SKIN January 2022 Volume 6 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 8 IN-DEPTH REVIEW Association Between Pseudoxanthoma Elasticum and Bleeding Lily Lebwohl1, Robert Phelps, MD1 1Icahn School of Medicine at Mount Sinai, New York, NY Pseudoxanthoma Elasticum (PXE) is a rare genetic disease caused by a mutation of the ABCC6 gene. This results in calcification of elastic fibers of the skin, eye and other organs and tissues that contain elastin. The internal elastic lamina of arteries can be affected, resulting in vascular complications including bleeding. Ringpfeil et. al. described mutations in the ABCC6 transporter protein inherited in a an autosomal recessive pattern in PXE.1 Consequently, any organ containing elastic tissue can be affected, with skin2 and eyes 3 being the most common. Skin lesions are characterized by yellow xanthoma-like patches, papules and folds (figure 1A,1B). Mucosal lesions have also been described, particularly on the oral mucosa (figure 2). and the classic eye characteristics are angioid streaks in the retina (figure 3) 4 though any elastic- containing tissue can be affected. Heart valves can be involved, resulting in mitral valve prolapse5 and myocardial infarctions at an early age6. The latter complication occurs as a consequence of calcification of the coronary arteries. PXE can be identified at any age and has been reported in ages as young as age 4. 7 It is associated with numerous complications including characteristic skin lesions (Figure 1A, 1B) and angioid streaks in the retina (Figure 3). Serious vascular complications including myocardial infarction and stroke at a young age have been reported 8. Because calcified arteries can bleed, hemorrhage from various organs is a reported complication of PXE. We therefore conducted a literature review of all English language published articles reporting bleeding in patients with PXE. ABSTRACT Pseudoxanthoma Elasticum (PXE) is a rare genetic disease caused by a mutation of the ABCC6 gene, resulting in calcification of elastic fibers of the skin, eye and other organs and tissues that contain elastin. Because calcified arteries can bleed, hemorrhage from various organs is a reported complication of PXE. We conducted a literature review of all English language published articles reporting bleeding in patients with PXE. In this literature review, we identified 51 papers. Of those, 30 (59%) included at least 1 case of bleeding. Within these 30 papers, bleeding was reported in a total of 130 patients. Of the cases of bleeding, 113 occurred in the gastrointestinal tract, 12 occurred in the brain, 2 in the skin, 1 in the nose, 1 in the gums and 1 in the uterus. Clinicians and patients should be made aware of the risk of these significant complications, to facilitate preventive measures, prompt recognition and treatment. INTRODUCTION https://sciwheel.com/work/citation?ids=11323469&pre=&suf=&sa=0&dbf=0 https://sciwheel.com/work/citation?ids=11604932&pre=&suf=&sa=0&dbf=0 https://sciwheel.com/work/citation?ids=11582277&pre=&suf=&sa=0&dbf=0 https://sciwheel.com/work/citation?ids=11582288&pre=&suf=&sa=0&dbf=0 SKIN January 2022 Volume 6 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 9 Figure 1. A) Yellow xanthoma-like papules typical of PXE B) Papules become confluent to form redundant folds in the axilla. A PubMed search was conducted using these terms: bleed, hemorrhage, haemorrhage, and pseudoxanthoma elasticum. Review articles were not included, nor were articles that did not include original cases of bleeding or hemorrhage. For reasons of scope, we did not include retinal bleeding in this review. For each report, we recorded the year of publication, number of subjects with PXE, the number with a bleeding event, the site of bleeding, and other complications among those with bleeding. Figure 2. Yellow papules and patches on the lower lip. Using the search terms outlined above, we identified 51 papers. Of those, 30 (59%) included at least 1 case of bleeding. 9-38 (The 21 remaining papers were excluded because they were review articles or did not include cases.) Within these 30 papers, bleeding was reported in a total of 130 patients. Of the cases of bleeding, 113 occurred in the gastrointestinal tract, 12 occurred in the brain, 2 in the skin, 1 in the nose, 1 in the gums and 1 in the uterus (see Table 1). Figure 3. Angioid streaks of the retina METHODS RESULTS A . B https://sciwheel.com/work/citation?ids=11604906&pre=&suf=&sa=0&dbf=0 SKIN January 2022 Volume 6 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 10 Figure 4 shows calcified elastic fibers in the skin biopsy of a patient with PXE. Retinal bleeding is very common, but bleeding at other sites can also occur and is the subject of this review. There were many sites of bleeding identified in this literature review, including the brain 9, skin 35, nose35, uterus 35 and gums, 13 but gastrointestinal bleeding was particularly common 11,15,28,30, followed by cerebral hemorrhage 12,14. Because of the bleeding tendency, certain management Table 1 Year Author Site of Bleeding Other complications Number in study Number with bleeding 2020 Sunmonu NA Brain stroke 1 1 2021 Lanfranconi S Brain stroke 1 1 2016 Dibi A gastrointestinal vascular disease 2 2 2014 Drue HC brain 1 1 2008 Adam AM gums 1 1 2008 Bock A brain 1 1 2007 Goral V gastrointestinal 1 1 2006 Antiga E gastrointestinal 1 1 2005 Golliet-Mercier N gastrointestinal 1 1 2004 Makharia GK gastrointestinal 1 1 2002 Ospedale S gastrointestinal/intercranial gastric artery aneurysm/ischaemic attack 29 2 1996 Spinzi G gastrointestinal 2 2 2000 Costopanagiotou E gastrointestinal 1 1 1992 Yap EY gastrointestinal aneurysms of the gastric arteries 1 1 1991 Yamamura H gastrointestinal 1 1 1990 Slade AK gastrointestinal 1 1 1988 Jacyk WK gastrointestinal 7 1 1988 Kundrotas L gastrointestinal 1 1 1988 Belli A gastrointestinal vascular abnormalities 2 2 1982 Drost H gastrointestinal 1 1 1982 Morgan AA gastrointestinal 1 1 1980 Keim HJ gastrointestinal total gastrectomy and partial jejunal resection 1 1 1973 Olbromska W gastrointestinal 1 1 1973 Van Waes L gastrointestinal 1 1 1968 Gignoux R gastrointestinal total gastrectomy 1 1 1966 Dhers A gastrointestinal 3 3 2000 van den Berg JS gastrointestinal, skin, nose, uterus 100 17 gastrointestinal; 2 skin; 1 nose; 1 uterus 1967 Grant AK gastrointestinal 3 3 2004 Bercovitch L gastrointestinal 306 66 1988 Neldner KH gastrointestinal and brain 100 8 DISCUSSION https://sciwheel.com/work/citation?ids=11604906&pre=&suf=&sa=0&dbf=0 https://sciwheel.com/work/citation?ids=11604911&pre=&suf=&sa=0&dbf=0 https://sciwheel.com/work/citation?ids=11604911&pre=&suf=&sa=0&dbf=0 https://sciwheel.com/work/citation?ids=11604913&pre=&suf=&sa=0&dbf=0 https://sciwheel.com/work/citation?ids=11604918,11609739,11604920&pre=&pre=&pre=&suf=&suf=&suf=&sa=0,0,0&dbf=0&dbf=0&dbf=0 SKIN January 2022 Volume 6 Issue 1 (c) 2022 THE AUTHORS. Published by the National Society for Cutaneous Medicine. 11 strategies can be used to minimize that adverse outcome. For example, the avoidance of blood thinners, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be considered given these risks. Other activities known to be associated with gastrointestinal bleeding such as heavy alcohol consumption, cigarette smoking, and dual antiplatelet therapy should be avoided. Periodic checks of the stool for blood should be considered as part of the routine examination of patients with PXE. Because of the known risk of retinal bleeding and intracranial hemorrhage, trauma to the head should be avoided, and certain sports such as boxing or soccer may not be ideal for patients with PXE. Figure 4. Calcified elastic fibers in the dermis of a patient with PXE In summary, PXE is associated with bleeding from many sites. While retinal bleeding is most common, there are many reports of gastrointestinal followed by bleeding in the brain. Clinicians and patients should be made aware of the risk of these significant complications, to facilitate preventive measures, prompt recognition and treatment. Conflict of Interest Disclosures: None Funding: None Corresponding Author: Lily Lebwohl The Leffell School 555 W Hartsdale Ave, Hartsdale, NY 10530 Email: lilylebwohl@gmail.com References: 1. Ringpfeil F, Lebwohl MG, Christiano AM, Uitto J. Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc Natl Acad Sci USA. 2000 May 23;97(11):6001–6. 2. Cui C, Zhou Z, Zhang Y, Sun D. A case report: pseudoxanthoma elasticum diagnosed based on ocular angioid streaks and the curative effect of Conbercept treatment. BMC Ophthalmol. 2021 Aug 23;21(1):307. 3. Nika M, Besirli CG. Choroidal neovascularization and angioid streaks in pseudoxanthoma elasticum. 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