Pseudoxanthoma elasticum (PXE)

 

Alternative Name : Grönblad–Strandberg syndrome

Definition:
Pseudoxanthoma elasticum (PXE) is a genetic disease that causes fragmentation and mineralization of elastic fibers in some tissues. The most common problems arise in the skin and eyes, and later in blood vessels in the form of premature atherosclerosis. PXE is caused by autosomal recessive mutations in the ABCC6 gene on the short arm of chromosome 16.

PXE is a rare condition that many doctors  may not  know much about, even though it was first described more than 100 years ago. It causes the elastic fibres that are normally found in the skin, the retina of the eyes and the blood vessels to become calcified and break up, so losing their elasticity.

The reported prevalence of pseudoxanthoma elasticum is about 1:25,000. Females are twice as likely to be affected as males. The disease occurs in all ethnicities, but Afrikaners are more likely to have PXE as a result of a founder effect (i.e. it was relatively prevalent in the small group of people from whom most Afrikaners descend).

Symptoms:
The most characteristic initial symptom of PXE is discolouring of the skin around the sides of the neck.
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Generally, affected areas of skin appear thickened. In some people, small yellowy-orange papules between 2mm and 5mm in diameter form groups, or join together as larger plaques. When this happens, the skin takes on a cobblestone or ‘plucked chicken’ appearance.

These skin changes then tend to appear in the skin flexures of the elbows, groins and knees, and under the arms. As the skin loses its elasticity, it becomes soft, floppy and wrinkled, hanging in folds. Although these changes do no physical harm, emotionally they cause great distress because of their appearance. However, it’s unusual for widespread areas of the skin to be affected.

Other problems are potentially more serious. Slow calcification of the thin elastic fibres of the retina at the back of the eyes eventually affects about 60 per cent of PXE sufferers, usually by the time they reach middle age. Sometimes this leads to a complete loss of central vision.
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In some cases, the blood vessels are affected, which makes heart attacks and strokes more likely. The painful condition of the legs called intermittent claudication – where blood can’t get to the muscles easily to deliver oxygen to the tissues – is also more common. Gastrointestinal bleeding is another problem that some people with PXE experience.

Causes:
80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene. Mutations in almost all parts of the gene have been described, of all types (missense, nonsense, splice alteration, insertion, small deletion or large deletion). Although there have been reports of autosomal dominant inheritance, the inheritance is typically autosomal recessive (both parents need to be carriers, and there is a 25% chance that a child will inherit both abnormal copies of the gene and therefore develop the condition).

Strong genetic linkage was found with mutations in the ABCC6 gene, which codes for the MRP6 protein, but the exact mechanism by which this protein (which is a membrane transporter from the large ATP-binding cassette transporter family) influences the disease course is unknown; the protein is expressed in most organs, but mainly in the liver and kidney. It is unclear in what way this would lead to abnormalities in skin, eyes and blood vessels. It is thought that particular mutations do not cause a more severe or less severe form of the disease. Given the variations in age of onset and severity it is likely that other unknown risk factors (genetic and dietary) may be involved.  One study suggested that mutations causing total absence of an MRP6 protein caused a more severe disease,[10] but this could not be confirmed in a subsequent case series.

Premature atherosclerosis is also associated with mutations in the ABCC6 gene, even in those without PXE. A syndrome almost indistinguishable from hereditary PXE has been described in patients with hemoglobinopathies (sickle-cell disease and thalassemia) through a poorly understood mechanism.  In addition, there appears to be another PXE-like syndrome with a similar phenotype but as a result of problems with another gene, gamma-glutamyl carboxylase

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Diagnosis
The presence of calcium in elastic fibers, as revealed by microscopic examination of biopsied skin, unequivocally establishes the diagnosis of PXE.

Treatment
PXE cannot be cured, but plastic surgery can treat PXE skin lesions, and laser surgery is used to prevent or slow the progression of vision loss. Excessive blood loss due to bleeding into the gastrointestinal tract or other organ systems may be treated by transfusion. Mitral valve prolapse (protrusion of one or both cusps of the mitral heart valve back into the atrium during heart beating) can be corrected by surgery, if necessary.

Measures should be taken to prevent or lessen cardiovascular complications. People with PXE should control their cholesterol and blood pressure, and maintain normal weight. They should exercise for cardiovascular health and to prevent or reduce claudication later in life. They should also avoid the use of tobacco, thiazide antihypertensive drugs, blood thinners like coumadin, and nonsteroidal anti-inflammatory drugs like aspirin and ibuprofen. In addition, they should avoid strain, heavy lifting, and contact sports, since these activities could trigger retinal and gastrointestinal bleeding.

People with PXE should have regular eye examinations by an ophthalmologist and report any eye problems immediately. Regular check-ups with a physician are also recommended, including periodic blood pressure readings.

Some people have advocated a calcium-restricted diet, but it is not yet known whether this aids the problems brought about by PXE. It is known, however, that calcium-restriction can lead to bone disorders.

Prognosis
The prognosis is for a normal life span with an increased chance of cardiovascular and circulatory problems, hypertension, gastrointestinal bleeding, and impaired vision. However, now that the gene for PXE has been identified, the groundwork for research to provide effective treatment has been laid. Studying the role of the ABCC6 protein in elastic fibers may lead to drugs that will ameliorate or arrest the problems caused by PXE.

Genetic tests are now available that can provide knowledge needed to both diagnose PXE in symptomatic persons and predict it prior to the onset of symptoms in persons at risk. Prenatal diagnosis of PXE, by testing fetal cells for mutations in the ABCC6 gene, can be done in early pregnancy by procedures such as amniocentesis or chorionic villus sampling. For most people, PXE is compatible with a reasonably normal life, and prenatal diagnosis is not likely to be highly desired.

Genetic testing to predict whether an at-risk child will develop PXE may be helpful for medical management. A child who is found to carry a mutation can be monitored more closely for eye problems and bleeding, and can begin the appropriate lifestyle changes to prevent cardiovascular problems.

 

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Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.

Resources:
http://en.wikipedia.org/wiki/Pseudoxanthoma_elasticum
http://www.bbc.co.uk/health/physical_health/conditions/pxe1.shtml
http://medical-dictionary.thefreedictionary.com/pseudoxanthoma+elasticum
http://www.aocd.org/skin/dermatologic_diseases/pseudoxanthoma-elasticum.html

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