Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum is a rare genetic disorder that causes calcium and other minerals to accumulate in elastic tissues throughout the body, primarily affecting the skin, eyes, and blood vessels, and leading to a range of symptoms that require lifelong management.

Table of contents

• What is Pseudoxanthoma Elasticum?
• Medical Classification Codes
• Alternative Names
• How Common is PXE?
• What Causes PXE?
• How is PXE Inherited?
• Skin Manifestations
• Eye Manifestations
• Cardiovascular Manifestations
• Other Manifestations
• How is PXE Diagnosed?
• Treatment and Management
• Lifestyle Recommendations
• Life Expectancy and Outlook
• Related Conditions

What is Pseudoxanthoma Elasticum?

Pseudoxanthoma elasticum (PXE) is a progressive disorder characterized by the accumulation of deposits of calcium and other minerals in elastic fibers. Elastic fibers are a component of connective tissue that provides strength and flexibility to structures throughout the body^[1]. The name was coined by French dermatologist Ferdinand-Jean Darier in 1896, referring to the yellowish tone of skin features that resembled xanthomas and the loose appearance of the skin at flexural surfaces^[15].

In PXE, mineralization can affect elastic fibers in the skin, eyes, and blood vessels, and less frequently in other areas such as the digestive tract^[1]. The condition is primarily caused by an underlying metabolic disorder, with dystrophic calcification (the abnormal accumulation of calcium and phosphate complexes) being the hallmark feature^[15]. The deposits consist of calcium hydrogen phosphate, calcium hydroxyapatite, and to a lesser extent, iron precipitates^[15].

Medical Classification Codes

Q82.8; H35.33

Alternative Names

PXE, Gronblad-Strandberg syndrome, Grönblad-Strandberg syndrome

How Common is PXE?

PXE affects approximately 1 in 50,000 people worldwide^[1]. The clinical prevalence has been estimated at between 1 per 100,000 and 1 per 25,000 of the general population^[15]. For reasons that are unclear, this disorder is diagnosed approximately twice as frequently in females as in males^[1]. The average age at diagnosis is typically 30 to 40 years, although this may vary depending on disease characteristics^[3].

What Causes PXE?

Mutations in the ABCC6 gene cause PXE^[1]. This gene provides instructions for making a protein called MRP6 (also known as the ABCC6 protein), which is found primarily in cells of the liver and kidneys, with small amounts in other tissues including the skin, stomach, blood vessels, and eyes^[1]. More than 300 different disease-causing mutations have been identified in the 31 coding regions of this gene^[6].

The MRP6 protein is thought to transport certain substances across the cell membrane. Some studies suggest that this protein stimulates the release of a molecule called adenosine triphosphate (ATP) from cells. ATP can be broken down into other molecules, including pyrophosphate, which helps control deposition of calcium and other minerals in the body^[1]. The ABCC6 protein encodes an ATP-dependent transporter that excretes inorganic phosphate (PPi), a strong inhibitor of mineralization. Research has shown that decreased levels of PPi in the blood due to loss-of-function mutations of ABCC6 likely drive abnormal calcification in PXE^[3].

Mutations in the ABCC6 gene lead to an absent or nonfunctional MRP6 protein. This shortage may impair the release of ATP from cells, resulting in little pyrophosphate being produced, allowing calcium and other minerals to accumulate in elastic fibers of the skin, eyes, blood vessels, and other tissues affected by PXE^[1].

How is PXE Inherited?

PXE is inherited in an autosomal recessive manner, which means both copies of the gene in each cell have mutations^[1]. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but do not show signs and symptoms of the condition^[1].

If both parents are carriers of the mutated gene, there is a 25% chance that their child will have the condition, a 50% chance that their child will be a carrier like the parents, and a 25% chance that their child will neither have the condition nor be a carrier^[9]. In a few cases, an affected individual has one affected parent and one parent without signs and symptoms of the disorder^[1].

Skin Manifestations

The first clinical sign of PXE, with onset typically in childhood or adolescence, tends to be characteristic skin changes^[15]. People with PXE may have yellowish bumps called papules on their necks, underarms, and other areas of skin that touch when a joint bends (flexor areas)^[1]. These appear as small, yellowish papules ranging from 1 to 5 millimeters, distributed over the lateral neck and flexural areas^[3].

The papules are initially isolated or found in patches but coalesce into larger plaques with a “cobblestone” or “plucked chicken” appearance as the disease progresses^[3][15]. Affected skin becomes soft, loose, and slightly wrinkled over time. The oral, vaginal, and rectal mucosae may also be affected^[15]. A prominent mental (chin) fold may develop at an early age^[8]. These skin lesions are asymptomatic and have a random pattern of growth and spread^[7].

Eye Manifestations

Bilateral ocular findings develop in all patients with PXE, beginning in childhood or early adolescence^[3]. People with PXE may 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, which gives a mottled, “orange peel” appearance to the temporal retina^[1][3].

Another characteristic eye abnormality known as angioid streaks occurs when tiny breaks form in the layer of tissue under the retina called Bruch’s membrane. These appear as narrow, irregular, grey to brown or dark red spoke-like bands radiating out from the optic disc or encircling it^[8]. Neither angioid streaks nor peau d’orange affect visual acuity in themselves^[8].

Bleeding and scarring of the retina may also occur, which can cause vision loss^[1]. Choroidal neovascularization (CNV) represents a major complication at later stages of the disease. Subretinal vessels grow through cracks in Bruch’s membrane, and when these blood vessels leak, they can lead to hemorrhage and central visual loss (not complete blindness) if they occur in the macula or fovea^[8]. The most frequent cause of morbidity and disability in PXE is reduced vision due to complications of subretinal neovascularizations and macular atrophy^[2].

Cardiovascular Manifestations

Mineralization of the blood vessels that carry blood from the heart to the rest of the body (arteries) may cause various signs and symptoms of PXE^[1]. As a result of mineralized buildup in the vascular wall, patients may be at a greater risk for intermittent claudication, a condition in which cramping pain in the leg is induced by exercise^[7].

People with PXE can develop narrowing of the arteries (arteriosclerosis) or decreased blood flow to the arms and legs^[1]. Occlusions in cerebral arteries can lead to reduced or blocked blood flow, resulting in serious complications including transient ischemic attack (TIA) and stroke^[7]. Similarly, blockages in the coronary circulatory system may develop, leading to angina and myocardial infarction (heart attack)^[7].

Other manifestations include premature gastrointestinal angina, renovascular hypertension, and mitral valve prolapse^[2][4]. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation^[15].

Other Manifestations

Rarely, bleeding from blood vessels in the digestive tract may occur^[1]. Although not much is known about potential gastroenterological manifestations, gastrointestinal bleeding is a rare symptom and represents a medical emergency^[7][16]. Patients should watch for signs of GI bleeding or chronic stomach upset, such as melena (black stools) or frank blood^[16].

Patients with PXE are at a greater risk of developing optic nerve head drusen, which are calcified lesions within the optic nerve. Careful monitoring should be considered to prevent further complications such as retinal artery occlusion and optic neuropathy^[7].

How is PXE Diagnosed?

The clinical diagnosis of PXE is established in a person with characteristic skin lesions and at least one characteristic retinal finding^[2]. When eye findings are characteristic but skin findings are questionable, identification of calcified dystrophic elastic fibers using a von Kossa or similar stain on a biopsy of potentially affected skin establishes the diagnosis^[2].

Diagnosis involves a combination of clinical evaluation, imaging studies, and genetic testing. The doctor will conduct a physical examination to assess the characteristic skin changes and perform an eye examination to look for retinal abnormalities such as angioid streaks^[9]. Skin biopsy shows calcification and fragmentation of elastic fibers in the mid and lower dermis^[8][12]. The highest yield is from biopsy of a primary lesion (papule)^[8].

The molecular diagnosis of PXE is established by the presence of biallelic ABCC6 pathogenic variants identified on molecular genetic testing^[2]. Genetic testing can detect the causative mutation and help confirm the diagnosis^[12]. Laboratory and imaging studies are performed for associated conditions, including complete blood count for anemia resulting from GI bleeding, lipid panel, coronary CT for prevention or detection of coronary artery disease, and cerebrovascular and brain imaging to detect cerebrovascular disease and stroke^[12].

Treatment and Management

There is no cure for PXE. Many of the pathologic changes associated with the condition are irreversible, but prophylactic measures can be undertaken to minimize the disease course^[11]. Management requires coordinated input from multidisciplinary specialists^[2].

Eye care: Management includes care by a retina specialist. Intravitreal injections of anti-VEGF (vascular endothelial growth factor) treatments, such as bevacizumab, for the treatment of macular neovascularization when indicated^[2][5]. These injections are effective at slowing the growth of damaging blood vessels in the eye^[5]. Photodynamic therapy and intravitreal triamcinolone may also be beneficial in treating ocular complications^[11]. Laser treatment is not usually used as it can cause further sight loss^[5].

Patients should use an Amsler grid regularly to detect early changes. If any sight changes occur, such as distortion or things that should be straight appearing wavy, it is likely the start of a retinal hemorrhage, and the patient must go to eye casualty immediately^[16]. Routine examination by a retina specialist is essential^[2].

Cardiovascular management: Standard-of-care interventions for gastrointestinal bleeding, claudication, stroke, renovascular hypertension, and cardiovascular complications (angina and myocardial infarction)^[2]. Diet and exercise are the main methods to minimize the extent of cardiovascular disease^[11]. Blood lipid levels should be well controlled to reduce risk of premature atherosclerosis and associated vascular complications^[12]. Lipid-lowering therapy and cardiovascular risk reduction are important^[4].

Skin lesions: The skin lesions are asymptomatic. However, affected individuals with unsightly redundant folds can undergo cosmetic surgical correction, in most cases with satisfactory wound healing^[8]. Fractional carbon dioxide laser treatment has been used to improve cosmetic appearance^[11].

Other treatments: GI hemorrhages may be managed by hospitalization, iron supplements, blood transfusions, endoscopic treatment, or surgery with partial gastrectomy if necessary^[11]. Intermittent claudication is best managed by weight reduction and an exercise program to stimulate collateral blood vessel development^[11].

Lifestyle Recommendations

Several substances and circumstances should be avoided. Contact sports or racquet sports without appropriate eye and head protection should be avoided^[2]. People with PXE should avoid contact sports because of the risk of retinal hemorrhage^[12]. Patients should not lift anything more than 20 pounds in weight as it is stressful on the eyes^[16].

Aspirin and nonsteroidal anti-inflammatory medications should be avoided because of increased risk of gastrointestinal bleeding^[2][4]. Occasional use is acceptable, though^[16]. Anticoagulants should also be avoided^[4]. Smoking should be avoided because of its vasoconstrictive properties^[2]. Patients are advised to stop tobacco use, as tobacco has been shown to aggravate the disease course^[11].

Maintain strict weight control and continue a low-calcium diet (not over 800 mg per day, increasing to 1000 mg per day during pregnancy)^[16]. Develop a regular exercise program (30 to 45 minutes three times per week). Swimming and walking are very good exercises^[16]. A healthy, balanced diet rich in antioxidants and staying hydrated are recommended^[9]. Follow a low-fat diet and eat five servings of fruit and vegetables each day^[16].

Use dietary supplements, especially antioxidants (vitamins A, C, E, zinc, selenium, and copper). Starting vitamin and mineral supplements at about age 40 years may be beneficial^[16]. Watch blood pressure and manage with exercise and weight control if possible; medications if necessary^[16].

Pregnancy management: Vaginal delivery appears safe for the retina of women with PXE if no active choroidal neovascularization (CNV) is present^[2]. Women with PXE should have a retinal examination to check for active CNV, as angioid streaks alone are not an indication for medical interventions during delivery^[2]. If choroidal neovascularization is present, elective cesarean section should be considered^[4][12]. It is recommended to limit pregnancies and keep dietary calcium at about 1000 mg per day during pregnancy^[16].

Life Expectancy and Outlook

Most affected individuals live a normal life span^[2]. Patients typically have a normal life span, but acute GI hemorrhage, myocardial infarction, or cerebral hemorrhage may be fatal in rare cases^[6]. The prognosis of PXE largely depends on the extent of extracutaneous organ involvement^[6]. Complications may limit life span and impact quality of life^[4][12].

It is important to note that no one with PXE has ever gone completely blind, and no one has needed a guide dog or has used Braille. Peripheral vision always remains^[16]. If poor central vision develops, there are many low-vision devices available to improve vision^[16].

Early diagnosis and the institution of prophylactic measures is paramount^[6]. While the condition progresses slowly and unpredictably with age, maintaining a positive mindset and seeking emotional support can be just as important as medical interventions^[9]. Connecting with support groups or communities can provide a platform to share experiences and gather knowledge^[9].

Related Conditions

Differential diagnosis includes conditions that may present with similar features. Solar elastosis (sun-damaged skin) can be confused with PXE skin changes. Fibroelastolytic papulosis (PXE-like papillary dermal elastolysis) can appear clinically identical to PXE^[8].

Overlapping phenotypes due to variants in ENPP1 and GGCX genes have been reported^[6]. PXE cases have been reported in association with beta thalassemia^[6]. Differential diagnosis also includes calcium fertilizer exposure, extended penicillamine use, localized acquired pseudoxanthoma elasticum (related to obesity, hypertension, and multiparity), or pseudoxanthoma-like disorder with coagulation deficiencies^[12].

• Skin (dermis)
• Eyes (retina, Bruch’s membrane, choroid)
• Blood vessels (arteries)
• Digestive tract
• Liver
• Kidneys