Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive calcification, mineralization, and thus fragmentation of the elastic fibers present in the skin, arterial wall, and retina [1]. This rare disorder affects the skin, eyes, cardiovascular system, and gastrointestinal (GI) system. It is a clinically heterogeneous disease that manifests in the second or third decade [2].

Skin features are the earliest sign. Lesions appear as small, yellow papules that coalesce to form a papule [3]. It may be described as a rash with "cobblestone" pattern. The skin changes occur on the lateral neck with progression to other sites such as the axillae, inguinal folds, periumbilical region, and the antecubital and popliteal fossa [4]. Hence, loose skin develops in these locations. The inner lower lip and mucosa of the vagina and rectum may be affected as well. Generally, these lesions do not resolve spontaneously [5].

Ocular signs include "peau d’orange" appearance on an ophthalmologic exam [1]. This is followed later by angioid streaks, which reflect the mineralization of Bruch's membrane. As a result, neovascularization and subretinal hemorrhage may develop, which leads to loss of visual acuity [6]. Blindness ensues if the macula is affected.

Cardiovascular manifestations include intermittent claudication, diminished or absent peripheral pulses, hypertension, mitral valve prolapse [7], and complications as described below.

Complications

Although rare, patients are at risk for developing life-threatening sequelae such as myocardial infarction, cerebral aneurysm, ischemic strokes and other cardiovascular complications [8] [9]. Also, GI bleeding is common, as it leads to hematemesis and melena [3].

• Intermittent Claudication

  claudication, hypertension, angina, and myocardial infarction Vascular fragility: Gastrointestinal hemorrhage and small-vessel bleeding with subsequent anemia Clinical evaluation Diagnosis of pseudoxanthoma elasticum is based on clinical and histologic [msdmanuals.com]

  claudication or hypertension Rarely, death may result from cerebral haemorrhage, coronary occlusion or massive haemorrhage in to the gut Ocular The ocular changes are variable Vascular lesions known as angioid streaks affect the retina of most patients [pcds.org.uk]

  Cardiovascular manifestations include intermittent claudication, diminished or absent peripheral pulses, hypertension, mitral valve prolapse, and complications as described below. [symptoma.com]

  Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. [ncbi.nlm.nih.gov]

  Ankle/brachial blood pressure using Doppler methods is useful in patients with intermittent claudication or significantly diminished peripheral pulses. Biopsy can give histological confirmation of the diagnosis. [patient.info]

• Pain

  Too little blood flow may result in chest pain ( angina ), a heart attack, and leg pain while walking ( intermittent claudication ). Bleeding may continue for prolonged periods. [merckmanuals.com]

  The patient presented at the Clinical Management Unit of the Department of Oral and Maxillofacial Surgery, Virgen del Rocio Hospital (Seville, Spain) with pain related to a semi-erupted lower first molar. [ncbi.nlm.nih.gov]

  Too little blood flow may result in chest pain (angina), a heart attack, and leg pain while walking (intermittent claudication). Children may develop atherosclerosis (deposits of fatty material in the arteries) at a young age. [msdmanuals.com]

  This may lead to pain in the legs on walking (claudication), stroke, heart pain (angina) and cardiomyopathy (heart muscle disease). Mitral valve prolapse occurs in about 5–8% of cases. [dermnetnz.org]

• Anemia

  […] gradual vision loss Cardiovascular system: Premature atherosclerosis with subsequent intermittent claudication, hypertension, angina, and myocardial infarction Vascular fragility: Gastrointestinal hemorrhage and small-vessel bleeding with subsequent anemia [msdmanuals.com]

  We describe three cases of the acquired PXE-like syndrome that often occurs in association with hemolytic anemias, in particular the hemoglobinopathies, and review the literature on the subject. [ncbi.nlm.nih.gov]

  Sickle cell anemia, the more familiar of the two diseases, has been better understood since the discovery by Pauling and his associates. 1 Their studies indicate [jamanetwork.com]

• Coronary Atherosclerosis

  Sudden death may occur due to coronary atherosclerosis with acute myocardial ischemia, systemic hypertension, mitral valve prolapse, restrictive cardiomyopathy, gastrointestinal hemorrhage, and cerebral ischemia or hemorrhage. von Kossa stain [histopathology-india.net]

• Easy Bruising

  […] susceptibility Bruise easily Easy bruisability Easy bruising [ more ] 0000978 Myopia Close sighted Near sighted Near sightedness Nearsightedness [ more ] 0000545 Striae distensae Stretch marks 0001065 5%-29% of people have these symptoms Abnormal endocardium [rarediseases.info.nih.gov]

  bruising, features that are frequent in thalassemic and SCD patients. [bloodjournal.org]

• Hematemesis

  Also, GI bleeding is common, as it leads to hematemesis and melena. The clinical assessment consists of the patient's history, physical exam, and the appropriate studies. [symptoma.com]

  Gastrointestinal hemorrhages, melena, and hematemesis can also be observed. Patients also develop atherosclerosis, cardiac arrest, and strokes at younger ages. [karger.com]

  […] related to the heart and blood vessels include: Angina (chest pain) Myocardial infarction/heart attack Intermittent claudication: Leg pain during walking that resolves at rest Signs and symptoms related to the gastrointestinal (digestive) tract include: Hematemesis [dovemed.com]

• Mitral Valve Prolapse

  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. [medical-dictionary.thefreedictionary.com]

  Mitral valve prolapse often occurs. This prolapse may not be significant unless there is also mitral regurgitation. GI haemorrhage is usually from the stomach and is the most significant vascular complication. [patient.info]

  Sudden death may occur due to coronary atherosclerosis with acute myocardial ischemia, systemic hypertension, mitral valve prolapse, restrictive cardiomyopathy, gastrointestinal hemorrhage, and cerebral ischemia or hemorrhage. von Kossa stain [histopathology-india.net]

• Vascular Disease

  Patients with this disease often have premature and severe vascular disease. [jamanetwork.com]

  Peripheral arterial vascular disease can lead to intermittent leg claudication. A skin biopsy often demonstrates calcified elastic fibers, even in a mildly affected area of skin. [ncbi.nlm.nih.gov]

  Acta (2005) [ Pubmed ] Genetically determined vascular diseases. Rafałowska, J. [wikigenes.org]

  Vascular Disease The basic vascular pathology in PXE is dystrophic calcification of the abnormal elastic fibers in the internal elastic lamina and media of middle sized arteries. [hypermobility.org]

• Heart Disease

  A 54-year-old Caucasian man with history of heart disease presented with visual loss in his right eye. An examination revealed choroidal neovascularization and reduced visual acuity, while no abnormalities were seen in his left eye. [ncbi.nlm.nih.gov]

  Cardiovascular checks can reduce the risks of heart disease and stroke. Particular care is needed during pregnancy and labour. [cafamily.org.uk]

  With the exception of aspirin, there should be standard management of high-risk coronary heart disease. If there is mitral regurgitation, antibiotic prophylaxis may be indicated for dentistry, etc. [patient.info]

  Cardiovascular manifestations usually develop last and result from slowly progressive calcification of elastic arterial walls with an increased risk of accelerated peripheral vascular disease, ischemic heart disease, hypertension and cerebrovascular disease [ijdvl.com]

• Leg Pain

  Too little blood flow may result in chest pain ( angina ), a heart attack, and leg pain while walking ( intermittent claudication ). Bleeding may continue for prolonged periods. [merckmanuals.com]

  Too little blood flow may result in chest pain (angina), a heart attack, and leg pain while walking (intermittent claudication). Children may develop atherosclerosis (deposits of fatty material in the arteries) at a young age. [msdmanuals.com]

  Other problems that occur in some people with PXE include: possible heart attacks or stroke resulting from abnormal elastin in blood vessels within heart muscle or brain leg pain as blood cannot easily reach the muscles bleeding in the stomach and digestive [cafamily.org.uk]

• Skin Lesion

  lesions, particularly secondary cutis laxa (loose hanging skin), can be improved by plastic surgery Patients and their families should receive genetic counselling Other resources Patient support group - PIXIE [pcds.org.uk]

  MENU Pseudoxanthoma elasticum-like skin lesions with congenital erythropoietic porphyria Volume 24, numéro 3, May-June 2014 Résumé Texte intégral Références Illustrations Compléments Auteurs 1 Department of Dermatology, 2 Department of Global Health, [jle.com]

  lesions consist of yellowish papules or plaques with an associated increase in skin laxity. [ijdvl.com]

  The two patients had submucosal yellowish nodular lesions similar to the xanthoma-like skin lesions seen in the disease. [thedoctorsdoctor.com]

  Clinical features of pseudoxanthoma elasticum Individuals with PXE have distinctive skin lesions, changes of blood vessels, and eye abnormalities. These may vary in distribution and severity Skin lesions The skin lesions of PXE are characteristic. [dermnetnz.org]

• Skin Plaque

  Symptoms - Pseudoxanthoma elasticum- recessive form * Gastrointestinal hemorrhage * Obstructed arteries * Calcified heart vessels * Yellowish skin papules * Yellowish skin plaques * Vision loss * Myopia * High arched palate * Increased skin elasticity [checkorphan.org]

  (A) Skin plaques and skin laxity in the axillary area. (B,C) Colour fundus photographs of the posterior pole of the right and left eye, respectively. [frontiersin.org]

• Striae Distensae

  distensae Stretch marks 0001065 5%-29% of people have these symptoms Abnormal endocardium morphology 0004306 Abnormal thrombocyte morphology Platelet abnormalities 0001872 Abnormality of the thorax Abnormality of the chest 0000765 Acne 0001061 Angina [rarediseases.info.nih.gov]

• Prolapse

  Mitral valve prolapse often occurs. This prolapse may not be significant unless there is also mitral regurgitation. GI haemorrhage is usually from the stomach and is the most significant vascular complication. [patient.info]

  This leads to a greater susceptibility to the conditions that are associated with hardening of the arteries in the normal aging population—high blood pressure, heart attack, stroke, and arterial obstruction—and, similarly, mitral valve prolapse. [medical-dictionary.thefreedictionary.com]

• Angioid Streaks of the Retina

  Elastic tissues become calcified and fragmented, leading to disruption of the involved organ systems: Ocular system: Angioid streaks of the retina, retinal hemorrhages, and gradual vision loss Cardiovascular system: Premature atherosclerosis with subsequent [msdmanuals.com]

  streaks affect the retina of most patients with PXE. [pcds.org.uk]

  In the physical examination, typical skin lesions were present and also an angioid streak of the retina. The patient and a control group were evaluated by the CR-2000 Research Cardiovascular Profiling System. [ncbi.nlm.nih.gov]

  streaks of the retina and similar elastic tissue degeneration and calcification in arteries. angioid streaks Degeneration of Bruch's membrane of the choroid characterized by brown or reddish lines or streaks in the fundus of the eye. [medical-dictionary.thefreedictionary.com]

• Blue Sclera

  The pathophysiology is yet unknown. [20] Other ocular findings: blue sclera Classification Dominant type 1, which contains cutaneous changes and the skin becomes thin, delicate and bruises easily. [eyewiki.aao.org]

  […] endocardium morphology 0004306 Abnormal thrombocyte morphology Platelet abnormalities 0001872 Abnormality of the thorax Abnormality of the chest 0000765 Acne 0001061 Angina pectoris 0001681 Atherosclerosis Narrowing and hardening of arteries 0002621 Blue [rarediseases.info.nih.gov]

• Central Scotoma

  Usually, central scotoma tends to increase in size if untreated, and subsequently, scarring of the macula occurs. [eyewiki.aao.org]

• Stroke

  Three days after the second procedure the patient was afflicted by acute stroke. [ncbi.nlm.nih.gov]

  Vision loss Ischemic or haemorrhagic stroke Heart attack Severe limb claudication Acute GI bleeding Miscarriage is more common in early pregnancy Striae (stretch marks) are almost universal in pregnancy. [dermnetnz.org]

The clinical assessment consists of the patient's history, physical exam, and the appropriate studies. The diagnosis is achieved based on the clinical picture, histopathology, and identification of mutations in the gene responsible for this disease.

Diagnostic criteria

The gold standard for diagnosis is the detection of one or two ABCC6 mutations. Proposed diagnostic criteria include the presence of 1) at least one ophthalmic finding: peau d’orange and/or angioid streaks and 2) at least one skin feature: characteristic lesion (with or without cutaneous laxity) and/or a positive biopsy of the skin [10]. It is imperative that both eye and skin manifestations are present for definitive diagnosis. If either is absent, then two pathogenic ABCC6 mutations must be identified [10].

Laboratory tests

Patients with GI bleeding are evaluated with a complete blood count (CBC) to screen for iron deficiency anemia as well as a fecal occult blood test (FOBT). Additionally, serum lipid levels are obtained since patients are at risk for atherosclerosis. Another component of the workup includes measurement of serum calcium and phosphate, which are usually normal but may be elevated. Also, a urinalysis should be done to test for hematuria.

Diagnostic procedures

Very importantly, echocardiography is performed in patients with cardiac manifestations and risk factors for cardiac disease. Also, GI endoscopy is indicated in individuals with clinical signs of bleeding while a computed tomography (CT) scan of the head is warranted for those with clinical signs suggestive of a cerebrovascular accident. Furthermore, an ankle-brachial index test is beneficial in the assessment of intermittent claudication.

A thorough ophthalmologic exam that includes fundoscopy should be performed. Moreover, biannual surveillance is recommended for patients greater than 40 years old and every 2 years for those less than 40 [11]. Additionally, patients are encouraged to monitor their visual acuity with the use of the Amsler Grid.

• Central Scotoma

  Usually, central scotoma tends to increase in size if untreated, and subsequently, scarring of the macula occurs. [eyewiki.aao.org]

There is no confirmed treatment that directly interferes with the disease process. [eyewiki.aao.org]

There is no specific treatment, but intravitreal injections of angiogenesis-blocking antibodies may be given for angioid streaks. Characteristic cutaneous papular lesions begin in childhood and are primarily of cosmetic concern. [msdmanuals.com]

[…] peripheral vascular aging in pseudoxanthoma elasticum - proof of concept for arterial calcification-induced cardiovascular disease. ( 30745467 ) 2019 2 Calciphylaxis and nephrogenic fibrosing dermopathy with pseudoxanthoma elasticum-like changes: Successful treatment [malacards.org]

What is the treatment for pseudoxanthoma elasticum? The most important aspect of treatment is to ensure that complications from blood vessel involvement are prevented or dealt with speedily by the appropriate specialist. [dermnetnz.org]

Pseudoxanthoma Elasticum: Progress in Research Toward Treatment: Summary of the 2012 PXE International Research Meeting. J Invest Dermatol. 2013 Jun;133(6):1444-9. [hypermobility.org]

In middle-aged or young adults with angioid streaks and no obvious systemic disease, the possibility of a hemoglobulinopathy or pseudoxanthoma elasticum (PXE) as etiologic entities should be investigated. [ncbi.nlm.nih.gov]

Thus, the etiology of heart failure in this rare condition might be associated with a variety of situations, including coronary artery disease, valvular disease, and cardiomyopathy. [jxym.amegroups.com]

THE low incidence of "essential" hypertension below the age of puberty has become more apparent as diagnostic methods have improved and new etiologic entities have been recognized. [nejm.org]

Etiology PXE is caused by homozygous or compound heterozygous mutations in the ABCC6 gene (16p13.1), which encodes a transmembrane protein from the ATP-binding cassette (ABC) transporter superfamily. [orpha.net]

While the true epidemiology of PXE is not currently known, the following has been estimated: Prevalence ranges from 1 in 100,000 to 1 in 25,000 which translates to a heterozygous carrier frequency of 0.63–1.26% Women and Caucasians may have a higher prevalence [dermnetnz.org]

Revised estimations based on genotyping in a high vascular risk cohort. ( 29800625 ) Kranenburg G....Spiering W. 2018 24 VISUAL ACUITY IN PSEUDOXANTHOMA ELASTICUM. ( 29652691 ) Risseeuw S....van Leeuwen R. 2018 25 Pseudoxanthoma elasticum in Italy: epidemiological [malacards.org]

[email protected]. 12 PXE International, 4301 Connecticut Avenue NW, Suite 404, Washington, DC 20008, USA. [email protected]. 13 Laboratory of Translational Genomics, The Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, [ncbi.nlm.nih.gov]

Washington University, College Of Arts and Sciences, 125 Michigan Avenue NE, Washington, DC 20017, USA 2 PXE International, 4301 Connecticut Avenue NW, Suite 404, Washington, DC 20008, USA 3 Laboratory of Translational Genomics, The Division of Cancer Epidemiology [mdpi.com]

Alternatively, a lack of functioning MRP6 may impair the transport of a substance that would normally prevent mineralization, leading to the abnormal accumulation of calcium and other minerals characteristic of PXE. [ghr.nlm.nih.gov]

Prevention and treatment of complications and injuries Because there is no cure for pseudoxanthoma elasticum, treatment is aimed at preventing and treating complications and injuries. [merckmanuals.com]

They should exercise for cardiovascular health and to prevent or reduce claudication later in life. [medical-dictionary.thefreedictionary.com]

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