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].

• 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

  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]

  Seen with pseudoxanthoma elasticum (most commonly), Ehler's Danlos syndrome, Paget's disease, sickle cell anemia, or Idiopathic ("PEPSI"). [webeye.ophth.uiowa.edu]

• Fatigue

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: January 30, 2019 [patientslikeme.com]

  It allows you to play more relaxed and without fatigue, resulting in better and smoother playing. Once you try it, you will never go back. Welcome to How To Meme 101: Your guide to making Spark content. [strandbergguitars.com]

  Patients may complain of fatigue from chronic blood loss or claudication from blood vessel involvement. Slowly, as the disease progresses, patients note more severe skin lesions and there may be cardiovascular disease like angina and hypertension. [patient.info]

  Other symptoms of the condition may include the following: Joint pain Rashes High blood pressure Fatigue Chest pain Diarrhea Pseudoxanthoma Elasticum Diagnosis It is generally diagnosed by dermatologists as the principal symptoms of PXE involve the skin [primehealthchannel.com]

• Weakness

  […] normal interlacing pattern, but may be faintly basophilic due to calcium Increased dermal mucin may be evident Vascular involvement consists of fragmentation of the internal and external elastic laminae, accompanied by intimal thickening, resulting in weakness [pathologyoutlines.com]

  Cardiovascular involvement leads to cramping and weakness of the lower and/or upper limbs due to early arteriosclerosis of medium sized arteries whose walls are calcified. Transient ischemic attacks and angina pectoris are rare. [clinmedjournals.org]

  PXE may cause the following symptoms: growth of yellowish bumps on the skin of the neck, under the arms, or in the groin area; reduced vision; periodic weakness in the legs ( claudication ); or bleeding in the gastrointestinal tract, particularly the [rarediseases.info.nih.gov]

  In addition to these coronary ischemic events, he has endured two strokes, with residual right arm weakness. [escholarship.org]

• 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]

  […] 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]

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

• Chest 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]

  As the disease progresses other symptoms may occur like gastrointestinal bleeding, high blood pressure, chest pain, and blood in the urine. [aocd.org]

  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 (vomiting blood) Melena (blood in stool) How is [dovemed.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 [contact.org.uk]

• Skin Papule

  Patients have yellowish skin papules on neck and flexural areas, angioid streaks on retina, retinal haemorrhage, diffuse arteriosclerosis and narrowing of small and medium sized arteries. [exeterlaboratory.com]

  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]

  Dominant type 2, which is characterized by atypical, yellowish, flatter skin papules than in dominant type 1, skin hyperelasticity, mild angioid streaks and blue sclera. Recessive type 1, which is the most common form with intermediate severity. [eyewiki.aao.org]

• Angioid Streaks of the Retina

  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]

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]

[…] 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]

Ranibizumab treatment was well tolerated with no adverse events reported. [ncbi.nlm.nih.gov]

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]

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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2. Li Q, Jiang Q, Pfendner E, Váradi A, Uitto J. Pseudoxanthoma elasticum: Clinical phenotypes, molecular genetics and putative pathomechanisms. Exp Dermatol. 2009;18(1):1-11.
3. Marconi B, Bobyr I, Campanati A, et al. Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment. Intractable Rare Dis Res. 2015;4(3):113-122.
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9. van den Berg JSP, Hennekam RCM, Cruysberg JRM, et al. Prevalence of symptomatic intracranial aneurysm and ischaemic stroke in pseudoxanthoma elasticum. Cerebrovasc Dis. 2000;10(4):315–9.
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11. Orssaud C, Roche O, Dufier JL. Visual Impairment in Pseudoxanthoma Elasticum: A Survey of 40 Patients. Ophthalmic Genet. 2015;36(4):327-32.