What is pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) also known as Gronblad-Strandberg syndrome, is the name given to a group of inherited connective tissue disorders that causes calcium and other minerals to accumulate in the elastic fibers of the skin, eyes, and blood vessels, and less frequently in other areas such as the digestive tract. Elastic fibers are a component of connective tissue, which provides strength and flexibility to structures throughout the body. People with pseudoxanthoma elasticum may have yellowish bumps called papules on the skin of their necks, underarms, in the groin area and other areas of skin that touch when a joint bends (flexor areas). They may also have abnormalities in the eyes, such as a change in the pigmented cells of the retina (the light-sensitive layer of cells at the back of the eye) known as peau d’orange. Another eye abnormality known as angioid streaks occurs when tiny breaks form in the layer of tissue under the retina called Bruch’s membrane. Bleeding and scarring of the retina may also occur, which can cause vision loss. Pseudoxanthoma elasticum may also cause the following symptoms: periodic weakness in the legs (claudication); or bleeding in the gastrointestinal tract, particularly the stomach.

Mineralization of the blood vessels that carry blood from the heart to the rest of the body (arteries) may cause other signs and symptoms of pseudoxanthoma elasticum. For example, people with this condition can develop narrowing of the arteries (arteriosclerosis) or a condition called claudication that is characterized by cramping and pain during exercise due to decreased blood flow to the arms and legs. Rarely, bleeding from blood vessels in the digestive tract may also occur.

Pseudoxanthoma elasticum affects approximately 1 in 25,000 to 1 in 100,000 people worldwide ¹. The average age of onset is 13 years; however, ages can vary between infancy and the seventh decade of life or older, with a peak in the number of new cases from ages 10-15 years. For reasons that are unclear, pseudoxanthoma elasticum is diagnosed twice as frequently in females as in males ².

A clinical diagnosis of pseudoxanthoma elasticum can be made when an individual is found to have both the characteristic eye findings and yellow bumps on the skin. ABCC6 (also known as multidrug resistance–associated protein 6 [MRP6]) is the only gene known to be associated with this condition.

Currently, there is no treatment for pseudoxanthoma elasticum, but affected individuals may benefit from routine visits to an eye doctor (ophthalmologist) who specializes in retinal disorders, and by having regular physical examinations with their primary physician. A team of doctors in other specialties – including dermatology, cardiology, plastic surgery, vascular surgery, genetics, and nutrition – may also help with the management this condition. Individuals should be alert to changes in their vision and should inform their eye doctor of any such changes. Several therapies may be effective for slowing the reduction in vision in pseudoxanthoma elasticum. Surgery may help to reduce skin symptoms, gastrointestinal symptoms, or severe vascular symptoms in the legs.

Pseudoxanthoma elasticum causes

Pseudoxanthoma elasticum is an inherited disorder caused by changes (mutations) in the ABCC6 transporter gene (also known as multidrug resistance–associated protein 6 [MRP6]) ³. The ABCC6 gene provides instructions for making a protein called MRP6 (also known as the ABCC6 protein). This protein is found primarily in cells of the liver and kidneys, with small amounts in other tissues, including the skin, stomach, blood vessels, and eyes. ABCC6 is one of a group of genes that transport certain molecules back and forth across cell membranes. MRP6 (multidrug resistance-associated protein 6) is thought to transport certain substances across the cell membrane; however, the substances have not been identified but it is thought that they may play a role in keeping the elastic fibers found in certain body tissues healthy. It is unclear how a lack of properly functioning MRP6 protein leads to pseudoxanthoma elasticum. Some studies suggest that the MRP6 protein stimulates the release of a molecule called adenosine triphosphate (ATP) from cells through an unknown mechanism. ATP can be broken down into other molecules, including adenosine monophosphate (AMP) and pyrophosphate. Pyrophosphate helps control deposition of calcium and other minerals in the body. Other studies suggest that a substance transported by MRP6 is involved in the breakdown of ATP. This unidentified substance is thought to help prevent mineralization of tissues.

Mutations in the ABCC6 gene lead to an absent or nonfunctional MRP6 protein. This shortage may impair the release of ATP from cells. As a result, little pyrophosphate is produced, and calcium and other minerals accumulate in elastic fibers of the skin, eyes, blood vessels and other tissues affected by pseudoxanthoma elasticum. Alternatively, a lack of functioning MRP6 may impair the transport of a substance that would normally prevent mineralization, leading to the abnormal accumulation of calcium and other minerals characteristic of pseudoxanthoma elasticum.

Acquired pseudoxanthoma elasticum

There have been occasional reports of late onset or acquired pseudoxanthoma elasticum.

• Acquired pseudoxanthoma elasticum has been associated with the medication penicillamine.
• Some cases have followed liver transplantation.
• It has also been reported in patients with beta thalassaemia.

Pseudoxanthoma elasticum inheritance pattern

Pseudoxanthoma elasticum is inherited in an autosomal recessive manner, which means both copies of the gene in each cell have mutations. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal 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 abnormal gene and, therefore, 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 is the same for males and females.

In a few cases, autosomal dominant inheritance has been reported in patients with pseudoxanthoma elasticum, but it is not clear if the dominant pattern is truly dominant or if it has been reported because, by chance, one parent is an asymptomatic carrier of a mutated ABCC6 gene while the second parent has the disorder. In these cases of pseudoxanthoma elasticum, however, the parent without apparent symptoms has an ABCC6 gene mutation. The affected offspring inherits two altered genes, one from each parent. This appearance of autosomal dominant inheritance when the pattern is actually autosomal recessive is called pseudodominance.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

It is rare to see any history of autosomal recessive conditions within a family because if someone is a carrier for one of these conditions, they would have to have a child with someone who is also a carrier for the same condition. Autosomal recessive conditions are individually pretty rare, so the chance that you and your partner are carriers for the same recessive genetic condition are likely low. Even if both partners are a carrier for the same condition, there is only a 25% chance that they will both pass down the non-working copy of the gene to the baby, thus causing a genetic condition. This chance is the same with each pregnancy, no matter how many children they have with or without the condition.

• If both partners are carriers of the same abnormal gene, they may pass on either their normal gene or their abnormal gene to their child. This occurs randomly.
• Each child of parents who both carry the same abnormal gene therefore has a 25% (1 in 4) chance of inheriting a abnormal gene from both parents and being affected by the condition.
• This also means that there is a 75% ( 3 in 4) chance that a child will not be affected by the condition. This chance remains the same in every pregnancy and is the same for boys or girls.
• There is also a 50% (2 in 4) chance that the child will inherit just one copy of the abnormal gene from a parent. If this happens, then they will be healthy carriers like their parents.
• Lastly, there is a 25% (1 in 4) chance that the child will inherit both normal copies of the gene. In this case the child will not have the condition, and will not be a carrier.

These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

Figure 1 illustrates autosomal recessive inheritance. The example below shows what happens when both dad and mum is a carrier of the abnormal gene, there is only a 25% chance that they will both pass down the abnormal gene to the baby, thus causing a genetic condition.

Figure 1. Pseudoxanthoma elasticum autosomal recessive inheritance pattern

Since pseudoxanthoma elasticum may be present but undiagnosed in other family members, it is recommended that all immediate relatives be screened for pseudoxanthoma elasticum by both an ophthalmologist and a dermatologist. The ophthalmologist should look for peau d’orange and angioid streaks. If suspicious for pseudoxanthoma elasticum, the dermatologist should take biopsies from the neck, under the arm and inside the elbow of a person suspected of having pseudoxanthoma elasticum. These biopsies may be necessary even if the skin doesn’t show any visible lesions. Even with a negative biopsy, it is possible that other family members have pseudoxanthoma elasticum. pseudoxanthoma elasticum affects each individual with great variability. A blood test is available to determine whether a person carries the gene.

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Pseudoxanthoma elasticum symptoms

Pseudoxanthoma elasticum results in a variety of signs and symptoms that vary in their number, type, and severity from person to person. Certain effects of pseudoxanthoma elasticum can cause serious medical problems, while others have less impact. Effects may include: skin changes, changes in the retina of the eye that may result in significant loss of central vision, changes in the cardiovascular system that may involve calcification of arteries and decreased blood flow in the arms and legs, and/or changes in the gastrointestinal system that may lead to bleeding in the stomach or intestines. At present, there is no way to predict the exact progression of the disorder for a particular individual. Some people have no skin lesions; others have no vision loss. Many people do not experience gastrointestinal complications or cardiovascular difficulties. A few have no manifestations of pseudoxanthoma elasticum except for a positive skin biopsy or irregular streaks resembling a blood vessel (angioid) in the retina of the eye. The effects of pseudoxanthoma elasticum and its rate of progression seem to have no discernible pattern.

Skin lesions

The skin lesions of pseudoxanthoma elasticum are characteristic. They consist of small, yellowish bumps in rows or a lacy pattern, which may join to make large patches. The skin is soft, lax and slightly wrinkled. The patches may be slightly pebbly in appearance, which has been described as cobblestoned.

The areas of the body that are most affected are those that bend and flex. The common sites affected in pseudoxanthoma elasticum are the sides of the neck, below the collar bones, the armpits, abdomen, groins, perineum, thighs and and the skin behind the knees may be progressively affected, leading to loose folds in these areas. Similar changes may occur in the soft palate, inside the lips, and lining of the stomach, rectum and vagina. Some of these effects may be alleviated by reconstructive, or plastic, surgery.

These skin changes may develop in childhood but usually develop in early adulthood (before the age of 30). They may, in some cases, first appear in old age. Once they appear, they usually persist unchanged indefinitely.

It is possible to have pseudoxanthoma elasticum and not have any apparent skin lesions. In some individuals, careful examination of the skin by a dermatologist does not reveal any visible sign of lesions, but a positive biopsy indicates the diagnosis of pseudoxanthoma elasticum. Since the identification of mutations in the ABCC6 transporter gene as the cause of pseudoxanthoma elasticum, analysis of blood can be performed in research centers to confirm the presence or absence of mutations.

Heart and blood vessels

The connective tissue of arteries of the heart and throughout the body are abnormal in pseudoxanthoma elasticum, this may lead to stroke, heart pain (angina) and cardiomyopathy (heart muscle disease). Because pseudoxanthoma elasticum can cause mineralization and narrowing of blood vessels, affected individuals may experience cramping in the legs when they are walking, due to decreased blood flow. This decreased flow of blood is called intermittent claudication. Decreased flow of blood to the arms and legs may mean that one’s pulse can no longer be felt in the wrists or feet. Some clinicians believe that high blood pressure (hypertension) and mitral valve prolapse may be more common among people with pseudoxanthoma elasticum than in the general population. Mitral valve prolapse occurs in about 5–8% of cases. Individuals with pseudoxanthoma elasticum should make periodic visits to their physician for monitoring of blood pressure, cholesterol, and pulses in the arms and legs. A heart-healthy lifestyle is recommended, with low-fat foods and plenty of exercise. Consistent exercise may decrease the effects of pseudoxanthoma elasticum on the blood vessels. Maintaining normal weight may also be beneficial. Smoking should be avoided.

Eye

Pseudoxanthoma elasticum affects the retina of the eye. The first changes, visible only during an ophthalmologic examination, are called “peau d’orange” because the retina begins to resemble the skin of an orange. This does not affect vision and neither do characteristic irregular vascular lesions, called angioid streaks that develop later. These streaks occur when mineralization of the highly elastic membrane behind the retina, called Bruch’s membrane, leads to cracking. Small blood vessels beneath this layer take advantage of these breaks in the membrane and grow through the membrane. This is called neovascularization. Sometimes, these blood vessels leak and bleed. This bleeding results in the loss of central vision. They usually appear between 20 and 40 years of age. Angioid streaks may lead to progressive visual failure and occasionally blindness. While people with pseudoxanthoma elasticum may lose so much vision that they become legally blind, almost all people with pseudoxanthoma elasticum continue to have peripheral vision.

People who have pseudoxanthoma elasticum can use a tool called an Amsler grid to monitor their central vision. If there is swelling or bleeding in the center of the retina, this may cause the intersecting lines of the Amsler grid to appear distorted. A retinal specialist can instruct a patient in the use of an Amsler grid.

Gastrointestinal system

Uncommonly, pseudoxanthoma elasticum may cause gastrointestinal bleeding. This is sometimes not recognized immediately and can be life-threatening. Little is known about the gastrointestinal effects of pseudoxanthoma elasticum, except that the bleeding is usually widespread in the stomach and/or intestines. In a few patients, this bleeding has been mistaken for ulcers. A person with pseudoxanthoma elasticum experiencing any gastrointestinal difficulty should be sure to tell the attending physician that he or she has pseudoxanthoma elasticum. Some physicians recommend that affected individuals avoid non-steroidal, anti-inflammatory medications, such as aspirin, ibuprofen, and naproxen.

Obstetric risk associated with pseudoxanthoma elasticum

Patients with pseudoxanthoma elasticum have an increased risk of miscarriage in the first three months of pregnancy. Stretch marks develop during pregnancy in virtually all patients.

Pseudoxanthoma elasticum diagnosis

Changes in the skin are usually the earliest sign of pseudoxanthoma elasticum and lead to the definitive diagnosis. Although the signs of pseudoxanthoma elasticum and the age of onset vary considerably, many people first notice an unusual appearance of their skin, typically on the sides or back of the neck. Small bumps, called lesions, may appear. Some individuals have described these as looking like a rash or an unwashed neck. Usually, a small biopsy of a lesion is done to confirm the diagnosis of pseudoxanthoma elasticum. This biopsy requires that a very small piece of skin, the size of a pencil eraser, be taken from the neck, underarm, and/or inside the elbow. The dermatologist sends this sample to a laboratory where a special stain, called a von Kossa stain, is used to detect calcium in the tissue. The pathology of pseudoxanthoma elasticum is characteristic.

Sometimes, changes in the eye are the first noticeable sign of pseudoxanthoma elasticum. Early changes in the eye are visible only during an ophthalmological examination. Later symptoms can include loss of central vision. Some people are first diagnosed with pseudoxanthoma elasticum when they notice distortion of their vision.

ABCC6 (formerly known as MRP6), which encodes the ATP-binding cassette protein multidrug resistance-associated protein 6, is the only gene known to be associated with pseudoxanthoma elasticum. Molecular genetic testing detects a pathogenic variant in one allele in almost all affected individuals and in both alleles in close to 90%. Once the ABCC6 mutations that cause pseudoxanthoma elasticum in a family are identified, unaffected relatives may be tested for the familial mutations to determine whether or not they are carriers.

Imaging studies are conducted to determine its affect on blood vessels and the heart.

Pseudoxanthoma elasticum treatment

Unfortunately, there is no cure for pseudoxanthoma elasticum. The most important aspect of treatment is to ensure that complications from blood vessel involvement are prevented or dealt with speedily by the appropriate specialist. A team of medical specialists (for example, an ophthalmologist, dermatologist, gastroenterologist, and primary care physician) may be needed to help manage pseudoxanthoma elasticum and its effects. People affected by pseudoxanthoma elasticum should be sure that all the health care professionals they visit are well-informed about the possible ramifications of pseudoxanthoma elasticum. Regular follow-up with a specialist vascular surgeon and/or cardiologist is recommended.

• There is currently no effective treatment for the skin lesions.
• Restriction of dietary calcium has been tried with some benefit, but this is controversial.
• Laser photocoagulation may be helpful in preventing further bleeding at the back of the eye.
• As there is a risk of passing pseudoxanthoma elasticum on to the next generation, genetic counseling may be helpful.

Suggested management of patients with pseudoxanthoma elasticum ⁴:

Eye examination

• 6–12 monthly check by ophthalmologist
• Regular use of Amsler grid by patients to monitor central vision (chart consisting of evenly spaced horizontal and vertical lines with a small dot in the centre of the grid)

Cardiology assessment

• Yearly check of blood pressure, peripheral pulses, and for heart murmurs
• If abnormal findings, refer to cardiologist for further investigations, e.g. echocardiogram

Laboratory tests

• In children low threshold/in adults 6–12 monthly
• Blood count, ferritin, serum lipids, urinalysis

Medications

• Avoidance of non-steroidal anti-inflammatory analgesics and warfarin
• Selective use of aspirin for prevention of thromboembolic events in high risk patients
• Avoidance of oestrogens, e.g. oral contraceptive pill, HRT

Diet

• Avoid high cholesterol
• Moderate calcium intake

Lifestyle

• Regular exercise but avoid contact sports and straining
• Weight control
• Avoidance of smoking
• Genetic counseling

A dermatologist will most likely be the physician to make the definitive diagnosis and offer advice on reconstructive surgery, if that is of interest to the patient. An ophthalmologist will dilate the eyes to look for peau d’orange and angioid streaks. If angioid streaks are found, it may be wise to consult a retinal specialist. A cardiologist can perform a baseline EKG and sonogram test.

In cases that involve retinal hemorrhage, laser treatment or injectable medications have been helpful for some people. However, not everyone can benefit from these treatments. In some cases, laser surgery does not restore vision. In others, scarring from both the bleeding and the laser surgery has made vision worse. A variety of visual aids can be provided to help compensate for loss of vision. A low vision clinic can be helpful in this regard.

It is generally thought that people affected by pseudoxanthoma elasticum should avoid activities that might cause direct trauma to the eyes. Activities that increase pressure in the eyes, such as weight lifting, should also be avoided.

Pseudoxanthoma elasticum life expectancy

The prognosis of pseudoxanthoma elasticum largely depends on the extent of extracutaneous organ involvement. Patients typically have a normal life expectancy, but acute gastrointestinal hemorrhage, heart attack (myocardial infarction) or cerebral hemorrhage may be fatal.

Spontaneous resolution of skin changes has been reported, but is exceedingly rare ³.

Early diagnosis and the institution of prophylactic measures is paramount.

References

1. Pseudoxanthoma elasticum. https://ghr.nlm.nih.gov/condition/pseudoxanthoma-elasticum
2. Bercovitch L, Terry P. Pseudoxanthoma elasticum 2004. J Am Acad Dermatol. 2004 Jul. 51(1 Suppl):S13-4.
3. Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A. Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. J Med Genet. 2005 Dec. 42(12):881-92.
4. Laube S, Moss C. Pseudoxanthoma elasticum. Archives of Disease in Childhood 2005;90:754-756. https://adc.bmj.com/content/90/7/754