Pseudoxanthoma Elasticum 

Updated: Oct 20, 2017
Author: Neil Alan Fenske, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by elastorrhexia, or progressive calcification and fragmentation, of elastic fibers primarily affecting the skin, the retina, and the cardiovascular system.[1, 2, 3, 4, 5] The condition was first described by the French dermatologist Rigal in 1881[6] and later named by Darier in 1896, who sought to differentiate PXE from common xanthomas.[7] Cutaneous lesions typically begin in childhood or early adolescence, but owing to their asymptomatic nature, diagnosis is delayed by an average of 9 years.[8]

Pathophysiology

Pseudoxanthoma elasticum (PXE) is associated with mutations in the ABCC6 gene, which encodes an ATP-binding cassette transporter protein localized to the mitochondria-associated membrane (MAM).[9] The gene is expressed predominantly in the liver and kidney; however, PXE most commonly involves the elastic fibers of the mid and deep reticular dermis of skin, the Bruch membrane of the eye, and the blood vessels. The disease’s manifestations are primarily due to an underlying metabolic disorder.

The underlying pathomechanisms of PXE have largely been unknown. A 2017 study attempted to gain better understanding of the pathophysiology of PXE by characterizing dermal myofibroblast differentiation. It was found that such deviations mediated by aberrant supramolecular extracellular matrix organization may be the driving cause of PXE.[10]

Etiology

Pseudoxanthoma elasticum (PXE) is caused by mutations in the ABCC6,[11, 12] also known as multidrug resistance–associated protein 6 (MRP6), which has been mapped to 16p13.1. To date, greater than 300 different disease-causing mutations, mainly missense and nonsense mutations, have been identified in the 31 exons coding ABCC6. Because the ABCC6 gene encodes the cellular transport protein ABCC6/MRP6, PXE may represent a systemic metabolic disorder rather than a purely structural disorder of connective tissue.

In support of this hypothesis, fibroblasts grown in the sera of patients with PXE interfered with the normal assembly of elastic fibers in vitro[12] and sera from normal mice reversed mineralization symptoms in ABCC6-deficient mice.[13] Subsequent studies support the notion that PXE is primarily a systemic metabolic disorder with secondary mineralization of connective tissues.[14]

Several mechanisms have been proposed to explain the pathological changes found in PXE. One theory is that increased oxidative stress, resulting in elevated levels of intercellular adhesion molecule-1 (ICAM-1) and P-selectin.[15, 16, 17] Another hypothesis is that ABCC6 secretes a vitamin-K precursor from the liver, supported by the finding that clinical features simulating PXE are seen in rats treated with vitamin-K antagonists and in patients with mutations of gamma-glutamyl carboxylase gene.

Based on this theory, a precursor of vitamin K that can be used by peripheral tissues should abate the process of pseudoxanthoma elasticum.[16] However, this has not been observed, and furthermore, supplementation with antioxidants such as vitamins C and E, selenium, and N -acetylcysteine have not been found to modify the ectopic mineralization process.[18]

Alternatively, the ectopic mineralization of peripheral tissues in PXE may be due to a reduced antimineralization capacity. Matrix Gla protein (MGP) and fetuin-A,[19, 20] two factors that inhibit mineralization and local artery calcification, have been found at lower levels in the serum of PXE patients and knockout ABCC6 mice.[21, 22, 23, 24] The "hepatic intoxication hypothesis" further suggests that a substrate (or several substrates) of ABCC6 accumulates within hepatocytes, leading to altered gene regulation of proteins that directly or indirectly effect peripheral mineralization.[25]

Epidemiology

US frequency

Pseudoxanthoma elasticum (PXE) has an estimated prevalence of 1 case per 25,000-100,000.[26] Current research supports a common (probably exclusive) autosomal recessive inheritance of pseudoxanthoma elasticum.

Race

PXE has been described in persons of all races. A higher prevalence has been reported in certain populations, including South African Afrikaners, likely due to a founder effect.[11]

Sex

The female-to-male ratio is 2:1.[26]

Age

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.

Prognosis

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

Spontaneous resolution of skin changes has been reported, but is exceedingly rare.[11]

Early diagnosis and the institution of prophylactic measures is paramount.

 

Presentation

History

Cutaneous changes are usually the first manifestation of pseudoxanthoma elasticum (PXE), classically arising on the lateral aspect of the neck. They are generally asymptomatic but may be of cosmetic concern.

Extracutaneous presentations include mucosal involvement leading to gastrointestinal hemorrhage with melena, frank bleeding, occult blood in the stool, or hematemesis.

Patients may report fatigue from chronic blood loss or claudication from blood vessel involvement.

Slowly, as the disease progresses, patients note more severe cutaneous and cardiovascular manifestations, such as angina and hypertension.

Hematuria has also been reported.

Retinal hemorrhages with loss of central vision are common after the fourth decade of life.

Physical Examination

Pseudoxanthoma elasticum (PXE) can present a diagnostic challenge as it exhibits a late onset of clinical manifestations that are subtle and often times overlapping with other diseases. Cutaneous findings are most frequently the first diagnostic sign of PXE, classically arising on the lateral aspect of the neck. Skin findings are generally asymptomatic and usually not recognized until the second or third decade of life. Individuals with PXE are frequently not diagnosed until the development of ocular and vascular complications.[27]

Physical findings of PXE can be divided into cutaneous, ocular, and cardiovascular manifestations.

Cutaneous manifestations

The cutaneous manifestations of PXE are highly characteristic. The lesions usually develop in childhood or early adolescence; however, occasionally, they first appear in late adulthood.[26, 28, 29]

Small, yellow papules of 1-5 mm in diameter are seen in a linear or reticular pattern and may coalesce to form plaques.[30] The skin takes on a plucked chicken, Moroccan leather, or cobblestone appearance. Typically, these changes are first noted on the lateral part of the neck and later involve the antecubital fossae; the axillae; the popliteal spaces; the inguinal and periumbilical areas; the oral mucosa involving the lower lip, cheek, and palate; and the vaginal and rectal mucosae.[31]

As the disease progresses, the skin of the neck, the axillae, and the groin may become soft, lax, and wrinkled, hanging in folds. The extent of these changes is usually limited, but generalized cutis laxa–like PXE has also been reported.[32]

Horizontal and oblique mental creases before age 30 years is highly specific for PXE.[33]

Other clinical presentations reported in literature include acneiform lesions, brown reticulated macules and chronic granulomatous nodules.[33, 34]

Elastosis perforans serpiginosa may coexist with PXE.

The cutaneous lesions of PXE usually remain unchanged throughout life, and are generally symmetrically distributed. See the images below.

Classic cobblestone appearance with yellow papules Classic cobblestone appearance with yellow papules and plaques on the lateral aspect of the neck.
Laxity and redundant skin folds in the axilla. Laxity and redundant skin folds in the axilla.
Flesh-colored reticulated plaques on the posterior Flesh-colored reticulated plaques on the posterior neck.

Ocular manifestations

The characteristic ocular manifestations of PXE are angioid streaks of the retina, which are slate gray to reddish brown curvilinear bands that radiate from the optic disc.[35] The streaks represent cracks and fissures in the calcified Bruch membrane. This ocular change is generally bilateral and is often noted several years after the onset of cutaneous lesions. Angioid streaks are present in 85% of patients with PXE.

Although these lesions are highly characteristic of PXE, they are not pathognomonic because they are also found in various other conditions including sickle cell anemia, thalassemia, Paget disease of the bone, Marfan syndrome, Ehlers-Danlos syndrome, and lead poisoning.

Angioid streaks are often preceded by peau d’orange changes, consisting of fine-yellow drusenlike pigment irregularities. These changes arise on average 1-8 years prior to angioid streaks, and suggest early retinopathy.[36]

Angioid streaks can serve as a nidus for choroidal neovascularization, which is associated with retinal hemorrhage and a poor prognosis if left untreated. Loss of central vision is progressive with each hemorrhage, but peripheral vision is spared.

Chorioretinal atrophies with a “comet tail” appearance appear to be pathognomonic for PXE, but their expression widely varies.[37]

Vascular manifestations

Cardiovascular manifestations, except for intermittent claudication, are usually the last complications to be recognized in PXE. Calcification of the elastica media and intima of the blood vessels leads to various physical findings. In adults, peripheral pulses are often severely diminished. Renal artery involvement is rare, but can lead to hypertension, and coronary artery disease can result in angina pectoris and subsequent myocardial infarction.[8] Mitral valve prolapse has a higher prevalence in PXE. This prolapse may not be significant unless the murmur of mitral valve insufficiency is also present.[35]

Of note, the increased risk of cardiovascular complications has been observed not only in patients with PXE but also in heterozygous ABCC6 mutation carriers.[27]

GI hemorrhage, usually gastric in origin, results from the increased fragility of calcified submucosal vessels.[4] Hemorrhaging may occur early in the disease progression, especially in the second to fourth decade, without warning. Depending on its severity, hospitalization, blood transfusion, and surgery may be necessary. Approximately 10-15% of patients with PXE experience a GI hemorrhage at some point in their lives. Less commonly, hemorrhaging may occur in the urinary tract or cerebrovascular system. Hematuria or potentially fatal increases in intracranial pressure can be found in these cases, respectively.[30, 38]

As discussed, vascular findings in PXE mainly involve changes in medium-sized and large vessels[39] ; however, microangiopathy involving diabetic retinopathy has also been described.[40]

Diagnostic criteria

A revised set of criteria has recently been proposed to aid in the diagnosis of PXE.[41] In order to make a definitive diagnosis, major criteria from two separate categories must be met; for a probable diagnosis, two major criteria from within the same category (skin or eye) or one major criterion and one or more minor criterion from another category must be present. A possible diagnosis is made when only one major criterion or only minor criteria are found.

Major diagnostic criteria include the following:

  • Skin - Yellow papules/plaques on the lateral neck or body, skin biopsy showing increased calcification with clumping of elastic fiber taken from affected skin

  • Eye - Peau d’orange changes, angioid streaks (confirmed by angiography)

  • Genetics - Presence of a pathogenic mutation of both alleles of ABCC6, a first-degree relative who meets criteria for definitive pseudoxanthoma elasticum.

Minor diagnostic criteria include the following:

  • Eye - One angioid streak shorter than one disk diameter, “comets” in the retina, one or more “wing signs” on the retina

  • Genetics - A pathogenic mutation in one allele of the ABCC6 gene

Complications

Pseudoxanthoma elasticum (PXE) ocular involvement with retinal hemorrhages can lead to the progressive loss of central vision. Peripheral vision is spared.

Involvement of the elastic media and intima of the arteries can lead to claudication, hypertension, angina, myocardial infarction, and GI or cerebral hemorrhage.

Cerebral and GI hemorrhage or coronary occlusion, although uncommon, may be fatal.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Perform a CBC count to screen for iron deficiency anemia.

Perform a fecal occult blood test to evaluate for GI bleeding.

Perform a urinalysis to screen for urinary tract hemorrhage.

Obtain serum lipid levels. Pseudoxanthoma elasticum (PXE) is associated with precocious atherosclerosis and elevated lipid levels should be treated aggressively.

Obtain serum calcium and phosphate levels. These are usually in the reference range in PXE, but hypercalcemia and hyperphosphatemia have been reported.

In patients with biopsy-confirmed PXE who have no or only one ABCC6 mutation identified, screening for gamma-glutamyl carboxylase (GGCX) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) mutations is recommended as there could be digenic inheritance.[42]

It has been described that the presence of one or two major eye findings (ie, peau d’orange and/or angioid streaks) in addition to one or two skin findings (ie, classic pseudoxanthomatous skin lesions with or without cutaneous laxity and/or a positive skin biopsy) is diagnostic of PXE. The disease may not be definitively diagnosed if either skin or eye findings are absent, unless two ABCC6 mutations are found with molecular genetic testing.[27]

Although finding two pathogenic ABCC6 mutations is the criterion standard for the diagnosis of classic PXE, approximately 10% of individuals who fulfill diagnostic criteria have no or only one detectable mutation in ABCC6.[27] This lack of sensitivity of genetic testing and potential lack heterogeneity makes the accompanying clinical criteria especially important for accurate diagnosis.

Imaging Studies

Echocardiography is indicated in pseudoxanthoma elasticum (PXE) patients who have a murmur of mitral valve insufficiency, anginal symptoms, or a personal or family history of coronary artery disease.

CT scanning of the head may be performed if the physical examination shows focal neurologic deficits or other signs of cerebral hemorrhage.

Radiography may show soft tissue or large artery calcification, which may be noted as incidental findings on imaging performed for unrelated purposes.

Procedures

An ophthalmologic examination, including funduscopy, is essential to detect early signs of retinopathy, angioid streaks, and retinal hemorrhages.

It has been recommended that patient’s with pseudoxanthoma elasticum (PXE) self-monitor their visual acuity with the Amsler grid as the risk for macular choroidal neovascularization increases with age. Additionally, fundus examinations are recommended every 2 years for those younger than 40 years and twice a year for those older than 40 years.[43]

Upper and/or lower endoscopy is indicated if the patient has hematemesis, occult blood in the stools, melena, or frank GI bleeding. Endoscopy allows for treatment as well as diagnosis and is more sensitive than upper GI series and barium enema.

Ankle/brachial blood pressure using Doppler methods is useful in patients experiencing intermittent claudication or in patients with significantly diminished peripheral pulses to ensure adequate tissue perfusion.

Skin biopsy can confirm the diagnosis of PXE and is most accurate when obtained from an area of primary skin changes.

Histologic Findings

On cutaneous hematoxylin-eosin stains, elastic fibers appear basophilic as a result of calcium deposition. The fibers are fragmented, swollen, and clumped in the middle and deep reticular dermis. Collagen fibers are also split and are said to unwind or flower. Similar calcification is noted in the tunica media and intima of the blood vessels.[44] Special stains for calcium deposits (eg, von Kossa) and elastic fibers (eg, Verhoeff van Gieson, Orcein) can confirm the diagnosis. See the images below.

Calcification and clumping of elastic fibers in ps Calcification and clumping of elastic fibers in pseudoxanthoma elasticum.
Aggregates of irregular calcified elastic fibers i Aggregates of irregular calcified elastic fibers in the dermis.
Basophilic clusters in the mid and deep reticular Basophilic clusters in the mid and deep reticular dermis representing calcium deposition within elastic fibers in PXE.
 

Treatment

Approach Considerations

While the development of novel strategies is currently at the preclinical level, recommended therapies to possibly slow the progression of the disease include smoking cessation, moderate physical exercise, and an appropriate diet with supplemented magnesium, phosphate binders, and pyrophosphate analogs.[27, 45, 46]

Medical Care

Many of the pathologic changes associated with pseudoxanthoma elasticum (PXE) are irreversible, but prophylactic measures can be undertaken to minimize the disease course.

Cutaneous lesions

The redundant sagging folds of skin that present late in the course of PXE can be corrected by surgical excision if the patient desires, but delayed healing and scarring have been reported secondary to transepidermal extrusion of calcium.[47] Collagen and autologous fat injections may be options for the treatment of mental creases.[48]

Fractional carbon dioxide laser treatment has been used to improve cosmetic appearance, particularly improving the texture, volume, dispensability, and irregularity of skin lesions.[49]

Cardiovascular lesions

Diet and exercise are the main methods to minimize the extent of cardiovascular disease. Elevated serum lipid levels and hypertension aggravate the disease course and should initially be treated by lifestyle modifications, followed by drug therapy if necessary. Intermittent claudication is best managed by weight reduction and an exercise program to stimulate collateral blood vessel development. Pentoxifylline has been used but should be done so with extreme caution due to increased risk of hemorrhage.

Signs and symptoms of GI hemorrhage, such as melena or frank blood, must be closely monitored. Aspirin, antiplatelet agents, and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided if possible. GI hemorrhage may be managed by hospitalization, iron supplements, blood transfusions, endoscopic treatment, or surgery with partial gastrectomy if necessary.

Patients are advised to stop tobacco use, as tobacco has been shown to aggravate the disease course.

Ocular lesions

Retinal hemorrhages are preceded by subretinal membrane formation, which can be detected by the use of an Amsler grid. Changes can be confirmed by intravenous fluorescein angiography, and prompt treatment can help minimize visual loss.

Intravitreal antivascular endothelia growth factor (VEGF) treatment, such as bevacizumab, appears promising in the management of choroidal neovascularization.[50, 51]

Photodynamic therapy and intravitreal triamcinolone may also be beneficial in treating ocular complications.[51]

Vitamins A, C, and E and zinc supplements may reduce the risk of hemorrhage.

A review article by Marconi et al reported that treatment options for choroidal neovascularization of retinal pigment epithelium found in PXE include laser photocoagulation, transpupillary thermotherapy and photodynamic therapy, macular translocation surgery, and antivascular endothelial growth factor (anti-VEGF) intravitreal injections.[52]

Consultations

All patients with pseudoxanthoma elasticum (PXE) should be monitored on a regular basis by an ophthalmologist.

GI hemorrhages should be referred to a gastroenterologist, and cardiovascular manifestations are best managed by a cardiologist.

If pulmonary, urinary tract, or cerebral involvement is present, appropriate referrals should be made.

Patients and their families should receive genetic counseling. Current evidence suggests that the inheritance pattern in PXE is autosomal recessive. Recurrence risks in sporadic cases are, therefore, generally low. The Medscape Genomic Medicine Resource Center may be of interest.

Diet

Excessive dietary calcium consumption should be avoided in childhood and adolescence because a correlation of severity of pseudoxanthoma elasticum (PXE) with high calcium intake has been suggested.

Activity

Patients should avoid heavy lifting, straining, and activities that may predispose them to head trauma, which increases the risk of retinal hemorrhage. Patients with pseudoxanthoma elasticum (PXE) should avoid strenuous weight lifting and contact sports.

Long-Term Monitoring

Regular fecal occult blood testing and CBC count should be performed every 6 months to 1 year to monitor for GI hemorrhaging.

An ophthalmologic examination should be performed on pseudoxanthoma elasticum (PXE) patients at least once a year to detect early retinopathy, angioid streaks, or retinal hemorrhage.

Regular physical examinations, with particular attention to the cardiovascular system, should be performed to detect mitral valve insufficiency, coronary artery disease, or peripheral vascular compromise.

Managing comorbid conditions, including diabetes, hyperlipidemia, and hypertension due to premature atherosclerosis and an increased risk of cardiovascular disease, is important.

Avoidance of contact sports, NSAIDs, aspirin, and anticoagulants, owing to risk of hemorrhage, and smoking cessation should also be stressed.

 

Medication

Medication Summary

The goals of pharmacotherapy for pseudoxanthoma elasticum (PXE) are to reduce morbidity and to prevent complications, although lifestyle modification remains the mainstay of treatment.

In a randomized, placebo-controlled trial of sevelamer hydrochloride, a phosphate binder, for the treatment of PXE, calcification and clinical severity scores improved but were not superior to placebo. The presence of magnesium in the placebo may have clouded the results by causing a therapeutic benefit.[53]

Hemorheologic agents

Class Summary

These agents are used for the symptomatic treatment of peripheral vascular disease.

Pentoxifylline (Trental)

Pentoxifylline alters erythrocyte rheology, which, in turn, reduces blood viscosity. It may be used but with extreme caution of hemorrhage.