SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 453 IN-DEPTH REVIEW Vascular Effects of Pseudoxanthoma Elasticum Erika L. Hubbard, BA1, Mark G. Lebwohl, MD1 1The Kimberly and Eric J. Waldman Department of Dermatology, Icahn School of Medicine at Mount Sinai Hospital, New York, NY Pseudoxanthoma elasticum (PXE) is a rare autosomal recessive disease caused by biallelic mutation of the ABCC6 gene. The condition is characterized by the degradation and calcification of elastic fibers in connective tissue, including the skin, eyes, and arterial media, resulting in cutaneous yellowish papules, angioid streaks in Bruch’s membrane, and vascular calcification. Prevalence of the condition is estimated from 1:25,000 to 1:56,000, with a 2:1 female to male ratio. 1,2 The vascular effects of PXE are extensive. The ABCC6 gene maintains inorganic phosphate levels that inhibit calcification, so it follows that loss of ABCC6 function results in systemic calcification.3 Arterial calcification caused by elastin degradation is associated with increased carotid intima- media thickness, which puts PXE patients at higher risk of developing cardiovascular and cerebrovascular disease.4 Some studies suggest that older PXE patients also have increased arterial compressibility and distensibility, though debate on this issue remains.5-7 In this paper, we reviewed the ABSTRACT Background: Pseudoxanthoma elasticum (PXE) is a rare hereditary disease caused by mutations in the ABCC6 gene, characterized by ectopic calcification of connective tissue throughout the body. Vascular conditions associated with PXE have been well-documented in the literature, but to our knowledge, analysis of the myriad of PXE case reports with associated vascular diseases in addition to larger cohort studies, has not been undertaken. Methods: A search of the PubMed database using the key words “pseudoxanthoma elasticum” and “vascular” was performed. Results: A total of 345 cases of PVD, 97 cases of CVD, and 123 case of CeVD were reported. Additionally, 88 cases of hypertension and 5 cases of CRM were reported. Conclusions: PXE patients are at risk of developing serious vascular conditions, particularly peripheral vascular disease. This condition also appears to have some connection to carotid rete mirabile, which is extremely rare in humans. Further research should be conducted to analyze the connection between PXE and CRM in order to better understand and treat both conditions. INTRODUCTION SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 454 literature published on vascular conditions associated with PXE, broadly categorized as peripheral vascular disease, cardiovascular disease, cerebrovascular disease, hypertension, and carotid rete mirabile, in order to capture a general idea of the prevalence and range of this association. We performed a PubMed search using the terms “pseudoxanthoma elasticum” and “vascular,” and limited our analysis to English-language, French-language studies, and studies with abstracts in English with extractable data. Animal studies, treatment studies, and PXE studies focusing on cutaneous or ophthalmologic symptoms were excluded. Articles without full-text availability were also excluded from our review. Of the 90 relevant articles, upon review of the case descriptions, 73 had extractable vascular conditions data to analyze, comprised of 59 case studies/series and 14 cohort/cross-sectional studies. From the 73 relevant articles, 1049 PXE patients were reported. Of these patients, 345 had some form of peripheral vascular disease (PVD), 97 had cardiovascular disease, and 123 had cerebrovascular disease. The most common PVD diagnoses included intermittent claudication (24 patients), lower limb atherosclerosis (67 patients), and peripheral arterial stenosis or occlusion (23 patients). Cardiovascular Table 1. Characteristics of included cohort and cross- sectional studies Reference Patients PVD CVD CeVD HT CRM Campens et al.8 32 13 0 10 8 0 Gutierrez- Cardo et al.9 18 5 2 1 6 0 Hammami et al.10 22 0 0 0 0 0 Iwanaga et al.11 76 24 18 0 0 0 Kauw et al.12 178 0 0 29 0 0 Leftheriotis et al.13 71 40 7 8 18 0 Legrand et al.14 194 84 37 17 0 0 Nollet et al.15 56 18 6 17 17 0 Omarjee et al.16 151 0 0 13 0 0 Omarjee et al.17 23 9 1 1 0 0 Passon et al.18 44 44 0 0 0 0 Pingel et al.19 46 45 0 0 0 0 Utani et al.20 14 0 4 0 0 0 Vanakker et al.21 38 22 7 6 17 0 TOTALS 963 304 82 102 66 0 PVD: peripheral vascular disease; CVD: cardiovascular disease; CeVD: cerebrovascular disease; HT: hypertension; CRM: carotid rete mirabile disease conditions primarily consisted of myocardial infarction (15 patients), angina pectoris (12 patients), and coronary artery disease (7 patients). Transient ischemic attacks (17 patients), ischemic strokes (67 patients), and carotid artery disease or stenosis (31 patients) accounted for the bulk of cerebrovascular disease cases. It is also worth noting that 88 PXE patients had hypertension. Additionally, 5 case study patients presented with carotid rete mirabile, a rare disorder characterized by an arterial METHODS RESULTS SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 455 network communicating between the internal and external carotid networks. From our PubMed search, it appears that peripheral vascular, cardiovascular, and cerebrovascular disease are all well- documented among PXE patients in the literature. These comorbidities are expected considering the arterial calcification of elastic tissue that occurs as a result of ABCC6 mutations. Arterial calcification alters the elastic properties of the arterial wall, causing it to stiffen, which consequently increases systemic arterial pressure.2 Peripheral vascular disease (PVD), detected by low ankle-brachial index (ABI), absence of ankle pulse, and lower limb claudication, is particularly well-documented in patients with PXE (45% of French PXE cohort, 53% of Belgian PXE cohort).21,81 Cardiovascular abnormalities, including angina pectoris and myocardial infarction, are relatively rare (15% with angina pectoris and 5% myocardial infarction in large cohort study).21 Cerebrovascular events are also relatively rare, but occur at significantly higher rates in PXE patients relative to the general population (around 8% prevalence of cerebrovascular accidents in PXE patients, compared to 3% prevalence in general population).82 Hypertension is quite common among PXE patients (25% in Leftheriotis et al. 2014; 41% in Vanakker et al.).13,21 Though hypertension has historically been viewed as a risk factor in developing arterial calcification, more recent research has found that arterial calcification also causes hypertension in the elderly, suggesting that arterial calcification and hypertension are part of a vicious cycle of vascular aging.83 This relationship has particular relevance to PXE patients, whose vascular condition can be characterized as early-onset vascular aging.51 Reports of five PXE patients with carotid rete mirabile (CRM) is particularly intriguing. A rete mirabile is a vascular network of arteries and arterioles that replaces the normal adult carotid arteries. CRM supplies the brain in lower mammals, but is absent in normal human development.84 Individuals with CRM most commonly present clinically with hemorrhagic or ischemic strokes. This and other cerebrovascular malformations have generally been treated as only coincidentally associated with PXE. However, of the 32 human cases of CRM reported in the literature before 2011, five (16%) were PXE patients.75 Given that both CRM and PXE are quite rare conditions, it seems unlikely that they would accidentally co-occur at this frequency. Some researchers have suggested that abnormal signaling caused by ABCC6 mutation during embryological development could create abnormalities in arterial wall construction, including CRM, implying a systematic association between PXE and CRM.75 In conclusion, PXE patients often suffer from a wide range of vascular conditions, most common of which is peripheral vascular disease. Hypertension is also quite prevalent among PXE patients, which is of particular concern, as hypertension is not only an effect of PXE, but also a cause of further arterial calcification. A finding of particular interest from this review is the potential systematic association between PXE and CRM. Further research should be conducted to discern the nature of the relationship, if any, between PXE and CRM, as an understanding of a vascular DISCUSSION CONCLUSION SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 456 developmental disorder such as CRM would further our understanding of PXE and its mechanisms of arterial onset. Table 2. Characteristics of included case studies/series Reference Patients PVD CVD CeVD HT CRM Aissaoui et al.22 5 0 0 0 1 0 Ammi et al.23 4 4 0 0 0 0 Araki et al.24 1 1 1 1 1 0 Araki et al.25 1 0 0 1 0 1 Bardsley et al.26 2 2 0 0 1 0 Barrie et al.27 2 1 0 1 1 0 Bete et al.28 1 0 1 0 0 0 Bock et al.29 1 0 0 1 0 0 Bruno et al.30 4 0 1 2 4 0 Cailleux et al.31 1 1 0 0 0 0 Carter et al.32 1 1 0 0 0 0 Chalk et al.33 1 0 0 1 0 0 Dalloz et al.34 1 0 0 1 0 0 Del Zotto et al.35 1 0 0 1 0 1 Devriese et al.36 1 1 0 0 0 0 Dibi et al.37 4 0 1 0 4 0 Dymock et al.38 1 1 1 0 1 0 Ekim et al.39 1 0 0 0 1 0 Elhatimi et al.40 1 0 0 0 1 0 Fasshauer et al.41 1 0 0 1 0 0 Galle et al.42 1 0 0 1 0 0 García Acuña et al.43 1 0 1 0 0 0 Gillgren et al.44 1 1 0 0 0 0 Heno et al.45 1 0 1 0 0 0 Jackson et al.46 1 1 0 0 0 0 Kévorkian et al.47 1 0 1 0 0 0 Khan et al.48 1 1 0 0 0 0 Lamb et al.49 1 1 0 0 0 0 Li et al.50 1 0 0 0 0 0 Mendelsohn et al.51 3 3 0 0 1 0 Miki et al.52 1 0 0 0 0 0 Miwa et al.53 1 0 0 0 1 0 SKIN September 2021 Volume 5 Issue 5 Copyright 2021 The National Society for Cutaneous Medicine 457 Montani et al.54 1 1 1 0 0 0 Neumann et al.55 1 1 0 0 0 0 Nishida et al.56 1 0 1 0 0 0 Nolte et al.57 1 0 1 0 0 0 Pavlovic et al.58 3 0 0 3 2 0 Perdu et al.59 7 7 0 0 0 0 Pieczuro et al.60 1 0 0 1 0 0 Rios-Montenegro et al.61 1 0 0 0 0 1 Rodríguez-Camarero et al.62 1 1 0 0 0 0 Rühlmann et al.63 1 1 0 0 0 0 Sabán-Ruiz et al.64 1 0 0 0 1 0 Sasai et al.65 1 1 0 0 0 0 Schröder et al.66 1 1 0 1 0 0 Sharma et al.67 1 0 0 1 1 0 Siskos et al.68 1 1 0 0 0 0 Slade et al.69 1 1 0 0 0 0 Song et al.70 1 1 2 0 0 0 Sunmonu et al.71 1 0 0 1 0 0 Takeshita et al.72 1 0 0 1 0 0 Tromp et al.73 2 1 0 0 0 0 ul Bari et al.74 1 1 0 0 1 0 Vasseur et al.75 1 0 1 0 0 1 Wahlqvist et al.76 2 2 0 0 0 0 Wolff et al.77 1 1 0 0 0 0 Yasuhara et al.78 1 0 1 1 0 1 Zimmo et al.79 1 0 0 0 0 0 Zuily et al.80 1 1 0 1 0 0 TOTALS 86 41 15 21 22 5 PVD: peripheral vascular disease; CVD: cardiovascular disease; CeVD: cerebrovascular disease; HT: hypertension; CRM: carotid rete mirabile Conflict of Interest Disclosures: None Funding: None Corresponding Author: Erika Hubbard 95 W 95th Street, 16th floor, New York, NY 10025 Phone: (435)890-5272 Email: elh2174@columbia.edu References: 1. 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