Practice Essentials
Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by elastorrhexia, or progressive calcification and fragmentation, of elastic fibers primarily affecting the skin, the retina, and the cardiovascular system. [1, 2, 3, 4] The condition was first described by the French dermatologist Rigal in 1881 [5] and later named by Darier in 1896, who sought to differentiate PXE from common xanthomas. [6] Cutaneous lesions typically begin in childhood or early adolescence and are often the first apparent manifestation of the disease, but owing to their asymptomatic nature, diagnosis is delayed by an average of 9 years. [7]
Prognosis
The prognosis of pseudoxanthoma elasticum (PXE) largely depends on the extent of extracutaneous organ involvement. Patients typically have a normal life span, but acute GI hemorrhage, myocardial infarction, or cerebral hemorrhage may be fatal.
Spontaneous resolution of skin changes has been reported but is exceedingly rare. [8]
Early diagnosis and the institution of prophylactic measures is paramount.
Diagnostics
See Workup.
Treatment
While the development of novel strategies is currently at the preclinical level, recommended therapies to possibly slow the progression of the disease include smoking cessation, moderate physical exercise, and an appropriate diet with supplemented magnesium, phosphate binders, and pyrophosphate analogs. [9, 10, 11]
Also see Treatment and Medication.
Pathophysiology
Pseudoxanthoma elasticum (PXE) is associated with mutations in the ABCC6 gene, which encodes an ATP-binding cassette transporter protein localized to the mitochondria-associated membrane (MAM). [12] The gene is expressed predominantly in the liver and kidney; however, PXE most commonly involves the elastic fibers of the mid and deep reticular dermis of skin, the Bruch membrane of the eye, and the blood vessels. The disease’s manifestations are primarily due to an underlying metabolic disorder.
Overlapping phenotypes due to variants in ENPP1 and GGCX have been reported. [13]
Bartstra et al correlated ABCC6 genotype with phenotype, finding that patients with mixed genotypes have a more favorable clinical status when compared to those with truncating or non-truncating genotypes. Specifically, mixed genotypes were associated with lower peripheral and total arterial calcification mass scores as well as lower prevalence of choroidal neovascularizations. [13]
The underlying pathomechanisms of PXE have largely been unknown. A 2017 study attempted to gain better understanding of the pathophysiology of PXE by characterizing dermal myofibroblast differentiation. It was found that such deviations mediated by aberrant supramolecular extracellular matrix organization may be the driving cause of PXE. [14]
PXE cases have been reported in association with beta thalassemia. [15]
Etiology
Pseudoxanthoma elasticum (PXE) is caused by mutations in the ABCC6, [8, 16] also known as multidrug resistance–associated protein 6 (MRP6), which has been mapped to 16p13.1. To date, greater than 300 different disease-causing mutations, mainly missense and nonsense mutations, have been identified in the 31 exons coding ABCC6. Because the ABCC6 gene encodes the cellular transport protein ABCC6/MRP6, PXE may represent a systemic metabolic disorder rather than a purely structural disorder of connective tissue.
In support of this hypothesis, fibroblasts grown in the sera of patients with PXE interfered with the normal assembly of elastic fibers in vitro [16] and sera from normal mice reversed mineralization symptoms in ABCC6-deficient mice. [17] Subsequent studies support the notion that PXE is primarily a systemic metabolic disorder with secondary mineralization of connective tissues. [18]
Several mechanisms have been proposed to explain the pathological changes found in PXE. One theory is that increased oxidative stress, resulting in elevated levels of intercellular adhesion molecule-1 (ICAM-1) and P-selectin. [19, 20, 21] Another hypothesis is that ABCC6 secretes a vitamin-K precursor from the liver, supported by the finding that clinical features simulating PXE are seen in rats treated with vitamin-K antagonists and in patients with mutations of gamma-glutamyl carboxylase gene.
Based on this theory, a precursor of vitamin K that can be used by peripheral tissues should abate the process of pseudoxanthoma elasticum. [20] However, this has not been observed, and furthermore, supplementation with antioxidants such as vitamins C and E, selenium, and N -acetylcysteine have not been found to modify the ectopic mineralization process. [22]
Alternatively, the ectopic mineralization of peripheral tissues in PXE may be due to a reduced antimineralization capacity. Matrix Gla protein (MGP) and fetuin-A, [23, 24] 2 factors that inhibit mineralization and local artery calcification, have been found at lower levels in the serum of PXE patients and knockout ABCC6 mice. [25, 26, 27, 28] The "hepatic intoxication hypothesis" further suggests that a substrate (or several substrates) of ABCC6 accumulates within hepatocytes, leading to altered gene regulation of proteins that directly or indirectly effect peripheral mineralization. [29]
Epidemiology
US frequency
Pseudoxanthoma elasticum (PXE) has an estimated prevalence of 1 case per 25,000-100,000. [30] Current research supports a common (probably exclusive) autosomal recessive inheritance of pseudoxanthoma elasticum.
Race-, sex-, and age-related information
PXE has been described in persons of all races. A higher prevalence has been reported in certain populations, including South African Afrikaners, likely due to a founder effect. [8]
The female-to-male ratio is 2:1. [30]
The average age of onset is 13 years; however, ages can vary between infancy and the seventh decade of life or older, with a peak in the number of new cases from ages 10-15 years.
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Classic cobblestone appearance with yellow papules and plaques on the lateral aspect of the neck.
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Laxity and redundant skin folds in the axilla.
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Flesh-colored reticulated plaques on the posterior neck.
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Calcification and clumping of elastic fibers in pseudoxanthoma elasticum.
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Aggregates of irregular calcified elastic fibers in the dermis.
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Basophilic clusters in the mid and deep reticular dermis representing calcium deposition within elastic fibers in PXE.
