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Ectopic calcification and dysregulated extracellular matrix remodeling are prominent hallmarks of the complex heterogenous pathobiochemistry of pseudoxanthoma elasticum (PXE). The disease arises from mutations in ABCC6, an ATP-binding cassette transporter expressed predominantly in the liver. Neither its substrate nor the mechanisms by which it contributes to PXE are completely understood. The fibroblasts isolated from PXE patients and Abcc6−/− mice were subjected to RNA sequencing. A group of matrix metalloproteinases (MMPs) clustering on human chromosome 11q21-23, respectively, murine chromosome 9, was found to be overexpressed. A real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescent staining confirmed these findings. The induction of calcification by CaCl2 resulted in the elevated expression of selected MMPs. On this basis, the influence of the MMP inhibitor Marimastat (BB-2516) on calcification was assessed. PXE fibroblasts (PXEFs) exhibited a pro-calcification phenotype basally. PXEF and normal human dermal fibroblasts responded with calcium deposit accumulation and the induced expression of osteopontin to the addition of Marimastat to the calcifying medium. The raised MMP expression in PXEFs and during cultivation with calcium indicates a correlation of ECM remodeling and ectopic calcification in PXE pathobiochemistry. We assume that MMPs make elastic fibers accessible to controlled, potentially osteopontin-dependent calcium deposition under calcifying conditions. [ABSTRACT FROM AUTHOR]

Aim: Angioid streaks (ASs) are a rare retinal condition and compromise visual acuity when complicated with choroidal neovascularization (CNV). They represent crack-like dehiscences at the level of the Bruch’s membrane. This objective narrative review aims to provide an overview of pathophysiology, current treatment modalities, and future perspectives on this condition. Materials and Methods: A literature search was performed using “PubMed”, “Web of Science”, “Scopus”, “ScienceDirect”, “Google Scholar”, “medRxiv”, and “bioRxiv.” Results: ASs may be idiopathic, but they are also associated with systemic conditions, such as pseudoxanthoma elasticum, hereditary hemoglobinopathies, or Paget’s disease. Currently, the main treatment is the use of anti-vascular endothelial growth factors (anti-VEGF) to treat secondary CNV, which is the major complication observed in this condition. If CNV is detected and treated promptly, patients with ASs have a good chance of maintaining functional vision. Other treatment modalities have been tried but have shown limited benefit and, therefore, have not managed to be more widely accepted. Conclusion: In summary, although there is no definitive cure yet, the use of anti-VEGF treatment for secondary CNV has provided the opportunity to maintain functional vision in individuals with AS, provided that CNV is detected and treated early.

Mário Lima-Fontes,1 Gonçalo Godinho,2 Ana Maria Cunha,1 Carolina Madeira,3 Manuel Falcão,1,4 Fernando Falcão-Reis,1,4 Ângela Carneiro1,4 1Department of Ophthalmology, Centro Hospitalar Universitário São João, Porto, Portugal; 2Department of Ophthalmology, Centro Hospitalar de Leiria, Leiria, Portugal; 3Department of Ophthalmology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal; 4Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, PortugalCorrespondence: Mário Lima-Fontes, Department of Ophthalmology, Centro Hospitalar Universitário São João, Alameda Professor Hernâni Monteiro, Porto, 4200-319, Portugal, Tel +351 918420563, Fax +351 225513669, Email marioruifontes@gmail.comPurpose: To describe a case of hypotony maculopathy following anti-VEGF intravitreal injection (IVI) in a patient with pseudoxanthoma elasticum (PE).Methods: Clinical case report.Results: A 52-year-old male complained of right eye (OD) vision loss 2 days after an uncomplicated anti-VEGF IVI for the treatment of choroidal neovascularization secondary to angioid streaks. Relevant medical history included PE, pathologic myopia, and a previous pars plana vitrectomy (PPV) due to a retinal detachment. OD best-corrected visual acuity (BCVA) dropped from 6/12 to 6/18 after the IVI. Intraocular pressure (IOP) was 3 mmHg and chorioretinal folds were evident in the posterior pole. Topical dexamethasone and atropine were prescribed, and full recovery was noticed after 3 days. Four months later, the patient developed a new episode of vision loss after another IVI. His BCVA was counting fingers, IOP was 2mmHg, and more noticeable chorioretinal folds were found. This time, an open scleral wound at the injection site was evident and a scleral suture was necessary. Once again, the patient recovered well.Conclusion: Hypotony maculopathy following intravitreal injection is a rare condition. However, the described patient presented several conditions which could be related with poor scleral wound closure: intrinsic scleral fragility due to myopia and pseudoxanthoma elasticum; repeated IVI procedures; and absence of vitreous in the posterior segment due to prior vitrectomy. Despite the good outcome, hypotony maculopathy may be a sight-threatening condition, and special attention is necessary for specific patients with risk factors.Keywords: hypotony maculopathy, intravitreal injection, anti-VEGF, pseudoxanthoma elasticum, angioid streaks

A 60-year-old woman with pseudoxanthoma elasticum (PXE) underwent thorough coronary artery disease assessments. Intravascular imaging tests suggested fragmented and calcified elastic fibers in the internal elastic lamina, suggesting a possible pathophysiology of coronary artery disease in PXE. Our case report would allow clinicians to acknowledge the clinical picture of PXE. (Level of Difficulty: Intermediate.)

Pseudoxanthoma elasticum (PXE) is a rare ectopic calcification disorder affecting soft connective tissues that is caused by biallelic ABCC6 mutations. While the underlying pathomechanisms are incompletely understood, reduced circulatory levels of inorganic pyrophosphate (PPi)—a potent mineralization inhibitor—have been reported in PXE patients and were suggested to be useful as a disease biomarker. In this study, we explored the relation between PPi, the ABCC6 genotype and the PXE phenotype. For this, we optimized and validated a PPi measurement protocol with internal calibration that can be used in a clinical setting. An analysis of 78 PXE patients, 69 heterozygous carriers and 14 control samples revealed significant differences in the measured PPi levels between all three cohorts, although there was overlap between all groups. PXE patients had a ±50% reduction in PPi levels compared to controls. Similarly, we found a ±28% reduction in carriers. PPi levels were found to correlate with age in PXE patients and carriers, independent of the ABCC6 genotype. No correlations were found between PPi levels and the Phenodex scores. Our results suggest that other factors besides PPi are at play in ectopic mineralization, which limits the use of PPi as a predictive biomarker for severity and disease progression. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is characterized by low levels of inorganic pyrophosphate (PPi) and a high activity of tissue-nonspecific alkaline phosphatase (TNAP). Lansoprazole is a partial inhibitor of TNAP. The aim was to investigate whether lansoprazole increases plasma PPi levels in subjects with PXE. We conducted a 2 × 2 randomized, double-blind, placebo-controlled crossover trial in patients with PXE. Patients were allocated 30 mg/day of lansoprazole or a placebo in two sequences of 8 weeks. The primary outcome was the differences in plasma PPi levels between the placebo and lansoprazole phases. 29 patients were included in the study. There were eight drop-outs due to the pandemic lockdown after the first visit and one due to gastric intolerance, so twenty patients completed the trial. A generalized linear mixed model was used to evaluate the effect of lansoprazole. Overall, lansoprazole increased plasma PPi levels from 0.34 ± 0.10 µM to 0.41 ± 0.16 µM (p = 0.0302), with no statistically significant changes in TNAP activity. There were no important adverse events. 30 mg/day of lansoprazole was able to significantly increase plasma PPi in patients with PXE; despite this, the study should be replicated with a large number of participants in a multicenter trial, with a clinical end point as the primary outcome. [ABSTRACT FROM AUTHOR]

Background: Pseudoxanthoma elasticum (PXE), a monogenic disorder resulting in calcification affecting the skin, eyes and peripheral arteries, is caused by mutations in the ABCC6 gene, and is associated with low plasma inorganic pyrophosphate (PPi). It is unknown how ABCC6 genotype affects plasma PPi. Methods: We studied the association of ABCC6 genotype (192 patients with biallelic pathogenic ABCC6 mutations) and PPi levels, and its association with the severity of arterial and ophthalmological phenotypes. ABCC6 variants were classified as truncating or non-truncating, and three groups of the 192 patients were formed: those with truncating mutations on both chromosomes (n = 121), those with two non-truncating mutations (n = 10), and a group who had one truncating and one non-truncating ABCC6 mutation (n = 61). The hypothesis formulated before this study was that there was a negative association between PPi level and disease severity. Results: Our findings confirm low PPi in PXE compared with healthy controls (0.53 ± 0.15 vs. 1.13 ± 0.29 µM, p < 0.01). The PPi of patients correlated with increasing age (β: 0.05 µM, 95% CI: 0.03–0.06 per 10 years) and was higher in females (0.55 ± 0.17 vs. 0.51 ± 0.13 µM in males, p = 0.03). However, no association between PPi and PXE phenotypes was found. When adjusted for age and sex, no association between PPi and ABCC6 genotype was found. Conclusions: Our data suggest that the relationship between ABCC6 mutations and reduced plasma PPi may not be as direct as previously thought. PPi levels varied widely, even in patients with the same ABCC6 mutations, further suggesting a lack of direct correlation between them, even though the ABCC6 protein-mediated pathway is responsible for ~60% of this metabolite in the circulation. We discuss potential factors that may perturb the expected associations between ABCC6 genotype and PPi and between PPi and disease severity. Our findings support the argument that predictions of pathogenicity made on the basis of mutations (or on the structure of the mutated protein) could be misleading. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is an autosomal recessive metabolic disorder that may be associated with a high prevalence of peripheral artery disease (PAD) and related symptoms. However, the evidence supporting this association is weak, as only small cohort studies are available. Furthermore, limited data are available on the outcome of lower limb peripheral arterial interventions (PAI) in patients with PXE. It was the aim of this study to clarify the prevalence of PAD, and the occurrence and outcome of PAI in patients with PXE. This was a retrospective review of prospectively collected data from the Dutch Expertise Centre for PXE database. Clinical data of consecutive patients with a definitive diagnosis of PXE were examined. The primary endpoint was the prevalence of PAD (defined as an ankle brachial index of < 0.9). The secondary endpoint was to report an overview of PAI and target lesion revascularisations. In 285 PXE patients (median age 58 years), 50.9% of patients (n = 145) met the criteria for PAD. Seventeen patients underwent a PAI, mostly for intermittent claudication, at a median age of 51 years. The incidence of PAI was 2.25 per 1 000 patient years in patients with PAD and PXE. A total of 58 interventions was recorded, of which 35 were target lesion revascularisations in nine patients. Twenty one revascularisations were performed within a year following the primary intervention, in 16 cases due to an acute occlusion. Within a well phenotyped and large PXE cohort, the diagnosis of PAD was prevalent in one in two patients. The observed rate of peripheral interventions was low, while the re-intervention rate was unfavourable after endovascular or bypass surgical procedures, with over half of these re-interventions indicated within a year. [ABSTRACT FROM AUTHOR]

Abstract Background Pseudoxanthoma elasticum (PXE, OMIM# 264800) is an inborn error of metabolism causing ectopic soft tissue calcification due to low plasma pyrophosphate concentration. We aimed to assess the prevalence of PXE in Finland and to characterize the Finnish PXE population. A nationwide registry search was performed to identify patients with ICD-10 code Q82.84. Information was gathered from available medical records which were requisitioned from hospitals and health centers. Misdiagnosed patients and patients with insufficient records were excluded. Results The prevalence of PXE in Finland was 1:260,000 with equal sex distribution. Patients with high conventional cardiovascular risk had more visual and vascular complications than patients with low risk. Four patients (19%) had at least one vascular malformation. A high proportion (33%) of ABCC6 genotypes were of the common homozygous c.3421C > T, p.Arg1141Ter variant. Nine other homozygous or compound heterozygous allelic variants were found. Conclusions The prevalence of diagnosed PXE appears to be lower in Finland than in estimates from other countries. Decreased visual acuity is the most prevalent complication. We suggest that various vascular malformations may be an unrecognized feature of PXE.

Pseudoxanthoma elasticum (PXE) is a rare metabolic disease, causing calcification in the arterial media layer and further peripheral artery disease (PAD). A high rate of failure has been reported after endovascular and open surgical management of PAD among patients with PXE. Critical limb ischemia (CLI) rarely develops in PXE, and there are only few reports of its treatment.We present a case report of a 57 year-old female diagnosed with pseudoxanthoma elasticum (PXE). She presented with critical limb ischemia (CLI) and was successfully treated with pedal bypass using the great saphenous vein.Despite obtaining suboptimal outcomes through the initial approach of percutaneous transluminal angioplasty to treat critical limb ischemia, the subsequent bypass operation proved to be a success. At the first follow-up appointment at 1 month, the patient was asymptomatic and the ulceration had almost healed. The patient underwent an ultrasound examination at 3, 6, 12, and 24 months after discharge, and the surveillance was uncomplicated.With a clear indication for surgery, limb-threatening ischemia can be successfully treated with distal bypass, if necessary, in patients with PXE similarly to atherosclerotic PADs. Appropriate diagnostic and surveillance imaging and the utilization of a multidisciplinary team are key components for effective management of PAD in patients with PXE. [ABSTRACT FROM AUTHOR]

Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC contributes to significant morbidity and mortality and is considered a major health problem for which no effective treatments currently exist. In recent years, growing emphasis has been placed on the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of EC. Impaired mitochondrial respiration and increased levels of reactive oxygen species can be directly linked to key molecular pathways involved in EC such as adenosine triphosphate homeostasis, DNA damage signaling, and apoptosis. While EC is mainly encountered in common diseases such as diabetes mellitus and chronic kidney disease, studies in rare hereditary EC disorders such as pseudoxanthoma elasticum or Hutchinson–Gilford progeria syndrome have been instrumental in identifying the precise etiopathogenetic mechanisms leading to EC. In this narrative review, we describe the current state of the art regarding the role of mitochondrial dysfunction and oxidative stress in hereditary EC diseases. In-depth knowledge of aberrant mitochondrial metabolism and its local and systemic consequences will benefit the research into novel therapies for both rare and common EC disorders. [ABSTRACT FROM AUTHOR]

ABCC6 promotes ATP efflux from hepatocytes to bloodstream. ATP is metabolized to pyrophosphate, an inhibitor of ectopic calcification. Pathogenic variants of ABCC6 cause pseudoxanthoma elasticum, a highly variable recessive ectopic calcification disorder. Incomplete penetrance may initiate disease heterogeneity, hence symptoms may not, or differently manifest in carriers. Here, we investigated whether incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. By integrating clinical and genetic data of 589 patients, we created the largest European cohort. Based on allele frequency alterations, we identified two incomplete penetrant pathogenic variants, c.2359G>A (p.Val787Ile) and c.1171A>G (p.Arg391Gly), with 6.5% and 2% penetrance, respectively. However, when penetrant, the c.1171A>G (p.Arg391Gly) manifested a clinically unaltered severity. After applying in silico and in vitro characterization, we suggest that incomplete penetrant variants are only deleterious if a yet unknown interacting partner of ABCC6 is mutated simultaneously. The low penetrance of these variants should be contemplated in genetic counseling. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is a genetic multisystem ectopic calcification disorder caused by inactivating mutations in the ABCC6 gene encoding ABCC6, a hepatic efflux transporter. ABCC6-mediated ATP secretion by the liver is the main source of a potent endogenous calcification inhibitor, plasma inorganic pyrophosphate (PPi); the deficiency of plasma PPi underpins PXE. Recent studies demonstrated that INZ-701, a recombinant human ENPP1 that generates PPi and is now in clinical trials, restored plasma PPi levels and prevented ectopic calcification in the muzzle skin of Abcc6 -/- mice. This study examined the pharmacokinetics, pharmacodynamics, and potency of a new ENPP1-Fc isoform, BL-1118, in Abcc6 -/- mice. When Abcc6 -/- mice received a single subcutaneous injection of BL-1118 at 0.25, 0.5, or 1 mg/kg, they had dose-dependent elevations in plasma ENPP1 enzyme activity and PPi levels, with an enzyme half-life of approximately 100 h. When Abcc6 -/- mice were injected weekly from 5 to 15 weeks of age, BL-1118 dose-dependently increased steady-state plasma ENPP1 activity and PPi levels and significantly reduced ectopic calcification in the muzzle skin and kidneys. These results suggest that BL-1118 is a promising second generation enzyme therapy for PXE, the first generation of which is currently in clinical testing., Competing Interests: Declaration of interests D.T.B. and P.R.S. are inventors on patents owned by Yale University for therapeutics treating ENPP1 deficiency. D.T.B. is an equity holder and receives research and consulting support from Inozyme Pharma, Inc., (Copyright © 2024 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Previous studies revealed a link between inflammation and overactivation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling in syndromes associated with aging. Pseudoxanthoma elasticum (PXE), a rare autosomal-recessive disorder, arises from mutations in ATP-binding cassette subfamily C member 6 (ABCC6). On a molecular level, PXE shares similarities with Hutchinson–Gilford progeria syndrome, such as increased activity of senescence-associated- beta-galactosidase or high expression of inflammatory factors. Thus, this study’s aim was the evaluation of activated STAT3 and the influence of JAK1/2-inhibitor baricitinib (BA) on inflammatory processes such as the complement system in PXE. Analysis of activation of STAT3 was performed by immunofluorescence and Western blot, while inflammatory processes and complement system factors were determined based on mRNA expression and protein level. Our results assume overactivation of JAK/STAT3 signaling, increased expression levels of several complement factors and high C3 protein concentration in the sera of PXE patients. Supplementation with BA reduces JAK/STAT3 activation and partly reduces inflammation as well as the gene expression of complement factors belonging to the C1 complex and C3 convertase in PXE fibroblasts. Our results indicate a link between JAK/STAT3 signaling and complement activation contributing to the proinflammatory phenotype in PXE fibroblasts.

This article discusses a case of bilateral angioid streaks in a young patient with pseudoxanthoma elasticum (PXE). PXE is a hereditary disease characterized by the degeneration of elastic fibers and calcification. Ocular manifestations of PXE include angioid streaks, peau d'orange appearance, and optic disc drusen. The patient in this case had angioid streaks in both eyes, as well as optic disc drusen. No treatment was required, but regular follow-up visits were advised. Ophthalmologists should be aware of the association between angioid streaks and PXE in order to prevent irreversible visual loss. [Extracted from the article]

ENPP1 encodes ENPP1, an ectonucleotidase catalyzing hydrolysis of ATP to AMP and inorganic pyrophosphate (PPi), and an endogenous plasma protein physiologically preventing ectopic calcification of connective tissues. Mutations in ENPP1 have been reported in association with a range of human genetic diseases. In this mutation update, we provide a comprehensive review of all the pathogenic variants, likely pathogenic variants, and variants of unknown significance in ENPP1 associated with three autosomal recessive disorders—generalized arterial calcification of infancy (GACI), autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and pseudoxanthoma elasticum (PXE), as well as with a predominantly autosomal dominant disorder—Cole disease. The classification of all variants is determined using the latest ACMG guidelines. A total of 140 ENPP1 variants were curated consisting of 133 previously reported variants and seven novel variants, with missense variants being the most prevalent (70.0%, 98/140). While the pathogenic variants are widely distributed in the ENPP1 gene of patientsgen without apparent genotype–phenotype correlation, eight out of nine variants associated with Cole disease are confined to the somatomedin‐B‐like (SMB) domains critical for homo‐dimerization of the ENPP1 protein. [ABSTRACT FROM AUTHOR]

Mutations in ABCC6, an ATP-binding cassette transporter with a so far unknown substrate mainly expressed in the liver and kidney, cause pseudoxanthoma elasticum (PXE). Symptoms of PXE in patients originate from the calcification of elastic fibers in the skin, eye, and vessels. Previous studies suggested an involvement of ABCC6 in cholesterol and lipid homeostasis. The intention of this study was to examine the influence of ABCC6 deficiency during adipogenic differentiation of human bone marrow-derived stem cells (hMSCs). Induction of adipogenic differentiation goes along with significantly elevated ABCC6 gene expression in mature adipocytes. We generated an ABCC6-deficient cell culture model using clustered regulatory interspaced short palindromic repeat Cas9 (CRISPR–Cas9) system to clarify the role of ABCC6 in lipid homeostasis. The lack of ABCC6 in hMSCs does not influence gene expression of differentiation markers in adipogenesis but results in a decreased triglyceride content in cell culture medium. Protein and gene expression analysis of mature ABCC6-deficient adipocytes showed diminished intra- and extra-cellular lipolysis, release of lipids, and fatty acid neogenesis. Therefore, our results demonstrate impaired lipid trafficking in adipocytes due to ABCC6 deficiency, highlighting adipose tissue and peripheral lipid metabolism as a relevant target for uncovering systemic PXE pathogenesis. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is a currently intractable genetic disorder characterized by progressive ectopic calcification in the skin, eyes and arteries. Therapeutic trials in PXE are severely hampered by the lack of reliable biomarkers. Serum calcification propensity T50 is a blood test measuring the functional anticalcifying buffer capacity of serum. Here, we evaluated T50 in PXE patients aiming to investigate its determinants and suitability as a potential biomarker for disease severity. Fifty-seven PXE patients were included in this cross-sectional study, and demographic, clinical, imaging and biochemical data were collected from medical health records. PXE severity was assessed using Phenodex scores. T50 was measured using a validated, nephelometry-based assay. Multivariate models were then created to investigate T50 determinants and associations with disease severity. In short, the mean age of patients was 45.2 years, 68.4% was female and mean serum T50 was 347 min. Multivariate regression analysis identified serum fetuin-A (p < 0.001), phosphorus (p = 0.007) and magnesium levels (p = 0.034) as significant determinants of T50, while no correlations were identified with serum calcium, eGFR, plasma PPi levels or the ABCC6 genotype. After correction for covariates, T50 was found to be an independent determinant of ocular (p = 0.013), vascular (p = 0.013) and overall disease severity (p = 0.016) in PXE. To conclude, shorter serum T50—indicative of a higher calcification propensity—was associated with a more severe phenotype in PXE patients. This study indicates, for the first time, that serum T50 might be a clinically relevant biomarker in PXE and may thus be of importance to future therapeutic trials. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE), a heritable multisystem ectopic calcification disorder, is predominantly caused by inactivating mutations in ABCC6. The encoded protein, ABCC6, is a hepatic efflux transporter and a key regulator of extracellular inorganic pyrophosphate (PPi). Recent studies demonstrated that deficiency of plasma PPi, a potent endogenous calcification inhibitor, is the underlying cause of PXE. This study examined whether restoring plasma PPi levels by INZ‐701, a recombinant human ENPP1 protein, the principal PPi‐generating enzyme, prevents ectopic calcification in an Abcc6−/− mouse model of PXE. Abcc6−/− mice, at 6 weeks of age, the time of earliest stages of ectopic calcification, were injected subcutaneously with INZ‐701 at 2 or 10 mg/kg for 2 or 8 weeks. INZ‐701 at both doses increased steady‐state plasma ENPP1 activity and PPi levels. In the 8‐week treatment study, histopathologic examination and quantification of the calcium content in INZ‐701‐treated Abcc6−/− mice revealed significantly reduced calcification in the muzzle skin containing vibrissae, a biomarker of the calcification process in these mice. The extent of calcification corresponds to the local expression of two calcification inhibitors, osteopontin and fetuin‐A. These results suggest that INZ‐701 might provide a therapeutic approach for PXE, a disease with high unmet needs and no approved treatment. [ABSTRACT FROM AUTHOR]

Fearing for possible consequences to the retina of women with pseudoxanthoma elasticum, vaginal delivery is sometimes discouraged. In our case series of 14 patients with pseudoxanthoma elasticum, we could not detect any (sub)retinal hemorrhages or progression of angioid streaks after childbirth. Vaginal delivery seems safe for the retina of patients with pseudoxanthoma elasticum if no active choroidal neovascularization is present. Background/Purpose: To investigate the effect of a vaginal delivery (VD) on retinal pathology in patients with pseudoxanthoma elasticum. Methods: Retrospective case series. All 14 consecutive women with pseudoxanthoma elasticum who visited the ophthalmology department during pregnancy and after delivery between 2010 and 2018 were included. Prepartum and postpartum imaging consisted of color imaging, near-infrared imaging, and optical coherence tomography and was assessed on occurrence of (sub)retinal hemorrhages and change in angioid streaks. Results: Fourteen patients (15 deliveries) were included, of whom 11 patients (79%) had a VD and three patients (21%) a secondary caesarian section. Data of three patients with VD (four deliveries) could not be assessed for (sub)retinal hemorrhage within 10 weeks postpartum. The median age at delivery was 31 years (IQR 29–37). One patient with VD (9%) had a choroidal neovascularization and was treated with anti-VEGF injections before assisted delivery. All patients had angioid streaks in the central 5,500 µ m of the posterior pole of both eyes. After delivery, no patient in the VD or caesarian section group presented with progression of angioid streaks or (sub)retinal hemorrhage. Conclusion: Pushing during the expulsion phase of VD seems safe in pseudoxanthoma elasticum patients without active choroidal neovascularization, and the presence of angioid streaks alone should not be an indication for elective caesarian section. [ABSTRACT FROM AUTHOR]

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Abstract Background This article is a case report of pseudoxanthoma elasticum (PXE) which was diagnosed based on significant angioid streaks (AS) with choroidal neovascularization (CNV) and regain normal visual function by intravitreal injection with Conbercept. Case presentation A 51-year-old woman was referred to the Ophthalmology Department of Qingdao Municipal Hospital (Qingdao, China) on September 14, 2020 for metamorphopsia and loss of vision in the left eye in the preceding three days. Past history: high myopia for more than 30 years, best corrected visual acuity (BCVA) of both eyes was 1.0 (5 m Standard Logarithm Visual Acuity chart in decimal notations), hypertension for six years, and cerebral infarction two years ago, no history of ocular trauma or surgeries or similar patients in family was documented. We used methods for observation, including fundus examination, optical coherence tomography (OCT), fluorescein angiography combined with indocyanine green angiography (FFA + ICGA). Due to her symptoms and manifestations, along with the appearance of her neck skin, which resembled ‘chicken skin’, we speculated that she should be further examined at the Department of Dermatology by tissue paraffin section and molecular pathology analyses, and the diagnosis of PXE was then confirmed. After intravitreal injection with Conbercept (10 mg/ml, 0.2 ml, Chengdu Kanghong Biotechnologies Co., Ltd.; Chengdu, Sichuan, China) she regained her BCVA. Conclusions This patient regained her best corrected visual acuity through intravitreal injection with Conbercept. To the best of our knowledge, no publications are available on cases in which a vision loss and the normal visual function can be reverted by intravitreal injection with Conbercept. Although PXE is a disease with low incidence and thus no effective cure established, targeted symptomatic treatment can effectively retard the disease progression and improve visual function, such as intravitreal injection with Conbercept.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by atypical elastic fibers that causes connective tissue abnormalities of the skin, eyes, and heart, among other organs. The disorder is rare, with a classic presentation of yellow-orange cobblestone-like papules on flexural areas, lax skin, ocular degeneration, and moribund vasculature in multiple organs. There is wide variability in the presentation of the affected organs [1]. We present two sisters with classic cutaneous findings of PXE with the additional unusual findings of numerous open comedones on the neck. To our knowledge, this is the first report of numerous open comedones in familial PXE.

Increased laxity of the skin can be caused by aging, significant weight loss, or defects in the elastic tissue. A 38-year-old female presented with increased laxity of the skin over the neck, thighs, and abdomen for 6 years, associated with headache and blurring of vision for a week. On cutaneous examination, prominent skin folds, laxity, and wrinkles were noted over the neck, abdomen, thighs, and groin, with yellowish papules along the neck creases. Ocular examination revealed features suggestive of angioid streaks. Skin biopsy showed fragmented elastic fibers and intervening calcium deposits on Verhoeff Van Gieson and Von Kossa stains. Based on these findings, a diagnosis of pseudoxanthoma elasticum (PXE) was made. The patient was started on oral and topical sunscreens and eye protection and advised regular follow-up. Diagnosing the condition early based on skin findings can help prevent further multi-system manifestations by taking appropriate preventive measures as this condition is progressive and has no cure.

Elastic pseudoxanthoma is a rare disease with autosomal recessive inheritance, also known as Grönblad-Strandberg syndrome, characterized by pathological mineralization of the elastic fibers in the connective tissue, affecting principally the dermis of skin, media, and intima of blood vessels and Bruch’s membrane of the eye. The genetic defect of the disorder is located on chromosome 16p13.1 and disease is caused by the lack of functional ABCC6 protein, which in turn causes extracellular accumulation and deposition of calcium and other minerals in the elastic tissue. In this article we present two cases of this rare disease. We emphasize, in the diagnostic criteria, the importance of its early diagnosis and the current therapeutic approaches.

Pseudoxanthoma elasticum is a rare connective tissue disease which affects the synthesis of the elastic fibres. It is an area of uncertainty for patients affected by this disease requiring surgical revascularization. We present a case report of a 43-year-old gentleman was known to have pseudoxanthoma elasticum syndrome (PXE) and coronary artery disease. He underwent successful off pump LIMA to LAD. Interestingly, this is the first case in UK and second one in the literature managed with an off-pump strategy. The predilection of the histopathological changes in PXE patients, should not prevent the routine use in of the left internal mammary artery as a standard conduit in CABG. Further studies are required to standardize the practice for surgical revascularization in the patients with PXE. [ABSTRACT FROM AUTHOR]

Autosomal recessive hypophosphatemic rickets type 2 (ARHR2; MIM #613312) is a very rare disorder caused by biallelic loss-of-function mutations in the ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) gene. ENPP1 deficiency encompasses a spectrum of phenotypes that includes, in addition to ARHR2, generalized arterial calcification of infancy (GACI), ossification of the posterior longitudinal ligament (OPLL), and pseudoxanthoma elasticum. ARHR2 can be found in GACI survivors, but it may also be the first manifestation of ENPP1 deficiency. Although the precise mechanisms are not fully elucidated, patients with GACI and ARHR2 have elevated serum FGF23 levels, leading to renal phosphate wasting and hypophosphatemia. As a result, the clinical and radiological phenotype of ARHR2 patients is very similar to that of patients affected with other forms of hypophosphatemic rickets, such as X-linked hypophosphatemia. Patients show signs of rickets (abnormal mineralization of growth plates in children) and osteomalacia (abnormal bone mineralization in children and adults) of varying severity. Clinical manifestations specific to ENPP1 loss-of-function mutations and common to GACI, such as ectopic calcifications (valvular, arterial, or periarticular), deafness, OPLL, and PXE, may also be found. Genetic confirmation of the disease is important so as to ensure that patients receive the appropriate treatment or have the opportunity to participate in clinical trials to evaluate the safety and efficacy of novel and promising recombinant enzyme therapies. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is an autosomal-recessively inherited multisystem disease. Mutations in the ABCC6 -gene are causative, coding for a transmembrane transporter mainly expressed in hepatocytes, which promotes the efflux of adenosine triphosphate (ATP). This results in low levels of plasma inorganic pyrophosphate (PPi), a critical anti-mineralization factor. The clinical phenotype of PXE is characterized by the effects of elastic fiber calcification in the skin, the cardiovascular system, and the eyes. In the eyes, calcification of Bruch's membrane results in clinically visible lesions, including peau d'orange, angioid streaks, and comet tail lesions. Frequently, patients must be treated for secondary macular neovascularization. No effective therapy is available for treating the cause of PXE, but several promising approaches are emerging. Finding appropriate outcome measures remains a significant challenge for clinical trials in this slowly progressive disease. This review article provides an in-depth summary of the current understanding of PXE and its multi-systemic manifestations. The article offers a detailed overview of the ocular manifestations, including their morphological and functional consequences, as well as potential complications. Lastly, previous and future clinical trials of causative treatments for PXE are discussed. [ABSTRACT FROM AUTHOR]

Ectopic calcification and dysregulated extracellular matrix remodeling are prominent hallmarks of the complex heterogenous pathobiochemistry of pseudoxanthoma elasticum (PXE). The disease arises from mutations in ABCC6, an ATP-binding cassette transporter expressed predominantly in the liver. Neither its substrate nor the mechanisms by which it contributes to PXE are completely understood. The fibroblasts isolated from PXE patients and Abcc6−/− mice were subjected to RNA sequencing. A group of matrix metalloproteinases (MMPs) clustering on human chromosome 11q21-23, respectively, murine chromosome 9, was found to be overexpressed. A real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescent staining confirmed these findings. The induction of calcification by CaCl2 resulted in the elevated expression of selected MMPs. On this basis, the influence of the MMP inhibitor Marimastat (BB-2516) on calcification was assessed. PXE fibroblasts (PXEFs) exhibited a pro-calcification phenotype basally. PXEF and normal human dermal fibroblasts responded with calcium deposit accumulation and the induced expression of osteopontin to the addition of Marimastat to the calcifying medium. The raised MMP expression in PXEFs and during cultivation with calcium indicates a correlation of ECM remodeling and ectopic calcification in PXE pathobiochemistry. We assume that MMPs make elastic fibers accessible to controlled, potentially osteopontin-dependent calcium deposition under calcifying conditions.

Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by systemic calcification of elastin fibers. Additionally, PXE is associated with an increased risk of stroke. It has been hypothesized that this may be caused by accelerated (intracranial) atherogenesis, as a consequence of specific genetic mutations underlying PXE. Hence, we compared the distribution and burden of intracranial atherosclerosis between PXE patients and healthy controls. Fifty PXE patients and 40 age-and-sex-matched healthy controls (without previous ischemic cerebrovascular disease) underwent 3T MRI to visualize atherosclerotic intracranial vessel wall lesions (VWLs). We compared the presence and burden of VWLs (total and for the anterior cerebral, middle cerebral, intracranial internal carotid, posterior cerebral, and basilar arteries separately) between PXE patients and healthy controls using logistic (presence versus absence) and negative binomial regression models (VWL count) adjusted for relevant confounders. All regressions included group (PXE patients vs. healthy controls) as independent variable. We found that 34 (68.0%) PXE patients and 28 (70.0%) healthy controls had a VWL (odds ratio for presence 1.06 [95%CI 0.38–2.91]). In addition, the total burden of VWLs was similar between PXE patients (68 VWLs) and healthy controls (73 VWLs, incidence rate ratio for count 0.81 [95%CI 0.55–1.20]). Findings were similar when analyses were stratified for artery. The distribution and burden of intracranial atherosclerosis were similar between PXE patients and healthy controls. This implies PXE and its underlying mutations do not involve increased (intracranial) atherogenesis and that vascular calcification or other mechanisms explains the increased stroke risk in PXE. [Display omitted] • Pseudoxanthoma elasticum (PXE) is hypothesized to be involved in atherogenesis. • PXE patients are at an increased risk for stroke. There is scientific debate on whether intracranial atherosclerosis plays a role. • We found the distribution and burden of intracranial atherosclerosis were not increased in PXE patients compared to controls. • Our findings imply PXE and its underlying mutations are not involved in atherogenesis.Other factors (calcification induced arterial stiffness or carotid hypoplasia) might explain the increased stroke risk in PXE. • Other factors (calcification induced arterial stiffness or carotid hypoplasia) might explain the increased stroke risk in PXE. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE) is an autosomal recessive multisystem disorder showing phenotypic heterogeneity giving rise to complex comorbidities. The most 'visible' signs are dermatological; however, these may be subtle and hidden from the view of an affected individual. Ophthalmic signs can be easily missed, and here we highlight the importance of a multisystem assessment. We report a patient who developed advanced sight loss due to maculopathy whose underlying PXE aetiology went unnoticed until subtle skin signs were noticed on the lateral aspect of his neck. He was aware of the skin changes. Careful review of his previous retinal imaging showed the presence of 'angioid streaks' and anatomic alteration at the outer retina-Bruch membrane associated with his prior history of choroidal neovascularisation. The diagnosis was subsequently confirmed by skin biopsy and genetic testing. This case highlights the subtlety of both dermatological and ophthalmic signs in PXE. [ABSTRACT FROM AUTHOR]

Background: Pseudoxanthoma elasticum (PXE, OMIM# 264800) is an inborn error of metabolism causing ectopic soft tissue calcification due to low plasma pyrophosphate concentration. We aimed to assess the prevalence of PXE in Finland and to characterize the Finnish PXE population. A nationwide registry search was performed to identify patients with ICD-10 code Q82.84. Information was gathered from available medical records which were requisitioned from hospitals and health centers. Misdiagnosed patients and patients with insufficient records were excluded.Results: The prevalence of PXE in Finland was 1:260,000 with equal sex distribution. Patients with high conventional cardiovascular risk had more visual and vascular complications than patients with low risk. Four patients (19%) had at least one vascular malformation. A high proportion (33%) of ABCC6 genotypes were of the common homozygous c.3421C > T, p.Arg1141Ter variant. Nine other homozygous or compound heterozygous allelic variants were found.Conclusions: The prevalence of diagnosed PXE appears to be lower in Finland than in estimates from other countries. Decreased visual acuity is the most prevalent complication. We suggest that various vascular malformations may be an unrecognized feature of PXE. [ABSTRACT FROM AUTHOR]

Pseudoxanthoma elasticum (PXE; OMIM 264800) is an autosomal recessive metabolic disorder characterized by progressive calcification in the skin, the Bruch's membrane, and the vasculature. Calcification in PXE results from a low level of circulating pyrophosphate (PPi) caused by ABCC6 deficiency. In this study, we used a cohort of 107 PXE patients to determine the pathophysiological relationship between plasma PPi, coronary calcification (CAC), lower limbs arterial calcification (LLAC), and disease severity. Overall, our data showed a deficit in plasma PPi in PXE patients compared to controls. Remarkably, affected females showed higher PPi levels than males, but a lower LLAC. There was a strong correlation between age and PPi in PXE patients (r = 0.423, p < 0.0001) but not in controls (r = 0.059, p = 0.828). A weak correlation was found between PPi and CAC (r = 0.266, p < 0.02); however, there was no statistically significant connection with LLAC (r = 0.068, p = 0.518) or a severity score (r = 0.077, p = 0.429). Surprisingly, we found no significant correlation between plasma alkaline phosphatase activity and PPi (r = 0.113, p = 0.252) or between a 10-year cardiovascular risk score and all other variables. Multivariate analysis confirmed that LLAC and CAC were strongly dependent on age, but not on PPi. Our data showed that arterial calcification is only weakly linked to circulating PPi levels and that time (i.e., age) appears to be the major determinant of disease severity and calcification in PXE. These data are important to better understand the natural history of this disease but also for the follow-up and management of patients, and the design of future clinical trials. Our results also show that PPi is not a good biomarker for the evaluation of disease severity and progression. [ABSTRACT FROM AUTHOR]

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Pseudoxanthoma elasticum (PXE; OMIM 264800) is a rare heritable multisystem disorder, characterized by ectopic mineralization affecting elastic fibres in the skin, eyes and the cardiovascular system. Skin findings often lead to early diagnosis of PXE, but currently, no specific treatment exists to counteract the progression of symptoms. PXE belongs to a group of Mendelian calcification disorders linked to pyrophosphate metabolism, which also includes generalized arterial calcification of infancy (GACI) and arterial calcification due to CD73 deficiency (ACDC). Inactivating mutations in ABCC6, ENPP1 and NT5E are the genetic cause of these diseases, respectively, and all of them result in reduced inorganic pyrophosphate (PPi) concentration in the circulation. Although PPi is a strong inhibitor of ectopic calcification, oral supplementation therapy was initially not considered because of its low bioavailability. Our earlier work however demonstrated that orally administered pyrophosphate inhibits ectopic calcification in the animal models of PXE and GACI, and that orally given Na4P2O7 is absorbed in humans. Here, we report that gelatin‐encapsulated Na2H2P2O7 has similar absorption properties in healthy volunteers and people affected by PXE. The sodium‐free K2H2P2O7 form resulted in similar uptake in healthy volunteers and inhibited calcification in Abcc6−/− mice as effectively as its sodium counterpart. Novel pyrophosphate compounds showing higher bioavailability in mice were also identified. Our results provide an important step towards testing oral PPi in clinical trials in PXE, or potentially any condition accompanied by ectopic calcification including diabetes, chronic kidney disease or ageing. [ABSTRACT FROM AUTHOR]