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PXE and the Primary Care Practitioner
Lionel Bercovitch, MD
Clinical Associate Professor of Dermatology
Brown University School of Medicine, Providence, RI
Medical Board Chairman, PXE International, Inc.
23 Mountain Street • Sharon, MA 02067
Voice: 781-784-3817 • Fax: 781-784-6672
E-mail: pxe@pxe.org • http://www.pxe.org
Pseudoxanthoma elasticum (PXE)
is a heterogeneous inherited disorder of connective
tissue, the hallmark of which is dystrophic calcification of elastic
tissue of the skin, retina, and
arteries. The primary care physician may be the first to suspect and
diagnose PXE because of the varied clinical manifestations involving
several body systems. He or she may coordinate the
lifelong specialty care of the affected patient, and most importantly,
may be expected to be an
authoritative resource as well as source of support for the patient
and family.
Incidence
PXE is a rare disease. Published reports estimate incidence at 1/25,000-50,000.
The true
incidence is unknown, as it is likely that affected individuals with
mild involvement and/or atypical
presentation escape diagnosis.
Skin manifestations
The primary lesion of PXE is a small 2-5 mm yellowish or yellow-orange
papule, irregular
or rhomboid in shape (hence the term pseudoxanthoma), which may form
groups or coalesce into larger plaques. The lesions are asymptomatic
and tend to be distributed symmetrically on flexural areas progressing
downward from the neck to the axillae and antecubital fossae, and later
to the groin and popliteal fossa. Less common areas of involvement include
the periumbilical area, oral, and anogenital mucosa. Oral lesions, seen
on the inner aspect of the lower lip resemble Fordyce spots.
The lesions may give the affected skin a "plucked chicken"
or "cobblestone" appearance.
The lesions may cause the skin of the neck to appear unwashed. Differential
diagnosis must
consider solar elastosis.
The skin lesions develop during childhood or adolescence, and progress
slowly and
unpredictably with age, spreading from the neck downward. The neck,
axillae, groin, or face may
sometimes manifest lax, redundant folds of skin in late stage PXE.
Skin biopsy of lesional (and sometimes non-lesional) skin confirms the
diagnosis if it shows calcification of fragmented, clumped elastic fibers
in the mid- and lower dermis can confirm the diagnosis. The highest
yield is from biopsy of a primary lesion (papule). In the absence of
primary lesions, punch biopsy of neck, axilary and/or antecubital fossa
are recommended.The skin lesions are asymptomatic. Affected individuals
with unsightly redundant folds can undergo cosmetic surgical correction,
usually with uncomplicated wound healing, although healing may sometimes
be poor or accompanied by calcium extrusion through the wound. Although
skin manifestations are most characteristic of PXE, the ocular and cardiovascular
manifestations are responsible for he morbidity of the disease. Indeed,
in some cases the skin lesions are not visible.
Retinal Disease
The earliest, and often subtle, manifestation of PXE in the retina is
peau d'orange, a diffuse yellowish mottling of the fundus usually seen
in the first two decades of life. The characteristic retinal lesion
is the angioid streak, seen in most adult affected individuals, and
seen sometimes in children. Angioid streaks are gray to brown or dark
red, spoke-like bands radiating out from the optic disc or encircling
the disc with peripapillary streaks. Angioid streaks correspond to breaks
in Bruch's membrane, an elastin rich layer of the choroid. Neovascular
capillary nets can grow through these breaks, leading to hemorrhage.
These can lead to central visual loss (not true blindness), if they
occur in the macula or fovea. Laser photocoagulation may be effective
in obliterating neovascularization, but it often recurs, and disciform
scarring can further compromise central vision.
Vascular Disease
The basic vascular pathology in PXE is dystrophic calcification of the
elastic tissue of the media. Subsequent intimal elastic calcification
and atherosclerosis and intimal fibrous proliferation leading to vascular
occlusion or fragility may occur. The most common manifestations of
arterial disease in PXE are diminished peripheral pulses and intermittent
claudication. Angina and symptoms of intestinal ischemia may occur relatively
early in life. Hypertension may be more common among affected individuals
with PXE. If present, this increases the risk of vascular complication
in the individuals affected by PXE, and needs to be well controlled.
GI bleeding, usually gastric, may be an early manifestation and even
the presenting sign of PXE. The mechanism is unknown, but gastroscopy
shows gastric mucosal changes resembling mucosal PXE elsewhere (yellowish
papules), and the histology of the gastric vessels resembles that of
other arteries affected by PXE.
Genetics of PXE
PXE may be inherited as either an autosomal recessive or dominant
trait. Sporadic cases either represent autosomal recessive transmission,
autosomal dominant transmission from an affected parent with minimal
or inapparent disease (who might actually represent a heterozygous recessive
carrier), or spontaneous dominant mutations. Some recessive carriers
may have mild clinical manifestations. Clinical expression is not helpful
in predicting the mode of inheritance; PXE is quite heterogeneous and
environmental influences may modify the clinical expression. The gene
is on the short arm of chromosome 16 (16p13.1) and codes for the membrane
transport protein, ABCC6. Mutational analysis is in progress, as are
functional studies of the gene.
Workup of the Individual Affected
by PXE
General workup of the individual affected by PXE should include:
• A history detailing with onset, symptoms of vascular and ocular
disease, and family history.
• Examination of the skin and cardiovascular system, including
peripheral pulses.
• Confirmation of diagnosis by skin biopsy with appropriate calcium
stains.
• Laboratory evaluation of lipids.
• Examination of first degree relatives.
Ophthalmologic consultation
should include:
• Recording visual acuity.
• Dilated indirect ophthalmoscopic exam.
• Amsler grid monitoring of central visual fields and fluorescein
angiogram if signs or symptoms
warrant.
Cardiovascular consultation
should include:
• Non-invasive studies of the peripheral vasculature (Doppler
ankle-brachial ratios).
• Baseline stress test and sonogram of heart valves.
• EKG's (if symptoms or clinical findings warrant).
Management of Individuals Affected
by PXE
As are most inherited diseases, PXE is incurable. Management should
focus on education
of the affected individual, genetic counseling, monitoring and treatment
of complications, and
dietary and lifestyle modifications to delay or possibly prevent complications.
This may involve a
team approach including dermatologist, primary care physician, ophthalmologist,
cardiologist,
vascular surgeon, plastic surgeon, genetic counselor, nutritionist and
support groups. Support
groups are of tremendous benefit in helping affected individuals cope
with the disorder.
The affected individual (or parent) needs to be educated in understandable
terms regarding
the various manifestations of the disease and the prognosis (which is
not as dire as some affected individuals are led to believe). Offer
genetic counseling with caution, as the genetic transmissibility of
the disease is not yet understood. Regular ophthalmologic examination
by a physician with expertise in retinal disease is essential, and affected
individuals should learn to use the Amsler grid to monitor for central
visual disturbances. Regular physical examinations with specific attention
to the gastrointestinal and cardiovascular systems are essential. Lipid
levels should be monitored periodically.
Surgical intervention may be indicated for gastrointestinal bleeding,
severe peripheral
vascular disease (if correctable), and the improvement of cosmetic deformities
of the face, neck,
axilla, and groin. Wound healing seems to be uncomplicated in PXE, although
cosmetic
acceptability is less predictable.
Weight control, avoidance of smoking, and aggressive management of hypertension
and
lipid disorders are all essential in delaying or reducing the severity
of vascular complications.
Pentoxifylline may be of value in managing claudication. Aspirin and
other non-steroidal anti-inflammatory medications should be avoided
due to the risk of gastrointestinal hemorrhage.
Most women with PXE have normal pregnancies, however gastric or uterine
bleeding may
very rarely complicate them. Fetal complications due to impaired uteroplacental
blood flow do not
appear to be a problem. There is no basis for women affected by PXE
to avoid becoming pregnant.
There are at present no tests for prenatal diagnosis of this disease.
With characterization of the
defective gene and gene products, such tests may eventually become available.
It has been reported that high calcium intake early in life may correlate
with the overall
severity of PXE, but this has not been confirmed by studies, and remains
controversial.
PXE International, Inc. maintains a Blood and Tissue Bank and an international
registry.
Please encourage affected individuals to register with them.
References
Bergen AA, Plomp AS, Schuurman EJ,
Terry S, Breuning M, Dauwerse H, Swart J, Kool M, van
Soest S, Baas F, ten Brink JB, de Jong PT. Mutations in ABCC6 cause
pseudoxanthoma
elasticum. 2000 Jun. Nat. Genet. 25, 228-231.
Lebwohl M., Neldner K., Pope F.M. et al: Classification of pseudoxanthoma
elasticum. Report of
a consensus conference. J Am Acad Dermatol. 1994; 30:103-107. A contemporary
clinical
classification that does not depend on heredity.
Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, Quaglino D, Pasquali-Ronchetti
I, Pope
FM, Richards A, Terry S, Bercovitch L, de Paepe A, Boyd CD. Mutations
in a gene encoding
an ABC transporter cause pseudoxanthoma elasticum. Nat Genet. 2000 Jun;25(2):223-7.
A
discussion of the gene defective responsible for pseudoxanthoma elasticum.
Neldner K.H. Pseudoxanthoma elasticum. Clin Dermatol 1988; 6: 1-159.
The most encyclopedic
review of the subject for the practitioner.
Renie, WA Pyeritz RE, Comb J et al: Pseudoxanthoma elasticum: High calcium
intake early in life
correlates with severity. Am J Hum Genet 1984;19: 235-244. Overall,
severity in both
sexes correlate with high calcium intake in early life, but sample size
to small to confirm for
either sex or individual features of disease. Indeed, correlation was
negative for women.
Viljoen D.L., Bloch C, Beighton P: Plastic surgery in pseudoxanthoma
elasticum: Experience in
nine patients. Plast Reconst Surg.1990; 233-38. A series discussing
wound healing and
surgical outcomes in a small group of women under going cosmetic surgery
of redundant
skin in PXE.
Uitto J, Boyd CD, Lebwohl MG, Moshell AN, Rosenbloom J, Terry S. International
Centennial
Meeting on Pseudoxanthoma Elasticum: progress in PXE research. J Invest
Dermatol. 1998
May; 110 (5): 840-2.
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