All About Xeroderma Pigmentosum And Its Genetics

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What Is Xeroderma Pigmentosum And What Are Its Symptoms?

Xeroderma pigmentosum (XP) is a genetic disorder which causes those who have it to be extremely sensitive to sunlight. This sensitivity leaves XP sufferers at high risk for cancer as their bodies have minimal or no ability to repair the damage made to their skin and eyes that is caused by ultraviolet light from the sun.

Many of those who have XP are prone to developing blisters and a severe sunburn that lasts for up to several weeks after even a very short exposure to the sun. Further, those who have XP typically develop many freckles, sometimes all over their bodies, at a very young age. Other skin problems that usually appear include abnormal dark spots, excessive dryness, thin skin, and rough growths, which are known as solar keratoses.

Eye problems that XP sufferers frequently develop include photophobia (which is extreme eye sensitivity to sunlight and well-lit areas), keratitis (inflammation of the eye’s cornea), loss of eyelashes and even wasting of the eye lids in the worst cases.

Roughly 30 percent of those who have XP also have one or more symptoms that affect the nervous system. These problems include abnormal thickening and thinning of certain areas of the brain, progressive hearing loss, and progressive loss of the ability to perceive, speak, remember, and think.

Risk of cancer also is a serious concern. XP sufferers under the age of 20 are 1000 times more likely to develop skin cancer and cancer of the eye than are other individuals of the same age group. In fact, it is very common to see non-melanoma skin cancer prior to age 10 in XP patients.

What Is Known About The Genetics Of Xeroderma Pigmentosum?

Much is known about the genetic causes of XP, which is an autosomal recessive disorder in which DNA repair processes in cells are aberrantly disrupted. It is known that having mutations in both copies of any one of the following nine genes makes a person highly susceptible to developing XP:

  • XPA (encodes a DNA repair protein)
  • ERCC3 (otherwise known as XPB; encodes a DNA helicase that is involved in gene transcription)
  • XPC (encodes a protein that is involved in nucleotide excision repair)
  • ERCC2 (otherwise known as XPD; encodes a protein that is involved in gene transcription)
  • DDB2 (otherwise known as XPE; encodes a DNA binding protein)
  • ERCC4 (otherwise known as XPF (encodes a protein that is involved in nucleotide excision repair)
  • ERCC5 (otherwise known as XPG; encodes a protein that is involved in nucleotide excision repair)
  • ERCC1 (otherwise known as XPH_;_ encodes a protein that is involved in nucleotide excision repair)
  • POLH (otherwise known as XP-V; encodes a DNA polymerase protein)

It should be noted, however, that the XPA and XPC genes are those which are most commonly mutated in XP sufferers, as more than 50% of individuals who have XP exhibit mutations in one of these two genes. Mutations in ERCC2 (XPD) and POLH are seen in 15% and 21% of XP individuals, respectively. The remaining genes are rarely mutated in XP sufferers.

Because XP is an autosomal dominant disorder, carriers of a mutation in one of the above genes are asymptomatic. However, if a each member of a couple intent on having children has XP in their family history, it is advised that each one be tested for mutations in at least the genes that are most commonly mutated (XPA, XPC, XPD, and POLH). In instances in which each member is carrier of a mutation in a particular gene, it is recommended that the couple speak to a genetic counselor, who can offer advice regarding how to proceed.


K.H. Kraemer, Gene Reviews, University of Washington, Xeroderma Pigmentosum:

Patient Information Publications, Clinic Center, National Institutes of Health, Understanding Xeroderma Pigmentosum: