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Pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE), also known as Grönblad–Strandberg syndrome, is a genetic disease that causes fragmentation and mineralization of elastic fibers in body tissues The most common problems arise in the skin and eyes, but complications in the cardiovascular and gastrointestinal systems may be seen as well2. PXE is caused by autosomal recessive mutations in the ABCC6 gene on the short arm of chromosome 16 (16p13.1).

Skin
Pseudoxanthoma elasticum usually affects the skin first. Symptoms are typically found during childhood, but they can appear later in life as well. Small, yellowish bumps, or papules, usually form first on the neck and may progress to flexural areas including the armpits, folds of the groin area, the inside of the elbows, and the backs of the knees. Skin Lesions may also be present in mucosal areas including the inside of the lip and the vaginal mucosa. With time, the papules coalesce to form plaques and the skin may become loose and redundant. Many individuals also have diagonal grooves in the chin called oblique mental creases. Skin symptoms do no have any medical significance.

Eyes
The earliest eye manifestations of PXE do not affect the vision and can only be identified by an eye doctor. Initially the Bruch’s membrane, the thin membrane separating the blood vessel-rich layer from the pigmented layer of the retina, becomes dimpled and mottled looking. This symptom is called peau d’orange, which is a French term meaning that the retina resembles the skin of an orange. The onset of peau d’orange usually happens between adolescence and the late 20’s, however, it can occur at any time. Less commonly, patients with PXE might also have “comet lesions” of the eye. These small white lesions do not affect the vision and are usually found in the mid-peripehery of the retina. They appear round and often with a pigmented tail, giving them a “comet-like” appearance. Optic disk drusen is also a rare eye manifestation that does not cause vision loss. Drusen, which means stones, are tiny white and yellow accumulations of extracellular membrane that appear in the Bruch’s membrane. As PXE progresses, cracks called Angioid streaks very commonly begin to form as the elastin rich Bruch’s membrane mineralizes. Angioid streaks also do not affect visual acuity until they reach the macula, or the small spot at the back of the eye, which facilitates central vision. Blood vessels from behind the Bruch’s membrane grow through the cracks. These blood vessels often hemorrhage or leak, and if the cracks are near to the macular this can cause macular degeneration, the build up of scar tissue in the macula, and thus severe and permanent central vision loss1. Patients with PXE rarely go completely blind, but many are declared legally blind in their 30’s and 40’s due to this loss of central vision. This is often sighted as the symptom that has greatest burden on quality of life for patients with PXE.

Cardiovascular and Circulatory Systems
PXE symptoms of the cardiovascular and circulatory systems are less typical than in the skin and eyes, but they are often more serious. Mineralization of arteries in the limbs can cause intermittent claudication, or leg pain during walking and loss or weakening of peripheral pulses. Patients with PXE are also at a greater risk for atherosclerosis, renovascular hypertension, angina pectoris, and rarely myocardial infarction.

Gastrointestinal Systems
The principal symptom in the gastrointestinal system is bleeding in the upper GI tract.6 This occurs in a very small number of patients, and the majority of gastrointestinal symptoms reported by patients of PXE are likely unrelated to their disease status. However, gastrointestinal issues related to PXE are generally severe when they do occur.

Pregnancy and PXE
Most women with PXE have normal pregnancies. The disease is not associated with a significantly higher rate of fetal loss or other adverse outcomes. Mineralization of the placenta may occur, but this does not pose any risk to the mother or the fetus. There is a small risk (<1%) of retinal complications and gastrointestinal bleeding during labor, but these rates have been overestimated in the past and do not represent the typical experiences of women with PXE that become pregnant.

Classification
The diagnostic criteria for PXE are the typical skin biopsy appearance and the presence of angioid streaks in the retina. If a diagnosis cannot be made using these criteria, then mutation analysis of the ABCC6 gene is recommended. Classification of the disease based on other systems has become somewhat outdated by the discovery of the ABCC6 mutations. There is no current system for categorizing clinical subtypes of PXE.

Pathophysiology
The symptoms of pseudoxanthoma elasticum are caused by ectopic mineralization in certain tissues of the body, in particular, the elastin rich layer of the dermis, Bruch’s membrane in the retina, and midsized arteries of the body. Elastic fibers are affected in all organs of the body, but symptoms seem only to present themselves in organs that are very elastin rich. One of the only exceptions to this seems to be the lungs, which are elastin rich, but appear to remain unaffected by PXE. The ectopic mineralization damages the elastin fibers in certain tissues of the body, which results in the symptoms of PXE.

Given its symptomotolgy, PXE was initially thought to be a connective tissue disorder. However, genetic research revealed that the gene involved with PXE was not involved with connective tissues, but rather with the ABCC6 gene, which encodes a multi-drug resistance transport protein called MRP6. Thus, researchers now believed that PXE is a metabolic disorder, or one that disrupts the chemical reactions in the body. The ABCC6 gene is expressed in all organs, the mutations in those affected cause the production of a faulty transporter protein. The gene makes these faulty proteins at the highest rate in the liver and kidneys, but those organs remain unaffected by the mineralization that is characteristic of PXE. In healthy individuals, this protein likely transports a substrate out of the liver and into the blood stream, which prevents the ectopic mineralization that causes PXE symptoms. Affected individuals on the other hand do not produce proteins that can transport this substrate into their blood. Case studies of three women that acquired PXE after liver transplants also lead researchers to believe that the missing substrate is produced in the liver. However, it cannot be transported out into the blood due to the faulty MRP6 proteins that are transcribed in the liver by the mutated ABCC6 gene.

Genetics
Pseudoxanthoma elasticum is caused by mutations in the ABCC6 gene. This gene, located on the short arm, or “p” arm of chromosome 16, spans 75 kb of the human genome and is made up of 31 exons. 80% of clinical cases of pseudoxanthoma elasticum have detectable mutations in the ABCC6 gene. More than 300 distinct PXE causing mutations have been discovered in the study of the ABCC6 gene. Mutations of almost all types have been described in all parts of the gene have been described (missense, nonsense, splice alteration, insertion, small deletion or large deletion).

PXE is an autosomal recessive disorder. In the early 1970’s, reports suggested that both autosomal recessive and autosomal dominant forms of PXE existed in multiple forms. However, mutation analysis allowed genetic evaluation of the question of inheritance, and as a result it is now clear that PXE is an autosomal recessive condition. There are reports of two and three consecutive generations of PXE patients, but these cases can be justified with one of three explanations. (1) An affected person has a child with a carrier of the PXE gene. (2) Parental consanguinity increased the risk that an affected individual will have a child with a carrier of the PXE gene. (3) Carriers of the PXE gene that manifest mild PXE symptoms and are misdiagnosed with the disease.

Strong genetic linkage for PXE was found with mutations in the ABCC6 gene, which codes for the multi-drug resistant protein MRP6. The ABCC6/MRP6 protein is a membrane transporter from the large ATP-binding cassette transporter family. The protein is expressed in most organs, but mainly in the liver and kidney. Researchers believe that the PXE gene produces a dysfunctional MRP6 protein, which is unable to transport certain substances out of the liver and into the blood stream that prevent ectopic mineralization.

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, but this could not be confirmed in a subsequent case series.

Treatment
There is no direct treatment for PXE, but there are several therapies for the symptoms.

Skin Symptoms
For excessive areas of loose skin, plastic surgery may be used to improve the skin’s physical appearance. However, this does not always glean optimal results, and some patients experience difficulty healing from the procedure.3 Further, the skin symptoms do not pose any medical significance, so these treatments are purely cosmetic.

Eyes Symptoms
PXE can cause a gradual permanent loss of central vision, and the majority of medical treatments available are designed to treat this aspect of the disease. Angioid streaks on the retina represent cracks and breaks in the elastin rich Bruch’s membrane. The bed of blood vessels below the Bruch’s membrane in the retinal pigment epithelium will grow through these cracks, a phenomenon known as choroidal neovascularization (CNV). These unwanted blood vessels can leak or hemorrhage; causing a build up of scar tissue around the macula that can blur and obscure the vision.

Although there is no treatment to prevent CNV, there are a number of treatments that can reduce the amount of damage it causes. Almost all the treatments used in PXE were developed for the treatment of wet age-related macular degeneration (AMD). Similar neovascularization and leakage, bleeding, and scarring can occur in AMD, but the mechanisms are different. PXE is so uncommon in comparison to AMD, that there have not been enough patients to conduct controlled clinical trials of these treatments.

In the past, photocoagulation, also known as “hot” laser, has been used. This technique is used to burn away the new blood vessels that form in the retina. The problem with this technique is that it destroys normal tissue along with the unwanted blood vessels. The damage to the surrounding retina will cause scarring and permanent vision changes. The major problem with laser therapy is that CNV and bleeding tend to recur after treatment, inevitably leading to more bleeding and scarring.

To address this issue, photodynamic therapy, also known as “cold” laser, was developed. Photodynamic therapy (PDT) involves an injection of a chemical into the bloodstream that concentrates in the new blood vessels in the retina and is activated by the wavelength of a cold laser. The energy released by the activation can help seal the blood vessels without producing a lot of damage to the surrounding retina. Unfortunately, although safer than laser, there are also recurrences of neovascularization, leaking, and bleeding in patients with PXE after PDT.

Most recently, anti-angiogenic treatments, such as Avastin® and Lucentis®, have been developed. CNV relies on vascular growth factors to develop, and these medications are specific antibodies to these growth factors. This treatment, given through injections into the eye, is directed against these growth factors to prevent the formation of new blood vessels. Significant improvements in visual acuity can be achieved in patients with PXE with the use of anti-angiogenic agents. In fact, the anti-angiogenic agents appear to be so effective that they have largely replaced previously used methods of treatment such as laser photocoagulation and photodynamic therapy. Long-term outcomes of these treatments have been deemed favorable in a study, which examined patients up to two years after their initial treatment. Researchers noted general visual acuity improvement with monthly injections, as well as decrease in CNV growth and frequency of hemorrhaging.

Treatment for long-standing vision loss is less developed. Retinal scarring and cell loss within the retina is often permanent.27 Low vision aids and rehabilitation are recommended when vision loss is disabling and permanent. For some patients, low vision aids and magnifying computer software can be very helpful in overcoming the restrictions imposed by central vision loss.

Additionally, any impact sports or activities that might cause direct eye injury such as football, boxing, deep sea diving, and weight lifting, should be avoided because impact to the eye area can cause macular bleeding.

Cardiovascular Symptoms
Cardiovascular disease is treated as in individuals without PXE, and the best way to avoid the more serious cardiovascular symptoms of PXE is to maintain a healthy lifestyle with nutritious diet and plenty of exercise.

Gastrointestinal Symptoms
To prevent the gastrointestinal symptoms of PXE, some doctors recommend avoidance of nonsteroidal anti-inflammatory drugs (NSAIDS) that increase bleeding risk, such as aspirin, and ibuprofen.

Mechanistic Treatments
Researchers are now exploring the possibility of treatments for the mechanism that causes PXE symptoms. However, these studies are mostly still in their infancy and have not yet yielded conclusive results.

Initially researchers believed that vitamin K might be the missing substrate the patients with PXE do not have in their blood stream. Thus if vitamin K could be introduced into the blood stream of patients with PXE, researchers believed they might be able to stop the process of ectopic mineralization. However, studies using mice as models of PXE do not support this idea, and supplements of vitamin K did not prevent mineralization in the models.

Researchers have also attempted to limit the uptake of dietary phosphorous in patients with PXE, believing that this might prevent unwanted mineralization, but these attempts were unsuccessful. In a clinical trail of this idea, results did not yield any significant differences between those that consumed a drug to prevent uptake of phosphorous, and those that were given a placebo. However, the trial did find that the condition of patients in both the treatment and placebo groups did show significant improvement in their PXE symptoms. Further examination indicated that the high content of magnesium in both the drug and the placebo might have confounded the results. Researchers are now looking further into the idea that a high dietary intake of magnesium might have a positive affect on the symptoms of PXE, and a clinical trial of this theory is beginning in 2012.

Epidemiology
Several Epidemiology studies have been conducted on pseudoxanthoma elasticum, but many of the results are inconclusive due to unavoidable difficulties with study design, and small study populations. The reported prevalence of pseudoxanthoma elasticum is estimated to be between 1:25000 and 1:100,000, but the prevalence is possibly significantly higher due to those in the population that remain undiagnosed. Females are reported twice as likely to be affected as males, but there is no scientific evidence to explain why this is the case. The disease occurs in all races and geographic areas, but some groups are more likely to have PXE as a result of a founder effect (i.e. it was relatively prevalent in the group of people from which they descended) and consanguinity.

History
The skin lesions associated with PXE were originally thought to be xanthomas, until approximately 1896, when a dermatologist differentiated them and therefore called the condition pseudoxanthoma elasticum. In 1929, a dermatologist and an ophthalmologist, Grönblad and Strandberg respectively, discovered the association between skin lesions and angioid streaks, and the condition was called Grönblad Strandberg by some for a short period of time. However, the condition is more commonly called by its original name, pseudoxanthoma elasticum.