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Pseudoxanthoma elasticum

This is part of Rare diseases.

Diagnosis: Pseudoxanthoma elasticum

Synonyms: PXE

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Publication date: 2014-12-10
Version: 2.1

ICD-10

Q82.8Q

The disease

Pseudoxanthoma elasticum (PXE) is an inherited disease in which the elastic tissues of the skin, the blood vessels, and the tissue lining the anterior surface of the eye, successively degenerate and calcify. This condition can cause loss of vision, impaired blood circulation in the limbs and also sometimes in the coronary arteries.

Skin abnormalities associated with the disease were first described in the 1890s. As areas of skin became yellow, it was first believed that this was caused by cholesterol accumulations and the areas were named xanthomas (defined areas of fatty deposits). When it became clear that the deposits consisted of calcified elastic fibres the name was changed to pseudo (false) xanthoma. In 1929 two Swedish physicians, ophthalmologist Ester Grönblad and dermatologist James Strandberg, concluded that changes in the eyes and blood vessels were symptoms of the same disease.

Occurrence

There is no definite information on how common pseudoxanthoma elasticum is in Sweden. International studies put the occurrence at between one and two per 100,000 inhabitants, the conclusion being that there are between 100 and 200 people with the disease in Sweden. In some people symptoms are mild and the condition may be undiagnosed. The disease is more common in women than men.

Cause

The cause is a mutation in gene ABCC6, located on the short arm of chromosome 16 (16p13.1). This gene controls the production of (codes for) a specific protein, MRP6 (multiple drug resistance-associated protein 6), which plays a role in the transport of substances, primarily through the membranes of liver and kidney cells.

The normal function of this protein has not yet been fully established. The mutation causes calcification (the formation of calcium deposits) of the elastic membranes of the skin, eyes and walls of blood vessels. This results in damage to the blood vessels, and causes the skin of the throat and skin folds to become yellow.

Heredity

The inheritance pattern of pseudoxanthoma elasticum is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. In each pregnancy with the same parents there is a 25 per cent risk that the child will inherit double copies of the mutated gene (one from each parent). In this case the child will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

In pseudoxanthoma elasticum a carrier with only one copy of the mutated gene may have only a mild form of the disorder.

Symptoms

At onset, the severity of the disease and the rate of its progression vary greatly. The first signs are often skin-related and may present at any time from early childhood to approximately thirty years of age. The diagnosis is usually made in adulthood.

Characteristic skin symptoms include small, raised yellow areas (one to three millimetres), which together form larger, palm-sized patches. They usually appear first on the sides of the throat, then symmetrically in the armpits, the flexure areas of the elbow, the navel, groin and backs of the knees. They do not cause itching or other symptoms, but they may be unsightly. With time the skin in these areas may become inelastic and form folds. In some cases there may be similar changes in the mucous membranes close to the body’s orifices.

Eye symptoms occur later, usually at between the ages of 20 and 40. An eye examination will reveal dark streaks (angioid streaks) in the back of the eye, forming an irregular pattern where the optic nerve enters the retina. The streaks are caused by tiny cracks in an elastic membrane behind the retina. They cause no symptoms, but these cracks are serious as new blood vessels can form in the damaged areas. These new blood vessels can cause the accumulation of fluid and haemorrhaging (bleeding), which can lead to severe loss of vision. This occurs most often after the ages of forty to forty-five. Sometimes retinal bleeding results from mild trauma to the head, for example a slight blow, and can result in serious loss of vision although seldom to blindness. Angioid streaks are also associated with other rare diseases including sickle cell anaemia, thalassemia and Paget disease. Separate information on thalassemia and sickle cell anaemia is available in the Swedish Rare Disease Database.

As well as increasing the risk of atherosclerosis, calcification in the walls of arteries can block the blood vessels and cause their fragile walls to break. It is primarily the arteries of the arms and legs which are damaged. One effect is that it can be difficult to feel the pulse in the wrists. Strenuous physical exercise may result in pain in the calf and thigh muscles, ceasing only when activity stops. This is called intermittent claudication (claudicatio intermittens).

Calcification occurs in the large blood vessels. Calcifications in the blood vessels of the heart may cause chest pains during periods of physical activity (angina pectoris), and heart attack. Blood vessels leading blood to the kidneys may be affected, resulting in high blood pressure. Blood vessels leading to the stomach may be affected in the same way, and gastric bleeding may result in blood in vomit or stools.

Women with pseudoxanthoma elasticum have normal fertility levels. Pregnancy and birth are not usually more complicated than normal, although gastrointestinal bleeding may occur.

Diagnosis

Early diagnosis is important in order to prevent and/or treat damage to the eyes, blood vessels and heart. The diagnosis is made on the basis of a skin biopsy. The tissue is dyed in order to show the damaged elastic fibres and the calcium deposits in the skin, both characteristic of pseudoxanthoma elasticum.

X-rays of blood vessels will sometimes show calcified blood vessel walls.

It is possible to make a diagnosis based on DNA testing. At the time of diagnosis it is important that the family is offered genetic counselling. Carrier and prenatal diagnosis, as well as pre-implantation genetic diagnosis (PGD) in association with IVF (in vitro fertilization), are available to families where the mutation has been identified.

People with only one copy of the mutated gene may have a mild form of the disease. For this reason parents and siblings of the person affected should be examined by a dermatologist and an ophthalmologist.

Treatment/interventions

There is no cure for pseudoxanthoma elasticum, and treatment focuses on treating risk factors, alleviating symptoms and compensating for loss of vision. People with the condition require contact with hospital medical, eye and skin departments.

Regular contact with an ophthalmologist is important so that tiny cracks in retinal tissue are followed up and the formation of new blood vessels discovered in good time. The formation of new blood vessels requires treatment to prevent vision being impaired. Treatment involves injecting anti-VEGF agents (vascular endothelial growth factor) into the eye to block the growth factor. Examples of such agents are ranibizumab and bevacizumab. VEGF is a powerful signalling substance, which otherwise stimulates inflammation and the formation of new blood vessels. Studies have shown positive results from this form of treatment. If vision does become impaired, contact with a low vision centre or similar is necessary. Various medications and techniques can do much to compensate for impaired vision.

Regular examinations of the blood vessels and the heart should be carried out. All the risk factors associated with heart disease must be monitored, including high blood pressure, elevated levels of blood lipids and blood sugar, and obesity. A dietician can give advice on suitable foods.

Preventive measures such as eating the right food and not smoking are important. Regular exercise is important although sports associated with sudden, intense periods of effort and involving a risk of injury to the head should be avoided, as they may precipitate bleeding in the retina.

People with the disease should avoid long-term use of medications containing acetylsalicylic acid and other non-steroidal anti-inflammatory (NSAID) medication. This group includes painkillers including ibuprofen and naproxen. These medications interfere with the blood’s ability to coagulate and increase the risk of bleeding in the eyes and the gastrointestinal canal. Short-term use is acceptable, but a doctor should be consulted first.

Another medication which increases the risk of bleeding is warfarin, which is often given to prevent to development of blood clots, for example in people with atrial fibrillation (abnormal heart rhythm) or who have been fitted with artificial cardiac valves. If the individual also has pseudoxanthoma elasticum it is important that a physician makes an assessment of which medication is most suitable.

If changes to the skin are unsightly a plastic surgeon can decide whether a cosmetic operation is possible.

The choice of occupation and the social lives of people with a severe visual impairment associated with pseudoxanthoma elasticum may be limited by their disease. Career guidance for people whose capacity to work is limited by disability is offered by the Swedish Public Employment Service. Swedish regional social insurance offices coordinate the measures needed to help a person with a disability find work, or return to work.

It is important that psychological and social support are available when needed.

Practical advice

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National and regional resources in Sweden

Sweden's regional and university hospitals have departments of clinical genetics.

Dermatologists have a broad knowledge of the disease. The Uppsala Genodermatosis Centre at the Dermatology Department of Uppsala University Hospital has specialist expertise in inherited skin diseases.

Resource personnel

Senior Physician Tommy Andersson, Eye Department, Sahlgrenska University Hospital/Mölndal, SE-431 80 Mölndal, Sweden. Tel: +46 31 343 10 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations etc.

There is no special association for people with pseudoxanthoma elasticum in Sweden.

In the US there is PXE International, www.pxe.org. The UK equivalent is PIXIE, www.pxe.org.uk.

SRF, The Swedish Association of the Visually Impaired, Sandsborgsvägen 52, SE-122 88 Enskede, Sweden. Tel: +46 8 39 90 00, fax: +46 8 39 93 22, email: info@srf.nu, www.srf.nu.

Courses, exchanges of experience for personnel

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Research and Development

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Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under "Mer hos oss" in the column on the right-hand side.

Literature

Abusamak M. Angioid streaks. http://emedicine.medscape.com/article/1190444-overview.

Campens L, Vanakker OM, Trachet B, Segers P, Leroy BP, De Zaeytijd J et al. Characterization of cardiovascular involvement in pseudoxanthoma elasticum families. Arterioscler Thromb Vasc Biol 2013; 33: 2646-2652.

Georgalas I, Tservakis I, Papaconstaninou D, Kardara M, Koutsandrea C, Ladas I. Pseudoxanthoma elasticum, ocular manifestations, complications and treatment. Clin Exp Optom 2011; 94: 169-180.

Grönblad E. Angioid streaks - pseudoxanthoma elasticum; vorläufige Mitteilung. Acta Ophthalmol 1929; 7: 329.

Neldner KH. Pseudoxanthoma elasticum. Int J Dermatol 1988; 27: 98-100.

Orssaud C, Roche O, Dufier JL, Germain DP. Visual impairment in psedoxanthoma elasticum: a survey of 40 patients. Ophtalmic Genet 2014 Apr 21. Epub ahead of print.

Plomp AS, Toonstra J, Bergen AA, Van Dijk MR, de Jong PT. Proposal for updating the pseudoxanthoma elasticum classification system and a review of the clinical findings. Am J Med Genet A 2010; 152A: 1049-1058.

Pomozi V, Brampton C, Fülöp K, Chen LH, Apana A, Li Q et al. Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins. J Invest Dermatol 2014; 134: 946-953.

Uitto J, Váradi A, Bercovitch L, Terry PF, Terry SF: Pseudoxanthoma elasticum: Progress in research toward treatment: Summary of the 2012 PXE International research meeting. J Invest Dermatol 2013; 133: 1444-1449.

Zebardast N, Adelman RA. Intravitreal ranibizumab for treatment of choroidal neovascularization secondary to angioid streaks in pseudoxanthoma elasticum: five-year follow-up. Semin Ophthalmol 2012; 27: 61-64.

Ålinder I, Boström H. Clinical studies on a Swedish material of pseudoxanthoma elasticum. Acta Med Scand 1972; 191: 273-282.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: pseudoxanthoma elasticum, pxe

GeneReviews (University of Washington)
www.ncbi.nlm.nih.gov/books/NBK1113 
Search: pseudoxanthoma elasticum

Orphanet (European database)
www.orpha.net 
Search: pseudoxanthoma elasticum

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is Associate Professor Håkan Mobacken, Sahlgrenska Academy, Gothenburg, Sweden.

Senior Physician Tommy Andersson at Sahlgrenska University Hospital in Gothenburg has contributed to this material.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2014-12-10
Version: 2.1
Publication date of Swedish version: 2014-08-20

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.