What is Xeroderma Pigmentosum?
Xeroderma pigmentosum (XP) is a very rare genetic skin disease caused by defects in the process by which damaged DNA is repaired. This disease is known for causing extreme sensitivity to sunlight, changes in skin pigment, growth of skin cancer and sometimes even the breakdown of the nervous system. In the United States, only about 1 in a million people have it, but in Japan, the rate is much higher, with 45 in a million.[1]
The disease was first identified by dermatologist Moriz Kaposi in 1874. Kaposi noticed patients with dry skin, noticeable skin color changes, and many skin tumors that formed when they were still young. Later research emphasized how exposure to sunlight played an important part in XP. Notably, Dr. James Cleaver performed studies in the 1960s that revealed people with XP had a defective DNA repair system when exposed to ultraviolet (UV) light, a type of light that’s present in sunlight. He also found that XP patients with nervous system issues had even worse DNA repair abilities after UV exposure compared to XP patients without nervous system issues. [2][3] These studies significantly improved our understanding of how exposure to UV light, DNA damage and repair, and the growth of cancer are connected.
What Causes Xeroderma Pigmentosum?
Xeroderma pigmentosum is a condition that arises from a mutation affecting a system in our body that fixes damage to DNA caused by ultraviolet (UV) light. This system is known as nucleotide excision repair and its function is to correct DNA damage such as pyrimidine dimers and 6-4 photoproducts, which are essentially defects in DNA caused by UV exposure. The problem in xeroderma pigmentosum is that DNA damage, caused by sun exposure, isn’t properly repaired, leading to the symptoms of the condition. There are eight different kinds of mutations linked to different types and symptoms of xeroderma pigmentosum, labeled as XP subtypes A through G and XP variants..
For example, the most common subtype in the United States involves a mutation in a gene known as XPC. This gene is responsible for making a molecule (an endonuclease) that detects and repairs damaged DNA. Because of the mutation, this molecule doesn’t work properly, resulting in extreme sun sensitivity and a high risk of skin and mucous membrane tumors. Unlike some xeroderma pigmentosum subtypes, people with an XPC mutation don’t show neurological abnormalities.
In contrast, the most common subtype in Japan is caused by a mutation in the XPA gene. This gene makes DNA damage binding protein 1 (DDB1), which helps with DNA repair. Patients with this subtype can exhibit both skin-related and neurological symptoms.
There are five other genes (XPB, XPD, XPE, XPF, and XPG) associated with rarer subtypes of the disease, all coding for different proteins involved in DNA repair. Mutations in each of these genes can lead to variations in the symptoms and medical conditions related to xeroderma pigmentosum.
About 30% of all cases are due to a mutation in the XPV gene, leading to what’s called a variant subtype of xeroderma pigmentosum. This mutation doesn’t affect nucleotide excision repair directly but is involved in a later stage of DNA repair called postreplication repair. People with this subtype don’t have any neurological symptoms.
Risk Factors and Frequency for Xeroderma Pigmentosum
Xeroderma pigmentosum is an uncommon skin disease that is inherited and affects about one per million people in the United States. This disorder is more prevalent in Japan with 45 cases per million, while Western Europe sees around 2.3 cases per million. The condition is also found in North Africa and the Middle East. Of the types of xeroderma pigmentosum, XPC is the kind we see most often in the United States, Africa, and Europe. In Japan, the XPA type is most common. The XP variant makes up about 30% of all xeroderma pigmentosum cases, and XPA, XPC, and XPV combined cover around 75% of worldwide cases. This skin disorder affects both men and women equally.
Typically, affected individuals display severe sensitivity to the sun early in their lives, even experiencing severe sunburns from minimal sun exposure. Babies may show signs of redness and blisters on areas of their skin that have been exposed to the sun. These individuals often exhibit changes in skin pigmentation before they turn two. On average, they may develop their first skin cancer that’s non-melanoma around the age of nine, and the first malignant melanoma around the age of 22.
Signs and Symptoms of Xeroderma Pigmentosum
Xeroderma pigmentosum is a disease that makes the skin incredibly sensitive to the sun. It comes in various forms, and each one may show different symptoms or physical signs. Typically, people with this disease experience changes in their skin due to their heightened sun sensitivity. They may also experience symptoms related to their mouth, eyes, and/or nervous system. Usually, the parents of a person with xeroderma pigmentosum don’t have the disease themselves, as it is passed down in a way that requires both parents to carry the gene, even if they don’t show symptoms themselves. If parents are closely related by blood, the chance of their child having the disease increases.
Children with xeroderma pigmentosum are born with normal skin, but they may start showing signs of the disease, such as changes in skin color and other abnormalities, usually before they turn two, especially with more exposure to the sun. Common skin symptoms include patches of both lighter and darker skin on the face, neck, chest, and upper parts of the hands and arms. They might also show signs of premature skin aging, like thinning, dryness, and wrinkling.
The average age for developing the first non-melanoma skin cancer is around 9. Common skin cancers include basal cell carcinomas, which appear as pink or dark bumps with a shiny surface and possibly a central sore, and squamous cell carcinomas, which look like a scaly, red spot.
- Patches of both lighter and darker skins
- Thinning, dryness, and wrinkling
- Basal cell carcinomas
- Squamous cell carcinomas
People with this disease may also experience more severe eye symptoms over time, like sensitivity to light or dryness. They may develop darker skin coloration on their eyelids and/or the inner part of their eye, and they may have visibly dilated blood vessels in their eyes. In some cases, they may see changes in their eyelashes, an abnormal blood vessel growth on the surface of their eye, or a cloudy area on their eye. They can also develop both non-cancerous and cancerous tumors in and around their eyes.
Two subtypes of the disease, XPA and XPD, also show progressive neurological symptoms. These symptoms, which affect about one in five patients with the disease, worsen over time, regardless of their sun exposure. These symptoms are due to the loss of nerve cells, shrinkage of brain tissue, and enlargement of the fluid-filled spaces within the brain. Symptoms might include difficulties with neurological development and/or hearing loss due to damage to the nerves. Patients might also have a smaller than normal head size, decreased reflexes, muscle stiffness and weakness, or trouble with coordination and balance.
Testing for Xeroderma Pigmentosum
Even though there are no standard lab tests or scans that can definitely confirm if you have xeroderma pigmentosum, there are two specific techniques that can provide a confirmation: unscheduled DNA synthesis techniques and gene sequencing.
Unscheduled DNA synthesis is a bit like a DNA damage test. In this procedure, doctors expose small amounts of your skin cells to UV light and then examine how well they can fix any DNA damage. The DNA repair that takes place after UV light exposure differs from the normal cell growth and replication process. This ‘out-of-schedule’ DNA repair process is tracked by calculating the number of building blocks (nucleotides) that get added into the DNA. This is typically accomplished using one of three methods: a fluorescence test, an autoradiography test, or a liquid scintillation counting test. If your cells show a low level of DNA repair (unscheduled DNA synthesis) post exposure to UV light, it would confirm the presence of xeroderma pigmentosum.
In cases of a different type of xeroderma pigmentosum called the variant subtype, skin cells don’t show drastic sensitivity to sun exposure like in other types. To successfully confirm diagnosis in the variant type, skin cells from patients are exposed to caffeine for many days after being subjected to UV light, the response of these skin cells is then compared to normal skin cells.
For unborn babies, the presence of xeroderma pigmentosum can be confirmed. This is done through testing the unborn baby’s amniotic fluid cells using unscheduled DNA synthesis or gene sequencing.
Once the disorder is confirmed, further tests can be done to identify the exact gene mutation related to your specific case. One such method involves fusing patient’s skin cells with each subtype of xeroderma pigmentosum to see how they react. If the fused cells don’t regain their normal ability of DNA repair post UV exposure, this helps in identifying the specific type of xeroderma pigmentosum.
Another technique is gene sequencing, which maps out the blueprint of your genes to identify the exact mutated gene and subtype of the disorder.
If you’ve been diagnosed with xeroderma pigmentosum, you may need to have several skin biopsies done over your lifetime to check for skin cancer. The samples taken during these biopsies will be examined under a microscope to confirm the diagnosis. If you have symptoms that point towards neurological issues, a neurologist might also perform an electroencephalography test that checks for abnormal patterns of electrical activity in your brain.
Treatment Options for Xeroderma Pigmentosum
Xeroderma pigmentosum is a condition where the skin is sensitive to sunlight and susceptible to developing skin cancer. The main aim of managing this condition is to reduce the chance of developing skin cancer, catch and treat any cancers early, and enhance the patient’s quality of life as much as possible.
The most effective way to reduce the risk of skin cancer in these patients is to avoid sunlight and protect the skin as much as possible. Patients and carers need to fully understand all the ways to minimize exposure to UV radiation. This includes staying indoors during daylight hours, and if outside, applying sunscreen every two hours. Using lip balm with sunscreen, wearing sun-protective clothing with long sleeves & pants, a hat, sunglasses with side shields, and covering all windows with UV-blocking film can also help.
Keeping in mind that sunlight is a major source of Vitamin D, patients who avoid sun exposure should take vitamin D supplements regularly and eat foods rich in vitamin D, like fish, eggs, mushrooms and fortified foods.
Regular skin checks should be performed by a dermatologist and also by caregivers at home. The patient should visit a dermatologist at least every three months for a thorough skin examination. Different types of skin changes and lesions should be treated as early as possible to prevent progression to skin cancer.
In a small study, it was found that high doses of an oral medication known as isotretinoin significantly reduced the number of skin cancers in patients with this condition. However, this medication also has many side effects including dry mouth, dry eyes, and abnormal liver function among others.
Xeroderma pigmentosum can also affect the eyes, with symptoms such as sensitivity to light and redness of the eyes. Patients could also develop eye conditions including cataracts, inflammation of the eye and eyelids, pigment changes, scarring, and even skin lesions or cancers on the eyelids. Regular eye exams by an ophthalmologist are recommended to manage these problems.
Lastly, if there are any neurological symptoms (related to the nervous system), the patient should be referred to a neurologist. Unfortunately, avoiding sunlight doesn’t slow down the progression of these neurological symptoms.
What else can Xeroderma Pigmentosum be?
In diagnosing xeroderma pigmentosum (XP), a skin condition, several other conditions with similar symptoms are taken into consideration. These conditions give valuable insights into the various proteins and genes involved in the repair of DNA.
- Cockayne syndrome: This syndrome is caused by a mutation in either the CSA or CSB genes and results in problems with DNA repair. Its symptoms include small head (microcephaly), eye-related issues, distinctive ear shapes, hearing loss, curved spine (kyphoscoliosis), and problems with movement. While people with this condition can also have light sensitivity, they do not have the same increased risk of skin cancers or changes in skin color as seen in XP.
- Cockayne-XP overlap (CS-XP): This conditions shares features of both Cockayne syndrome and xeroderma pigmentosum. It’s characterized by light sensitivity, neurological degeneration, stiff joints, short stature, and skin conditions similar to XP. After achieving some initial development milestones, these patients may stop progressing and eventually decline. This syndrome is very rare, with only 43 cases reported in medical literature.
- Trichothiodystrophy (TTD): TTD often presents with light sensitivity, brittle hair, skin scaling (ichthyosis), short stature, reduced fertility, and developmental delay. However, unlike XP patients, those with TTD are not at an increased risk of skin cancers or color changes. There have been reports of a rare overlap syndrome between trichothiodystrophy and xeroderma pigmentosum (TTD-XP).
- Cerebro-oculofacial-skeletal syndrome (COFS): This condition also has overlapping features with xeroderma pigmentosum. Symptoms include distinctive facial features, light sensitivity, small head, developmental delay, congenital cataracts, and stiff joints.
These alternatives are always taken into account to ensure the correct diagnosis and treatment.
What to expect with Xeroderma Pigmentosum
People with a rare skin condition known as xeroderma pigmentosum usually show symptoms before they’re two-years-old, these typically involve severe sensitivity to sunlight which can cause skin redness and blisters even after minimal exposure to the sun. Over time, the skin will continue to change due to sun exposure, causing pigment changes, the development of small, dilated blood vessels or “spider veins” (telangiectasias), and rough, scaly patches (actinic keratoses).
Around the age of nine, those with xeroderma pigmentosum may start developing their first non-melanoma skin cancer. It’s possible for these individuals to develop dozens to hundreds of these skin cancers annually. Unfortunately, they are at a far greater risk (over 10,000 times) of developing non-melanoma skin cancer compared to the general population. Also, they are at a significantly increased (over 2000 times) risk of developing malignant melanoma, a more severe type of skin cancer, typically around 22 years of age.
Regular and thorough skin exams by a dermatologist are crucial for these individuals, along with prompt treatment of any pre-cancerous lesions and skin malignancies that are found.
The life expectancy of someone with xeroderma pigmentosum can vary depending on the subtype of the condition. Those who experience neurological symptoms usually live a shorter life compared to those with the condition without neurological issues. Specifically, the median age of death in patients without neurological issues is about 37 years old, while it’s about 29 years old for those with neurological issues. Individuals with a certain subtype, known as the ‘XP variant,’ tend to live longer compared to those with other subtypes. While skin cancer is the most common cause of death among these patients, neurodegeneration – the progressive loss of structure or function of neurons, including their death – is the second most common cause.
Unfortunately, these individuals are also at a higher risk of developing cancer in other body parts, such as the front part of the tongue or the surface of the eye. Moreover, if they smoke, they’re at a notably higher risk of developing lung cancer. Lastly, they’re over 50 times more likely to develop tumors of the central nervous system, which includes conditions like spinal cord astrocytoma, schwannoma, medulloblastoma, and glioblastoma.
Possible Complications When Diagnosed with Xeroderma Pigmentosum
Xeroderma pigmentosum, a health condition we previously discussed, can cause many complications. For instance, patients usually develop their first non-melanoma skin cancer around the age of 9. They can have anywhere from dozens to hundreds of these cancers each year. Those with xeroderma pigmentosum are at an incredibly high risk, more than 10,000 times the average, of developing non-melanoma skin cancer.
They also get their first malignant melanoma, a more dangerous type of skin cancer, around the age of 22. Their risk for this is also significantly higher than for the average person – over 2,000 times as much.
Typically, someone with xeroderma pigmentosum who doesn’t also have neurodegeneration can expect to live until about age 37. If they do have neurodegeneration, their lifespan is generally shorter, around 29 years. The most common cause of death for someone with this condition is either metastatic malignant melanoma (a type of skin cancer that spreads to other parts of the body) or invasive squamous cell carcinoma (another type of skin cancer). Neurodegeneration is the second most common cause of death.
Summary of Risks:
- First non-melanoma skin cancer usually occurs at age 9
- Can have dozens to hundreds of non-melanoma skin cancers per year
- Risk of non-melanoma skin cancer is over 10,000 times the average
- First malignant melanoma, a dangerous type of skin cancer, usually happens around age 22
- Risk for malignant melanoma is over 2,000 times the average
- Average life expectancy without neurodegeneration is about 37 years
- Average life expectancy with neurodegeneration is around 29 years
- Most common cause of death is skin cancer that’s spread or invasive skin cancer
- Second most common cause of death is neurodegeneration
Preventing Xeroderma Pigmentosum
People with a high risk of developing cancerous tumors, as well as their caregivers, should be properly informed and frequently reminded about various steps necessary to lower the chance of these tumors forming, and to speed up their detection and treatment if they do.
Sunlight avoidance and protection is the best way to reduce the occurrence of these dangerous tumors in patients with XP, a rare skin condition. It’s important that patients and their caregivers understand every tactic to limit exposure to harmful UV (ultraviolet) rays. Patients should try not to leave their homes during daylight hours. If they must go out, they should protect themselves head-to-toe with sunscreen. Sunscreen for all skin types needs to be applied every two hours. Also, they should use lip balm containing sunscreen. Patients are advised to wear clothes that shield their skin from the sun, such as long sleeve shirts, pants, hats, and sunglasses with side protector. UV-blocking films should be used to cover windows at home, in the car, and at school to keep out harmful rays. Exposures to certain types of lights like fluorescent, metal halide, and halogen lights that give off UV rays should also be avoided.
Regular total body checkups for skin abnormalities should be carried out by a skin specialist (dermatologist) as well as by caregivers. A visit to a dermatologist at least every three months throughout the patient’s lifetime is recommended. Caregivers should do daily checks of skin at home and be informed of any changes that need the doctor’s immediate attention.
Individuals with XP who smoke are also at a higher risk of developing lung cancer compared to the average person. Therefore, they should be advised to avoid or quit smoking.
Patients and their caregivers should also be directed towards support groups for XP, so they can connect with others who are dealing with the same condition.
