Pseudoxanthoma_0913 Derm Clinic 2
A 51-year-old legally blind man was referred to the dermatology clinic by ophthalmology after being diagnosed with angioid streaks. The man reported no history of a rash. Physical examination revealed yellow reticulated plaques that looked like “plucked chicken skin” in bilateral inguinal folds. No lesions were appreciated in the oral mucosa.
The inguinal lesions were asymptomatic and had never been previously diagnosed or treated. No history of stroke, MI, or GI bleeding was reported. The man’s father and brother had also been diagnosed with angioid streaks.
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Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease with an estimated prevalence of 1 in 50,000 and a carrier frequency of 1 in 150-300.1 PXE exhibits no racial or geographic predilection but affects women slightly more than men.2 Recent focus on the molecular genetics and pathomechanisms of PXE has promising therapeutic implications.
PXE is a disorder of abnormal mineralization of connective tissue. Most patients have loss-of-function mutations in both copies of the ABCC6 gene, which encodes an efflux transporter primarily expressed in the liver.
Other patients have mutations in both copies of the GGCX gene, which encodes an enzyme involved in the activation of several anti-mineralization proteins and coagulation factors. These patients present with both PXE-like skin findings and a deficiency in vitamin K-dependent coagulation factors.
PXE is also associated with a significant reduction in serum fetuin-A, a GGCX-independent anti-mineralization protein that is secreted from the liver into the blood. Because PXE skin findings have also been reported in patients who have a combination of heterozygous mutations in both ABCC6 and GGCX, it is possible that defective ABCC6 prevents the proper export of a GGCX cofactor and/or fetuin-A into the circulation, thereby resulting in abnormal calcification of elastic fibers in the skin, arteries, and eyes.2
Although PXE is fully penetrant, there is significant phenotypic heterogeneity. Cutaneous manifestations are most common but may not be noticeable or may be regarded with suspicion until serious ocular or cardiovascular complications develop. Yellow papules appear in such flexural sites as the lateral neck, wrists, groin and axillae during the first or second decade of life and may coalesce into pebbly plaques that resemble plucked chicken skin. Perforating PXE, which refers to the expression of yellowish substance across the epidermis, occurs occasionally. Other cutaneous manifestations include saggy skin, chin creases, and yellow papules on the lower lip.
Ocular angioid streaks attributable to breaks in the calcified Bruch’s membrane are seen in almost all PXE patients by age 30 years and may result in choroidal neovascularization with subsequent progressive loss of central vision, possibly leading to blindness. Cardiovascular consequences of PXE can result in significant morbidity and mortality and are most concerning. Arterial calcification of the elastic intima and media of medium-sized arteries can lead to accelerated atherosclerosis and vascular complications ranging in severity from intermittent claudication, to GI bleeding, to MI and stroke.2
Histopathologically, PXE is characterized by fragmented elastic fibers in the reticular dermis or media of midsized arteries. In advanced PXE, purple clumps of calcium deposits are seen on hematoxylin and eosin staining with normal serum calcium and phosphate levels. Verhoeff-Van Gieson stain for elastin or von Kossa stain for calcium may be necessary for visualization early in the disease.2 In patients with angioid streaks but normal-looking skin, biopsy of normal-appearing flexural skin or preexisting scars may be helpful in diagnosis.3
The differential diagnosis of PXE includes xanthomas, actinic damage, late-onset focal dermal elastosis, and fibroelastolytic skin disorders. Similar but reversible skin changes are seen in patients who have been exposed to potassium nitrate or D-penicillamine, or those who have chronic end-stage renal disease. In these patients, however, ocular and cardiovascular findings are absent.
PXE-like skin findings with or without angioid streaks can also be seen in patients with β-thalassemia or sickle-cell anemia without accompanying mutation in the ABCC6 gene. Amyloid elastosis may also produce PXE-like skin findings but is distinguished histologically by amyloid deposits surrounding elastic fibers.2
Although there are currently no specific systemic treatments for PXE, intravitreal injection of vascular endothelial growth factor antagonists to treat ocular neovascularization has proven beneficial, along with regular ophthalmologic and cardiovascular monitoring with diet and lifestyle counseling.4
Oral phosphate binders or increased dietary magnesium may ameliorate ectopic mineralization of peripheral tissues by preventing calcium phosphate deposition.5 Surgical excision may be an option for cutaneous manifestations of PXE that are aesthetically undesirable to the patient. Further development of more sophisticated molecular therapies is dependent on greater understanding of the pathophysiology of PXE.2
In the case described here, a right inguinal punch biopsy revealed fragmented basophilic elastic fibers in the dermis consistent with PXE. The patient has scheduled follow-up appointments with his primary-care provider, cardiologist, gastroenterologist, and ophthalmologist. Given the patient’s family history, genetic testing is currently under way in light of a possible autosomal dominant inheritance pattern.
Vicky Ren is a third-year student and Apphia Wang is a fourth-year student at Baylor College of Medicine in Houston, where Kerri Robbins, MD, is an instructor in the Department of Dermatology.
- Uitto J, Bercovitch L, Terry SF, Terry PF. Pseudoxanthoma elasticum: progress in diagnostics and research towards treatment : Summary of the 2010 PXE International Research Meeting. Am J Med Genet A. 2011;155A:1517-1526. Available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3121926/.
- Ringpfeil F, Uitto J. Heritable disorders of connective tissue. In: Bolognia JL, Jorizzo JL, Schaffer JV, eds. Dermatology. 3rd ed. Philadelphia, Pa.: Elsevier Saunders; 2012:1612-1615.
- Lebwohl M, Phelps RG, Yannuzzi L, et al. Diagnosis of pseudoxanthoma elasticum by scar biopsy in patients without characteristic skin lesions. N Engl J Med. 1987;317:347-350.
- Finger RP, Charbel Issa P, Schmitz-Valckenberg S, et al. Long-term effectiveness of intravitreal bevacizumab for choroidal neovascularization secondary to angioid streaks in pseudoxanthoma elasticum. Retina. 2011;31:1268-1278.
- Yoo JY, Blum RR, Singer GK, et al. A randomized controlled trial of oral phosphate binders in the treatment of pseudoxanthoma elasticum. J Am Acad Dermatol. 2011;65:341-348.