What is XP?

From: NORD (National Organisation for Rare Diseases)

Xeroderma pigmentosum (XP) is a rare inherited skin disorder characterized by a heightened sensitivity to the DNA damaging effects of ultraviolet radiation (UV). The main source of UV is the sun. The symptoms of XP can be seen in any sun-exposed area of the body. The effects are greatest on the skin, the eyelids and the surface of the eyes but the tip of the tongue may also be damaged. In addition, approximately 25% of XP patients also develop abnormalities of the nervous system manifesting as progressive neuro-degeneration with hearing loss. People with XP have a 10,000-fold increased risk for developing skin cancer including basal cell carcinoma, squamous cell carcinoma and melanoma. They also have a 2000-fold increased risk for cancer of the eye and surrounding ocular tissues. These symptoms appear early in life, typically before age 10 years.

XP is an autosomal recessive genetic condition caused by alterations (mutations) in nine different genes. Eight of the genes make up the nucleotide excision repair pathway (NER) that identities and repairs UV induced DNA damage. The ninth gene acts to bypass unrepaired damage.

Introduction

XP was first described in Vienna, Austria in 1870. In a dermatology textbook, Moriz Kaposi described a new disorder called xeroderma, which translates to “parchment skin.”

Signs & Symptoms

Individuals with XP are particularly sensitive to the DNA damaging effects of UV. Sources of UV include the sun, unshielded florescent light bulbs, mercury vapor lights and halogen light bulbs. Symptoms may differ from person to person, but typically impact the skin, eyes, and nervous system.

Cutaneous (Skin) Effects
Approximately half of XP patients develop blistering burns on sun exposed skin after minimal sun exposure (sometimes less than 10 minutes in the sun). These burns evolve over several days and may take greater than a week to heal. Sometimes these burns are so severe, child abuse is suspected. The other 50% of XP patients do not burn, but tan after sun exposure. However, both types of sun reactions result in the early onset of lentigos (freckling) of the skin.

Lentigos, are a patchy freckling of the skin, that appear before the age of two years in XP patients. The lentigos can be seen on all sun exposed skin, but are often seen first on the face. Lentigos are a sign of unrepaired UV damage in the skin. Repeated sun exposure also results in xerosis (dry, parchment-like skin) and poikiloderma a mixture of both hyper (increased) and hypo (decreased) skin pigmentation, skin atrophy (thinning of skin tissue), and telangiectasia (a widening of the small blood vessels, which produces red lines and patterns on the skin). In people who do not have XP, poikiloderma is typically seen in older adults, such as farmers or sailors, with many years of sun exposure.

For people with XP continuous repeated sun exposure has severe effects, resulting in the early development of precancerous skin spots (a.k.a., actinic keratosis) and skin cancers (see below).

Ocular (Eye) Effects
The eyelids and the surface of the eyes exposed to sunlight will usually be affected within the first decade of life.

Photophobia (light sensitivity, or pain upon seeing light) is common and is often noted in infancy or early childhood. The conjunctiva (the white portion of the eye) may show sunlight induced inflammation. People with XP also develop dry eye. Symptoms of dry eye include a feeling of ‘something being in the eye’, constant irritation and redness of the eye. Dry eye can also result in chronic inflammation and keratitis. Keratitis, or inflammation of the cornea (the clear outer dome of the eye) may also occur in response to sunlight. In severe cases, keratitis can result in corneal opacification (lack of transparency) and vascularization (an increase in blood vessel density). These combined effects may obscure vision, contributing to blindness. With repeated sun exposure, the lids of the eyes may atrophy (degenerate), eyelashes may fall out, leaving the eyes unprotected and contributing to vision loss.

Cancers of the eyelids, tissues surrounding the eyes, cornea and sclera (white part of the eye) can occur very early in life. Surgeries to remove ocular cancers can lead to lid abnormalities resulting in difficulty completely closing the eyes and vision loss. When cancers in or near the eye are large or invasive, the eye itself may need to be removed.

Neurologic (Nerve) Effects
Approximately 25% of patients with XP develop a progressive neurodegeneration. The degeneration can vary in time of onset and rate of progression. Symptoms of the neurodegeneration include: acquired microcephaly (a condition marked by smaller head size and structural changes in the brain), diminishing (or absent) deep tendon reflexes, progressive high-frequency sensorineural hearing loss (deafness caused by damage to the nerves of the inner ear), progressive cognitive impairment, spasticity (tightness/rigidity of the skeletal muscles), ataxia (poor muscle control and coordination), seizures, difficulty swallowing and/or vocal cord paralysis.

These issues are thought to arise due to the loss of nerve cells in the brain. The brains of XP patients with neurologic degeneration show atrophy (shrinkage) with marked dilation of the ventricles (fluid filled spaces in the middle of the brain). It is thought that accumulating unrepaired DNA damage in the brain cells results in their death, however, the source of this damage is has not been identified.

Neoplasias (Cancer)
Individuals with XP have a much greater chance of developing certain cancers. The risk of acquiring non-melanoma skin cancers (e.g., basal cell carcinoma and squamous cell carcinoma) is 10,000 times greater than in the general population in patients under 20 years of age. Median age of first non-melanoma cancer for XP patients is 9 years old, which is 50 years earlier than in the general population. For melanoma skin cancer, the risk is 2,000 times greater for those with XP. The median age of onset is 22 years, which is 30 years earlier than in the general population.

Oral cavity neoplasms, specifically squamous cell carcinoma of the tip of the tongue (a non-pigmented sun exposed area), is common especially in dark skinned patients. Internal cancers that have been reported in individuals with XP include: glioblastoma of the brain, astrocytoma of the spinal cord, and cancer of the lung in patients who smoke, and rarely, leukemia (cancer of the white blood cells). Cancers of the thyroid, uterus, breast, pancreas, stomach, kidney, and testicles, have also been reported.

Causes

Inheritance
XP is an autosomal recessive genetic disorder. Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. Recessive genetic disorders occur when an individual inherits two copies of a non-working gene for the same trait, one from each parent. If an individual inherits one normal gene and one non-working gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk for inheriting the disease is the same for males and females.

Parents who are blood relatives (consanguineous) have a higher chance than unrelated parents to both carry the same non-working gene, increasing the risk to have children with a recessive genetic disorder.

Relevant Genes
Chromosomes are located in the nucleus of human cells and carry the genetic information for each individual. Human body cells normally have 46 chromosomes arranged in 23 pairs. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q.” Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genes are small parts of a chromosome. There are 9 different genes that may be altered in patients with XP and include: the DDB2 (XP-E) gene, located on the short arm of chromosome 11 (11p11.2), the ERCC1 gene, located on the long arm of chromosome 19 (19q13.32), the ERCC2 (XP-D) gene, located on the long arm of chromosome 19 (19q13.32), the ERCC3 gene (XP-G), located on the long arm of chromosome 2 (2q14.3), the ERCC4 gene (XP-F), located on the short arm of chromosome 16 (16p13.12), the ERCC5 (XP-B) gene, located on the long arm of chromosome 13 (13q33.1), the POLHgene (XP-V or variant), located on the short arm of chromosome 6 (6p21.1), the XPAgene, located on the long arm of chromosome 9 (9q22.33), and the XPC gene, located on the short arm of chromosome 3 (3p25.1). The proteins resulting from normal expression of these genes are involved in DNA repair and serve to recognize damaged DNA, remove the damage and fill in the resulting gap.

Affected Populations

XP affects males and females in equal numbers. Some gene mutations associated with XP are more common in certain parts of the world; in these locations there is a higher prevalence of XP. In the United States and Europe, prevalence of XP is 1 in 1,000,000. In Japan, XP is much more common, affecting 1 in 22,000. Areas of North Africa (e.g., Tunisia, Algeria, Morocco, Libya, Egypt) and the Middle East (e.g., Turkey, Israel, Syria) also show an increased prevalence of XP.

 

Related Disorders

There are several genetically related disorders caused by mutations in genes in the nucleotide excision (NER) pathway. People with these diseases demonstrate very different symptoms despite having mutations in some of the same genes as XP patients. These conditions include Cockayne syndrome (CS), cerebro-oculo-facio-skeletal (COFS) syndrome, trichothiodystrophy (TTD), and UV-sensitive syndrome.

Cockayne syndrome is a rare form of dwarfism characterized by short stature, UV sensitivity, and prematurely aged appearance (progeria). Although prenatal growth is normal, developmental abnormalities usually appear within two years of life; height, weight, and head circumferences tend to fall below the 5th percentile, and death usually occurs within the first two decades. For more information on this disorder, choose “Cockayne syndrome” as your search term in the Rare Disease Database.

Cerebro-oculo-facio-skeletal syndrome (COFS) is a genetic neuro-degenerative disorder of the brain and spinal cord that begins before birth. The disorder is characterized by growth failure at birth, little or no neurological development, structural abnormalities of the eye, and fixed bending of the spine and joints. Abnormalities of the skull, face, limbs, and other parts of the body may also occur. COFS syndrome is inherited as an autosomal recessive genetic trait and is now considered to be part of the spectrum of disorders within Cockayne syndrome. For more information on this disorder, choose “cerebro oculo facio skeletal syndrome” as your search term in the Rare Disease Database.

Trichothiodystrophy (TTD) is a hereditary disorder characterized by short brittle hair that demonstrates alternating dark and light ‘tiger tail’ banding when examined through a polarized microscope. Symptoms may include photosensitivity, intellectual impairment, short stature, and microcephaly. Unlike, XP patients, TTD patients do not have an increased cancer risk. Individuals with TTD have a 20x increased risk of death before the age of 10 (typically due to infections). Patients with TTD tend to have complications during their gestations and exhibit neonatal abnormalities. For more information on this disorder, choose “trichothiodystrophy” as your search term in the Rare Disease Database.

UV-sensitive syndrome is a form of photosensitivity that does not involve pigmentary abnormalities or nervous system deficits. People with UV sensitive syndrome develop sun burns after very minimal sun exposure but do not have increased cancer risk.

In addition, there are patients who demonstrate combinations of XP with other NER disorders, most notably, xeroderma pigmentosum with Cockayne syndrome (XP/CS) and xeroderma pigmentosum with trichothiodystrophy (XP/TTD). There have been a few patients reported with cerebraloculofacioskeletal syndrome and trichothiodystrophy (COFS/TTD) and Cockayne syndrome and trichothiodystrophy (CS/TTD). Individuals with these ‘overlap’ syndromes show a mixture of the symptoms that are normally present in both of the disorders. For example, those with XP/CS show facial freckling (typical of XP), as well as short stature, sunken eyes and wasting (typical of CS). XP/CS differs from XP alone in that there is dysmyelination (defective structure/function of the myelin sheath) along with the neuronal degeneration typically seen in people with XP and neurologic disease.

 

Diagnosis

XP is typically first diagnosed on the basis of clinical symptoms (see “Signs & Symptoms”), many patients with XP do not have a past family history of the condition., (see “Causes”).

Molecular genetic testing for mutations in the XP genes is available to confirm the diagnosis.

 

Standard Therapies
Prevention
Rigorous sun (UV) protection is necessary beginning as soon as the diagnosis is suspected to prevent continued DNA damage and disease progression. Individuals with XP should avoid exposing the skin and eyes to ultraviolet (UV) radiation. This can be done by wearing protective clothing such as hats, hoods with UV blocking face shields, long sleeves, pants, and gloves. High sun-protective factor (SPF) sunscreens, UV-blocking glasses with side-shields, and long hair can also provide protection.

The XP patient’s surroundings (e.g., home, school, and work) should be tested for levels of UV using a UV light meter. The meter can help identify areas of increased UV and sources of damaging UV (e.g., from halogen, and unshielded florescent light bulbs and mercury vapor lamps) can be eliminated from the environment. Since UV can pass through glass, widows in homes, schools, work places and cars of XP patient should be treated with UV blocking film.

Vitamin D is an essential vitamin, which helps maintain healthy bones. Vitamin D is manufactured by the interaction of UV with the skin. Since people with XP avoid UV, oral dietary supplements may be taken as needed to avoid complications of inadequate vitamin D levels.

Certain carcinogens in cigarette smoke damage DNA in ways similar to UV and exposure to second hand cigarette smoke should be avoided. XP patients who have smoked cigarettes have developed lung cancers.

Dermatologic Care
The skin (including the scalp, lips, tongue, and eyelids) should be examined by a dermatologist every 6-12 months (or more often if necessary) to detect precancerous and cancerous lesions. Prompt removal of any skin cancers is necessary to prevent further growth or spread of the lesions. Affected individuals and guardians of children should be instructed in skin examination techniques to aid in the early detection of possible skin cancers.

Individuals should also undergo routine eye exams by an ophthalmologist. The eyelids should be examined for ectropion (drooping and sagging), entropion (inward rotation, which may cause eye irritation), and pterygia/pinguecula (benign growths on the surface of the eyes). The cornea, which covers the eye, should be assessed for clouding, and the eyes should be tested for dryness; in the Schirmer test, a filter paper is placed under the eyelids to measure absorption of tears. A dilated eye exam is important to assess for any changes in the retina (back of the eye).

Basic neurologic examinations including measuring the occipital frontal circumference (to determine the presence of microcephaly) and assessing for the presence of deep tendon reflexes, should be part of the routine care of an XP patient. Hearing exams should be done on a regular basis to assess for early onset hearing loss, which is an indicator of XP with neurologic disease. If hearing loss is detected, hearing aids can be very beneficial in correcting the deficits. If neurologic problems are identified, more in depth exams by a neurologist are indicated. In addition, MRIs can assess for changes that are commonly seen in the brains of XP patients who have neurodegeneration. XP patients who develop neurologic disease can have a peripheral neuropathy, which may be assessed by testing nerve conduction velocity (speed of electrical transmission) through the nerves of the arms and legs.

Treatment of Skin Cancers
Small, premalignant skin lesions, (e.g., actinic keratosis) can be treated by freezing with liquid nitrogen. For larger areas of damaged skin, topical creams such as 5-fluorouracil or imiquimod may be applied; dermatome shaving and dermabrasion have been used for larger areas of skin. Small skin cancers on the trunk and extremities can be treated with electrodessication and curettage, or surgical excision. Deeply invasive skin cancers or skin cancers on the face and areas that require tissue-sparing techniques can be treated with Mohs micrographic surgery. In severe cases, large portions of skin may be re-grafted (or replaced) with sun-protected skin. X-ray therapy can be used to treat inoperable or larger neoplasms or as adjuvant therapy to surgery. The oral retinoids isotretinoin or acitretin can be used to prevent new skin neoplasms, but have many side effects including: liver toxicity, elevated levels of cholesterol, calcification of the ligaments and tendons, and premature closure of the growing bone shafts. These retinoid drugs are known to cause birth defects and are contraindicated in pregnant women or women who are trying to become pregnant.

Treatment of XP Eye Abnormalities
Lubricating eye drops used frequently keep the cornea moist and protects against the inflammatory effects of dry eye. Soft contact lenses can be worn to protect against mechanical trauma caused by deformed eyelids. It is best to start with simpler treatments first.

Neoplasms of eyelids, conjunctiva, and cornea can be treated with surgery. In some cases, corneal transplantation has been attempted to correct UV induced ocular damage and corneal clouding. However, the transplants may not be successful due to immune rejection. Unfortunately, immunosuppressive drugs used to prevent immune rejection may lead to additional skin cancers.

Treatment of XP Neurologic Abnormalities
Neurologic abnormalities are associated with increased high frequency sensory-neural hearing loss. The hearing loss is progressive (gets worse over time) and can be treated with hearing aids. Cognitive delays can be seen in childhood and special education classes, physical and occupational therapies along with UV safe accommodations at school are very helpful for XP children. As they get older, people with XP neurologic disease also experience increasing ataxia, dysphagia (difficulty swallowing) and dysarthria (difficulty speaking) as the condition progresses. They may require wheel chairs, feeding tubes and long term nursing care.

Source: https://rarediseases.org/rare-diseases/xeroderma-pigmentosum/