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18 pages, 2495 KiB

Open AccessArticle

Phenotypic Features and Genetic Findings in a Cohort of Italian Pseudoxanthoma Elasticum Patients and Update of the Ophthalmologic Evaluation Score

by Federica Boraldi, Vittoria Murro, Francesco Demetrio Lofaro, Dario Pasquale Mucciolo, Sonia Costa, Laura Pavese and Daniela Quaglino

J. Clin. Med. 2021, 10(12), 2710; https://doi.org/10.3390/jcm10122710 - 19 Jun 2021

Cited by 8 | Viewed by 2302

Abstract

Background: Pseudoxanthoma elasticum (PXE) is a rare ectopic calcification genetic disease mainly caused by ABCC6 rare sequence variants. The clinical phenotype is characterized by typical dermatological, ophthalmological and cardiovascular manifestations, whose frequency and severity are differently reported in the literature. Methods: A retrospective [...] Read more.

Background: Pseudoxanthoma elasticum (PXE) is a rare ectopic calcification genetic disease mainly caused by ABCC6 rare sequence variants. The clinical phenotype is characterized by typical dermatological, ophthalmological and cardiovascular manifestations, whose frequency and severity are differently reported in the literature. Methods: A retrospective study was performed on 377 PXE patients of Italian origin, clinically evaluated according to the Phenodex Index, who underwent ABCC6 biomolecular analyses. Moreover, 53 PXE patients were further characterized by in-depth ophthalmological examinations. Results: A total of 117 different ABCC6 rare sequence variants were detected as being spread through the whole gene. The severity of the clinical phenotype was dependent on age, but it was not influenced by gender or by the type of sequence variants. In-depth ophthalmological examinations focused on the incidences of coquille d’oeuf, comet lesions, pattern dystrophy-like lesions, optic disk drusen and posterior-pole atrophy. Conclusion: Given the large number of patients analyzed, we were able to better evaluate the occurrence of less frequent alterations (e.g., stroke, myocardial infarction, nephrolithiasis). A more detailed description of ophthalmological abnormalities allowed us to stratify patients and better evaluate disease progression, thus suggesting a further update of the PXE score system. Full article

(This article belongs to the Special Issue Pseudoxanthoma Elasticum Pathophysiology, from Clinic to Bench Side)

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7 pages, 833 KiB

Open AccessArticle

Cutaneous and Vascular Deposits of 18F-NaF by PET/CT in the Follow-Up of Patients with Pseudoxanthoma Elasticum

by Eugenia Lillo, Antonio Gutierrez-Cardo, Belén Murcia-Casas, Juan Luis Carrillo-Linares, Francisco Garcia-Argüello, Reinaldo Chicharo de Freitas, Isabel Baquero-Aranda, Pedro Valdivielso, María García-Fernández and Miguel Ángel Sánchez-Chaparro

J. Clin. Med. 2021, 10(12), 2588; https://doi.org/10.3390/jcm10122588 - 11 Jun 2021

Cited by 3 | Viewed by 1620

Abstract

Active microcalcification of elastic fibers is a hallmark of pseudoxanthoma elasticum and it can be measured with the assessment of deposition of 18F-NaF using a PET/CT scan at the skin and vascular levels. It is not known whether this deposition changes over time [...] Read more.

Active microcalcification of elastic fibers is a hallmark of pseudoxanthoma elasticum and it can be measured with the assessment of deposition of 18F-NaF using a PET/CT scan at the skin and vascular levels. It is not known whether this deposition changes over time in absence of specific therapy. We repeated in two years a PET/CT scan using 18F-NaF as a radiopharmaceutical in patients with the disease and compared the deposition at skin and vessel. Furthermore, calcium score values at the vessel wall were also assessed. Main results indicate in the vessel walls that calcification progressed in each patient; by contrast, the active microcalcification, measured and target-to-background ratio showed reduced active deposition. By contrast, at skin levels (neck and axillae) the uptake of the pharmaceutical remains unchanged. In conclusion, because calcification in the arterial wall is not specific for pseudoxanthoma elasticum condition, the measurement of the deposition of 18F-NaF in the neck might be potentially used as a surrogate marker in future trials for the disease. Full article

(This article belongs to the Special Issue Pseudoxanthoma Elasticum Pathophysiology, from Clinic to Bench Side)

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12 pages, 9242 KiB

Open AccessArticle

Dermal Alterations in Clinically Unaffected Skin of Pseudoxanthoma elasticum Patients

by Federica Boraldi, Francesco Demetrio Lofaro, Lorena Losi and Daniela Quaglino

J. Clin. Med. 2021, 10(3), 500; https://doi.org/10.3390/jcm10030500 - 01 Feb 2021

Cited by 4 | Viewed by 2069

Abstract

Background: Pseudoxanthoma elasticum (PXE), due to rare sequence variants in the ABCC6 gene, is characterized by calcification of elastic fibers in several tissues/organs; however, the pathomechanisms have not been completely clarified. Although it is a systemic disorder on a genetic basis, it is [...] Read more.

Background: Pseudoxanthoma elasticum (PXE), due to rare sequence variants in the ABCC6 gene, is characterized by calcification of elastic fibers in several tissues/organs; however, the pathomechanisms have not been completely clarified. Although it is a systemic disorder on a genetic basis, it is not known why not all elastic fibers are calcified in the same patient and even in the same tissue. At present, data on soft connective tissue mineralization derive from studies performed on vascular tissues and/or on clinically affected skin, but there is no information on patients’ clinically unaffected skin. Methods: Skin biopsies from clinically unaffected and affected areas of the same PXE patient (n = 6) and from healthy subjects were investigated by electron microscopy. Immunohistochemistry was performed to evaluate p-SMAD 1/5/8 and p-SMAD 2/3 expression and localization. Results: In clinically unaffected skin, fragmented elastic fibers were prevalent, whereas calcified fibers were only rarely observed at the ultrastructural level. p-SMAD1/5/8 and p-SMAD2/3 were activated in both affected and unaffected skin. Conclusion: These findings further support the concept that fragmentation/degradation is necessary but not sufficient to cause calcification of elastic fibers and that additional local factors (e.g., matrix composition, mechanical forces and mesenchymal cells) contribute to create the pro-osteogenic environment. Full article

(This article belongs to the Special Issue Pseudoxanthoma Elasticum Pathophysiology, from Clinic to Bench Side)

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10 pages, 863 KiB

Open AccessArticle

Osteoarthritis in Pseudoxanthoma Elasticum Patients: An Explorative Imaging Study

by Willem Paul Gielis, Pim A. de Jong, Jonas W. Bartstra, Wouter Foppen, Wilko Spiering and Annemarie M. den Harder

J. Clin. Med. 2020, 9(12), 3898; https://doi.org/10.3390/jcm9123898 - 01 Dec 2020

Cited by 3 | Viewed by 3178

Abstract

Pseudoxanthoma elasticum (PXE) is a systemic disease affecting the skin, eyes, and cardiovascular system of patients. Cardiovascular disease is associated with osteoarthritis (OA), which is the most common cause of joint pain. There is a lack of systematic investigations on joint manifestations in [...] Read more.

Pseudoxanthoma elasticum (PXE) is a systemic disease affecting the skin, eyes, and cardiovascular system of patients. Cardiovascular disease is associated with osteoarthritis (OA), which is the most common cause of joint pain. There is a lack of systematic investigations on joint manifestations in PXE in the literature. In this explorative study, we aimed to investigate whether patients with PXE are more at risk for developing osseous signs of OA. Patients with PXE and hospital controls with whole-body low-dose CT examinations available were included. OA was assessed using the OsteoArthritis Computed Tomography (OACT)-score, which is a 4-point Likert scale, in the acromioclavicular (AC), glenohumeral (GH), facet, hip, knee, and ankle joints. Additionally, intervertebral disc degeneration was scored. Data were analyzed using ordinal logistic regression adjusted for age, body mass index (BMI), and smoking status. In total, 106 PXE patients (age 56 (48–64), 42% males, BMI 25.3 (22.7–28.2)) and 87 hospital controls (age 55 (43–67), 46% males, BMI 26.0 (22.5–29.2)) were included. PXE patients were more likely to have a higher OA score for the AC joints (OR 2.00 (1.12–3.61)), tibiofemoral joint (OR 2.63 (1.40–5.07)), and patellofemoral joint (2.22 (1.18–4.24)). For the other joints, the prevalence and severity of OA did not differ significantly. This study suggests that patients with PXE are more likely to have structural OA of the knee and AC joints, which needs clinical confirmation in larger groups and further investigation into the mechanism. Full article

(This article belongs to the Special Issue Pseudoxanthoma Elasticum Pathophysiology, from Clinic to Bench Side)

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23 pages, 2830 KiB

Open AccessArticle

Assessment of Inflammation and Calcification in Pseudoxanthoma Elasticum Arteries and Skin with 18F-FluroDeoxyGlucose and 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography Imaging: The GOCAPXE Trial

by Loukman Omarjee, Pierre-Jean Mention, Anne Janin, Gilles Kauffenstein, Estelle Le Pabic, Olivier Meilhac, Simon Blanchard, Nastassia Navasiolava, Georges Leftheriotis, Olivier Couturier, Pascale Jeannin, Franck Lacoeuille and Ludovic Martin

J. Clin. Med. 2020, 9(11), 3448; https://doi.org/10.3390/jcm9113448 - 27 Oct 2020

Cited by 15 | Viewed by 3158

Abstract

Background: Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and ectopic calcification. There is growing evidence that vascular calcification is associated with inflammatory status and is enhanced by inflammatory cytokines. Since PXE has never been considered as an [...] Read more.

Background: Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease characterized by elastic fiber fragmentation and ectopic calcification. There is growing evidence that vascular calcification is associated with inflammatory status and is enhanced by inflammatory cytokines. Since PXE has never been considered as an inflammatory condition, no incidence of chronic inflammation leading to calcification in PXE has been reported and should be investigated. In atherosclerosis and aortic stenosis, positron emission tomography combined with computed tomographic (PET-CT) imaging has demonstrated a correlation between inflammation and calcification. The purpose of this study was to assess skin/artery inflammation and calcification in PXE patients. Methods: 18F-FluroDeoxyGlucose (18F-FDG) and 18F-Sodium Fluoride (18F-NaF) PET-CT, CT-imaging and Pulse wave velocity (PWV) were used to determine skin/vascular inflammation, tissue calcification, arterial calcium score (CS) and stiffness, respectively. In addition, inorganic pyrophosphate, high-sensitive C-reactive protein and cytokines plasma levels were monitored. Results: In 23 PXE patients, assessment of inflammation revealed significant 18F-FDG uptake in diseased skin areas contrary to normal regions, and exclusively in the proximal aorta contrary to the popliteal arteries. There was no correlation between 18F-FDG uptake and PWV in the aortic wall. Assessment of calcification demonstrated significant 18F-NaF uptake in diseased skin regions and in the proximal aorta and femoral arteries. 18F-NaF wall uptake correlated with CS in the femoral arteries, and aortic wall PWV. Multivariate analysis indicated that aortic wall 18F-NaF uptake is associated with diastolic blood pressure. There was no significant correlation between 18F-FDG and 18F-NaF uptake in any of the artery walls. Conclusion: In the present cross-sectional study, inflammation and calcification were not correlated. PXE would appear to more closely resemble a chronic disease model of ectopic calcification than an inflammatory condition. To assess early ectopic calcification in PXE patients, 18F-NaF-PET-CT may be more relevant than CT imaging. It potentially constitutes a biomarker for disease-modifying anti-calcifying drug assessment in PXE. Full article

(This article belongs to the Special Issue Pseudoxanthoma Elasticum Pathophysiology, from Clinic to Bench Side)

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11 pages, 1728 KiB

Open AccessArticle

Increased Elastin Degradation in Pseudoxanthoma Elasticum Is Associated with Peripheral Arterial Disease Independent of Calcification

by Jonas W. Bartstra, Wilko Spiering, Jody M. W. van den Ouweland, Willem P. T. M. Mali, Rob Janssen and Pim A. de Jong

J. Clin. Med. 2020, 9(9), 2771; https://doi.org/10.3390/jcm9092771 - 26 Aug 2020

Cited by 11 | Viewed by 2210

Abstract

Pseudoxanthoma elasticum (PXE) results in extensive fragmentation and calcification of elastin fibers in the peripheral arteries, which results in peripheral arterial disease (PAD). Current research focuses on the role of calcifications in the pathogenesis of PXE. Elastin degradation and calcification are shown to [...] Read more.

Pseudoxanthoma elasticum (PXE) results in extensive fragmentation and calcification of elastin fibers in the peripheral arteries, which results in peripheral arterial disease (PAD). Current research focuses on the role of calcifications in the pathogenesis of PXE. Elastin degradation and calcification are shown to interact and may amplify each other. This study aims to compare plasma desmosines, a measure of elastin degradation, between PXE patients and controls and to investigate the association between desmosines and (1) arterial calcification, (2) PAD, and (3) PAD independent of arterial calcification in PXE. Plasma desmosines were quantified with liquid chromatography-tandem mass spectrometry in 93 PXE patients and 72 controls. In PXE patients, arterial calcification mass was quantified on CT scans. The ankle brachial index (ABI) after treadmill test was used to analyze PAD, defined as ABI < 0.9, and the Fontaine classification was used to distinguish symptomatic and asymptomatic PAD. Regression models were built to test the association between desmosines and arterial calcification and arterial functioning in PXE. PXE patients had higher desmosines than controls (350 (290–410) ng/L vs. 320 (280–360) ng/L, p = 0.02). After adjustment for age, sex, body mass index, smoking, type 2 diabetes mellitus, and pulmonary abnormalities, desmosines were associated with worse ABI (β (95%CI): −68 (−132; −3) ng/L), more PAD (β (95%CI): 40 (7; 73) ng/L), and higher Fontaine classification (β (95%CI): 30 (6; 53) ng/L), but not with arterial calcification mass. Lower ABI was associated with higher desmosines, independent from arterial calcification mass (β (95%CI): −0.71(−1.39; −0.01)). Elastin degradation is accelerated in PXE patients compared to controls. The association between desmosines and ABI emphasizes the role of elastin degradation in PAD in PXE. Our results suggest that both elastin degradation and arterial calcification independently contribute to PAD in PXE. Full article

(This article belongs to the Special Issue Pseudoxanthoma Elasticum Pathophysiology, from Clinic to Bench Side)

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Review

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5 pages, 178 KiB

Open AccessReview

Comprehensive Literature Review of Obstetric Outcomes and Fetal Risk during Pregnancy with Pseudoxanthoma Elasticum

by Raphael Lee and Mark Lebwohl

J. Clin. Med. 2021, 10(11), 2532; https://doi.org/10.3390/jcm10112532 - 07 Jun 2021

Viewed by 2038

Abstract

Individuals with pseudoxanthoma elasticum (PXE) have often been advised against becoming pregnant due to a fear of the exacerbation of existing symptoms, likelihood of inheritance of the disease, and possible obstetric risks associated with the mother and child. PXE is a recessive multisystem [...] Read more.

Individuals with pseudoxanthoma elasticum (PXE) have often been advised against becoming pregnant due to a fear of the exacerbation of existing symptoms, likelihood of inheritance of the disease, and possible obstetric risks associated with the mother and child. PXE is a recessive multisystem disorder that leads to calcification of elastic tissues and fibers that can result in arterial rupture and gastrointestinal (GI) bleeding, possibly endangering the fetus and mother. PXE often manifests in skin lesions as well and the risk of exacerbation is a principal concern. To address these complications and to provide transparent understanding to healthcare providers and mothers of the associated risk factors with pregnancy and PXE, we conducted a comprehensive review of the current literature and found that there is no inherent risk for obstetric complications for PXE pregnancies and patients need not be advised against becoming pregnant as previously suggested. PXE-related pregnancies are unremarkable to the mother’s wellbeing and fetal complications are few, if any at all. Full article

(This article belongs to the Special Issue Pseudoxanthoma Elasticum Pathophysiology, from Clinic to Bench Side)

16 pages, 1562 KiB

Open AccessReview

Therapeutics Development for Pseudoxanthoma Elasticum and Related Ectopic Mineralization Disorders: Update 2020

by Hongbin Luo, Qiaoli Li, Yi Cao and Jouni Uitto

J. Clin. Med. 2021, 10(1), 114; https://doi.org/10.3390/jcm10010114 - 31 Dec 2020

Cited by 22 | Viewed by 3091

Abstract

Pseudoxanthoma elasticum (PXE), the prototype of heritable ectopic mineralization disorders, manifests with deposition of calcium hydroxyapatite crystals in the skin, eyes and arterial blood vessels. This autosomal recessive disorder, due to mutations in ABCC6, is usually diagnosed around the second decade of [...] Read more.

Pseudoxanthoma elasticum (PXE), the prototype of heritable ectopic mineralization disorders, manifests with deposition of calcium hydroxyapatite crystals in the skin, eyes and arterial blood vessels. This autosomal recessive disorder, due to mutations in ABCC6, is usually diagnosed around the second decade of life. In the spectrum of heritable ectopic mineralization disorders are also generalized arterial calcification of infancy (GACI), with extremely severe arterial calcification diagnosed by prenatal ultrasound or perinatally, and arterial calcification due to CD73 deficiency (ACDC) manifesting with arterial and juxta-articular mineralization in the elderly; the latter disorders are caused by mutations in ENPP1 and NT5E, respectively. The unifying pathomechanistic feature in these three conditions is reduced plasma levels of inorganic pyrophosphate (PPi), a powerful endogenous inhibitor of ectopic mineralization. Several on-going attempts to develop treatments for these conditions, either with the goal to normalize PPi plasma levels or by means of preventing calcium hydroxyapatite deposition independent of PPi, are in advanced preclinical levels or in early clinical trials. This overview summarizes the prospects of treatment development for ectopic mineralization disorders, with PXE, GACI and ACDC as the target diseases, from the 2020 vantage point. Full article

(This article belongs to the Special Issue Pseudoxanthoma Elasticum Pathophysiology, from Clinic to Bench Side)

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