• Progressive mental impairment

• Dermatologist
• Ophthalmologist
• Oncologist
• Neurologist
• Audiologist
• Otolaryngologist
• Medical geneticist