Vascular Abnormalities and Complications Associated with

Pseudoxanthoma Elasticum and a Medical Management Plan

Jan ThompsonFeb. 21, 2008

Advisor: Dr. Doris Rapp

Pseudoxanthoma Elasticum (PXE)

• Slow progressive disease• Lesions in connective tissue of skin, retina,

and arterial walls• Characterized by fragmentation of elastin and

calcification of the extracellular matrix

Epidemiology

• Prevalence of 1:75,000• 2:1 female to male • PXE International Registry

– 3,609 cases worldwide including U.S.– 1,913 cases in U.S.– 31 cases in KY

• Underdiagnosed/Misdiagnosed– Variability in degree of presentation – Awareness– Accuracy of diagnosis

Genetics• Autosomal recessive• Mutations mapped to ABCC6 gene on

chromosome 16p13.1• Encodes a multidrug resistant protein (MRP6)

– Efflux transporter of an unknown substrate

• MRP6 found predominantly in hepatocytes, and much lesser extent in tissues affected by PXE

Pathophysiology

• Pathophysiology is unclear• Current theory

– Metabolic disorder with secondary connective tissue manifestations

Diagnosis: Clinical features(Lebwohl et al., 1994)

• Skin lesions (2nd decade of life) • 1st criteria (physical)

– Yellow macules, papules, or plaques (“plucked chicken” or “cobblestone” appearance) in flexural areas of body

– Later in life—skin hangs in folds

• 2nd criteria (histology)– Biopsy skin lesions– Elastin fragmentation and

calcium deposition in ECMBergen et al. Pflügers Archiv 2007;453:685 -91

Vanakker, OM et al. J Invest Dermatol 2007;127:581-7 Chassaing, N et al. J Med Genet 2005;42:881-892

Skin Lesions: Skin Folds

Clinical Features: Diagnosis(Lebwohl et al., 1994)

• Retinal lesions (2nd to 3rd decade of life)• 3rd criteria

– Peau d’orange– Angioid streaks

– Leads to– Choroidal

neovascularization– Retinal hemorrhages– Loss of visual acuity and

central vision Bergen et al. Pflügers Archiv 2007;453:685 -91

Differential Diagnosis• PXE diagnosis: Meet all 3 of the criteria or

meet 1 of the criteria with a family history of PXE

• PXE-like skin lesions– hemoglobinopathies (thalessemia), vitamin K-

dependent clotting factor deficiencies, cutis laxa, solar elastosis

• Angioid streaks– Marfan syndrome, osteitis deformans (Paget

disease), hemoglobinopathies (e.g. sickle cell disease)

Other Clinical Features(Can be life-threatening)

• Gastrointestinal bleeding (4th-5th decade of life)

• Cardiovascular Complications (4th-5th decade of life)– Diminished peripheral pulses– Intermittent claudication– Accelerated atherosclerosis– Peripheral artery disease– Coronary artery disease– Stroke

Prevalence of Cardiovascular Complications

• Vanakker et al. (2008)– Prevalence of cardiovascular complications in

Belgium PXE patients vs. Belgium general population

• Strokes (15% vs 0.3-0.5%)• Abnormal Doppler examinations of lower extremities (53% vs 10-

30%)• Intermittent claudication (22% vs 1-4.6%)

Vascular Abnormalities

• Germain et al. (2003)– Noninvasive measurements of common carotid and

radial arteries– 27 PXE patients and 27 control subjects matched by

age, sex, BP, HR, smoking, and lipid profile– Results: Outward hypertrophic remodeling of PXE

carotid arteries• Intima-media (IM) thickening without narrowing of arteries• Proteoglycan accumulation, calcium, elastin fragmentation• Atherosclerotic plaque formation

Vascular Abnormalities

• Germain et al. (2003)– Results: Inward remodeling of PXE radial arteries

• Narrowing of internal and external diameters• IM abnormalities extruded into lumen• Atherosclerotic plaque formation• Obstructive artery diseases

Vascular Abnormalities

• Kornet et al. (2004)– Non-invasive age-related comparisons of common

carotid arteries in PXE and control cohorts (nonsmokers, no hypertension, no cardiovascular problems)

• PXE patients (<45 yo)—IM thicker than age-related cohort

• Comparison of older PXE (>45 yo) with age-related cohort—IM thicker, more calcification, more elastin fragmentation, walls less stiff and more elastic

• Arterial wall changes provide an environment conducive for atherosclerotic plaque formation

Vascular Abnormalities

Kornet L et al. Ultrasound Med Biol. 2004;30:1041 -8

PXE

Control

Calcium deposition Elastin Fibers

Treatment• No cures or treatments to prevent

progression of PXE• Evidence that antioxidants and phosphate

binders may aid in regression of skin lesions• Evidence correlating high dietary intake of

calcium and phosphorus in younger years with increased severity of PXE manifestations

• More controlled studies needed to support these hypotheses

Medical Management• Normal life span• Team approach: PCP, dermatologist, retinal specialist,

cardiologist, genetic counselor• Educate patient on disease, clinical manifestations, healthy

lifestyle choices• Genetic counseling• Routine skin evaluations, ocular assessments,

cardiovascular assessments, and laboratory tests• Address risk factors

– Cardiovascular (atherosclerosis)– Obesity, smoking, hypertension, hyperlipidemia

– Hemorrhages• No NSAIDS or warfarin• No contact sports and straining exercises

• Treat symptoms of clinical manifestations

Skin assessment Complete skin examination including biopsy from axilla or neck (by dermatologist)

Cosmetic surgical consult if skin lesions are a problem

Ophthalmology assessment Routine visual acuity evaluation Regular use of Amsler grid to monitor central vision Routine dilated eye examinations by retinal specialist

Cardiology assessment Routine evaluation of blood pressure, peripheral pulses, and heart rate/sounds Routine EKG Baseline examination including Doppler evaluation of peripheral vasculature,

cardiac stress test, echocardiogram, and sonogram of heart valves

Laboratory tests Routine blood count, ferritin, serum lipids, urinalysis

Medication restrictions Avoid blood-thinning medications such as NSAIDs and warfarin Selective use of aspirin for prevention of thromboembolic events in high risk

patients

Diet Avoid high cholesterolLifestyle Regular exercise but avoid contact sports and straining

Weight control Avoidance of smoking

Genetic counseling Affected individuals Families Genetic risk factors for offspring

Table 2: Suggested management schedule for patients with PXE*

*Table from Laube and Moss (2005) with modifications based on information from Bercovitch (2007), Sherer et al. (1999), Terry and Bercovitch (2007).

-PXE International, Inc., Washington DChttp://www.pxe.org

-GeneTests: Medical Genetics Information Resource (database online), University of Washington, Seattle http://www.genetests.org

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