Pseudoxanthoma elasticum

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Pseudoxanthoma elasticum

Kenneth H. Neldner and Mark G. Lebwohl

Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disorder causing abnormal calcification of the elastic fibers in the skin, retina, and cardiovascular system. The major clinical features include slightly thickened, leather-like skin lesions most commonly seen in flexural skin, retinal angioid streaks, and hemorrhages, with central vision loss. Cardiovascular problems are less common, intermittent claudication in the lower extremities being the most common finding. Gastrointestinal bleeding is reported in about 10% of patients, which may also be due to non-PXE related factors. The prevalence of PXE in the population is approximately 1 : 70 000. For unknown reasons there is an approximately 2 : 1 predominance in females.

The PXE gene(s) is located on chromosome 16p13.1 and a specific gene(s) has been identified in the ABCC6 group of genes.

Management strategy

Establishing the diagnosis of PXE may be difficult during the early stages of the disorder. The initial clinical signs appear most commonly during the early teenage years in flexural skin sites on the neck, axillae, antecubital fossae, and groin, as variably sized patches of slightly thickened, leathery-looking skin. The diagnosis is often missed during these early years. Larger patches gradually develop with age. Angioid streaks in the retina usually appear later, beginning in the late teens or early 20s. Frank retinal hemorrhages begin most commonly in the fifth decade, causing central vision loss. Cardiovascular changes are rarely noted in children, although rare cases have been reported. A heart healthy lifestyle including low cholesterol diet, aerobic exercises, and avoidance of smoking should be encouraged. Because of the bleeding diathesis in PXE, patients should be advised to avoid aspirin and other blood thinners unless essential. There is some evidence that increased dietary calcium results in more rapid progression of the disease. Therefore, patients should be encouraged to avoid calcium supplementation and excessive ingestion of milk products. An interdisciplinary approach involving dermatologists, retina specialists, and cardiologists is ideal.

Specific investigations

Complete skin examination, with special reference to all flexural skin sites and oral mucosa

A 3–4 mm punch biopsy of suspicious lesions and a von Kossa stain to detect calcified elastic fibers to establish a diagnosis

General physical examination and routine laboratory tests

Retinal examination and photographs for evidence of angioid streaks and hemorrhages

Family history for evidence of similar problems

Genetic studies on blood may be used to verify the diagnosis of PXE in questionable cases.

The tests are expensive and rarely essential to confirm the diagnosis.

Pseudoxanthoma elasticum.

Neldner KH. Clin Dermatol 1988; 6: 1–159.

For the interested physician, patients, or their families, this is the only book devoted solely to PXE. It is out of print from the publisher but can be obtained in paperback with full color clinical photos from the National Association for PXE, 8760 Manchester Road, St Louis, MO 64144–2724; email: NAPEstlouis@sbcglobal.net.

First-line therapies

Thorough discussion of PXE with the patient and family, stressing the importance of lifelong follow-up and potential complications
Attention to current PXE medical literature for new therapies
Good nutrition; avoidance of trans fats; dietary calcium intake based on patient age and the current recommended dietary intake	B
Regular exercise program, with care to avoid sports with potential for head or eye injury	B
Vigorous control of hypertension and abnormal lipid profiles	C
Avoid long-term use of anticoagulants (gastrintestinal bleeding)	C
Retinal referral and follow-up on regular basis with a retinal specialist familiar with PXE. If early or threatened retinal hemorrhages, check for possible treatment with bevacizumab (Avastin) or ranibizumab (Lucentis)	C

Pseudoxanthoma elasticum: a connective tissue disease or a metabolic disorder at the genome/environment interface?

Uitto J. J Invest Dermatol 2004; 122: ix–x.

Pseudoxanthoma elasticum is a metabolic disease.

Jiang Q, Endo M, Dibra F, Wang K, Uitto J. J Invest Dermatol 2009; 129: 348–534.

Long-term effectiveness of intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks in pseudoxanthoma elasticum.

Finger RP, Charbel IP, Schmitz-Valckenberg S, Holz FG, Scholl HN. Retina 2011; 31: 1268–78.

Intravitreal bevacizumab improved visual acuity, stabilized leakage from active choroidal neovascularizations and reduced central retinal thickness. There was improvement of visual acuity in early disease and preservation of function in advanced disease. Initiation of therapy as early as possible is important to preservation of vision.

Intravitreal injection of vascular endothelial growth factor inhibitors has dramatically improved the prognosis of PXE eye disease.

Second-line therapies

Consider cardiology referral for signs of mitral valve prolapse

B

Pseudoxanthoma elasticum and mitral valve prolapse.

Lebwohl MG, Distefano D, Prioleau PG, Uram M, Yannuzzi LA, Fleischmajer R. N Engl J Med 1982; 307: 228–32.

Mitral valve prolapse (MVP) is quite common in PXE patients as well as the general population (exact frequencies are unknown). It is of no clinical significance unless accompanied by a heart murmur. If this is present, the patient should take antibiotics prior to surgical and dental procedures. An echocardiogram is the best way to diagnose the presence of MVP.

Third-line therapies

Referral to cosmetic surgeon for removal of objectionable lesions if desired by patient for cosmetic reasons	B
Observe pregnant women more carefully. Incidence of gastrointestinal hemorrhage is questionably increased during pregnancy	C
Encourage the patient and their family to follow the medical literature available on PXE at various computer sites. Provide information on joining one or both PXE support groups: National Association for PXE (NAPE) and PXE International. Check the internet for websites and details on updates regarding new therapies
Sevelamer hydrochloride 800 mg three times daily	A
Increase in dietary magnesium	E

Other therapies

There are several important new studies under way that could have significant long-term benefits in the management of PXE if they prove successful. A brief list is presented below.

A randomized controlled trial of oral phosphate binders in the treatment of pseudoxanthoma elasticum.

Yoo JY, Blum RR, Singer GK, Stern DR, Emanuel PO, Fuchs W, et al. J Am Acad Dermatol 2011; 65: 341–8.

Sevelamer hydrochloride 800 mg three times daily resulted in reduced calcification of elastic fibers on microscopy and improved clinical scores, but the benefit was not significant compared to placebo.

The placebo was discovered to contain magnesium which may explain the benefit achieved by the placebo group.

Pseudoxanthoma elasticum, the paradigm of heritable ectopic mineralization disorders: can diet help?

LaRusso J, Li Q, Uitto J. Dtsch Fermatol Ges 2011; 9: 586–93.

A fivefold increase in dietary magnesium inhibited tissue mineralization in a mouse model of PXE.

Treatment of Skin Disease Comprehensive Therapeutic Strategies 4e