Vascular Abnormalities and
Complications Associated with
Pseudoxanthoma Elasticum and a
Medical Management Plan
Jan Thompson
Feb. 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 ECM
Bergen et al. Pflügers Archiv 2007;453:685 -91
Skin Lesions: Skin Folds
Vanakker, OM et al. J Invest Dermatol 2007;127:581-7
Chassaing, N et al. J Med Genet 2005;42:881-892
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 Kdependent 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 1030%)
• 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
Calcium deposition
Elastin Fibers
PXE
Control
Kornet L et al. Ultrasound Med Biol. 2004;30:1041 -8
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
Table 2: Suggested management schedule for patients with PXE*
Skin assessment








Complete skin examination including biopsy from axilla or neck (by
dermatologist)
Cosmetic surgical consult if skin lesions are a problem
Routine visual acuity evaluation
Regular use of Amsler grid to monitor central vision
Routine dilated eye examinations by retinal specialist
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
Lifestyle







Avoid high cholesterol
Regular exercise but avoid contact sports and straining
Weight control
Avoidance of smoking
Affected individuals
Families
Genetic risk factors for offspring
Ophthalmology assessment
Cardiology assessment
Genetic counseling
*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 DC
http://www.pxe.org
-GeneTests: Medical Genetics
Information Resource (database online),
University of Washington, Seattle
http://www.genetests.org
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Med. 1978; 102:298-302
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