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Many systemic diseases go along with dermal involvement. Only a few of systemic diseases show characteristic skin derangements directly leading to the diagnosis of the underlying disease. Ten of these entities are described within this article. Some of these are autoimmune diseases, such as systemic lupus erythematodes, dermatomyositis or the anti-synthetase-syndrome. Others are genetic diseases with benign or malignant neoplasias (Peutz-Jeghers-syndrome, neurofibromatosis, tuberous sclerosis, Birt-Hogg-Dubé-syndrome, Cowden-syndrome). Other genetically based diseases with typical skin manifestations are characterised by vascular malformations (Pseudoxanthoma elasticum and Osler-Weber-Rendu syndrome) or metabolic and structural organ defects (Morbus Fabry, cystic fibrosis). Being familiar with the typical skin-appearance of these diseases will allow physicians and general practitioners to make a timely diagnosis.

Background/aimsTo determine the association of age, presence of optic nerve head drusen (ONHD) and number of previous intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections with inner retinal layer thicknesses in patients with pseudoxanthoma elasticum (PXE).MethodsIn this retrospective case–control study, longitudinal spectral-domain optical coherence tomography imaging data from patients with PXE were compared with controls. A custom deep-learning-based segmentation algorithm was trained and validated to quantify the retinal nerve fibre layer (RNFL) and ganglion cell layer (GCL). The association of age, number of anti-VEGF injections and ONHD with the RNFL and GCL thickness in the outer ETDRS subfields as dependent variables was investigated using mixed model regression.ResultsFourty-eight eyes of 30 patients with PXE were compared with 100 healthy eyes. The mean age was 52.5±12.9 years (range 21.3–68.2) for patients and 54.2±18.7 years (range 18.0–84.5) for controls. In patients, ONHD were visible in 15 eyes from 13 patients and 31 eyes had received anti-VEGF injections. In the multivariable analysis, age (−0.10 µm/year, pConclusionsThis study demonstrates a significant association of ageing and ONHD with GCL thinning in patients with PXE, but not with the number of anti-VEGF injections. Given the severity of inner retinal degeneration in PXE, a clinical trial investigating neuroprotective therapy warrants consideration.

We present a rare case of surgical aortic valve replacement (SAVR) in a patient with pseudoxanthoma elasticum (PXE). Our patient developed severe symptomatic aortic stenosis (AS) at a relatively young age of 61 despite a trileaflet valve. Notable intraoperative challenges included difficulties with arterial access and hemodynamic monitoring accuracy due to PXE effects on peripheral arteries. Additionally, the diseased valve itself was unusual in its very crumbly nature with micro-popcorn-like calcifications, which easily broke apart with handling. Lastly, rivaroxaban was chosen and warfarin avoided to anticoagulate for postoperative atrial fibrillation in PXE to prevent thromboembolism.

We compared velocity pulsatility, distensibility, and pulsatility attenuation along the intracranial ICA and MCA between 50 patients with pseudoxanthoma elasticum and 40 controls. Patients with pseudoxanthoma elasticum had higher pulsatility and lower distensibility at all measured locations, except for a similar distensibility at C4. The pulsatility attenuation over the siphon was similar between patients with pseudoxanthoma elasticum and controls. This finding suggests that other disease mechanisms are the main contributors to increased intracranial pulsatility in pseudoxanthoma elasticum.

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. Objective: To review existing literature reporting peripheral vascular disease (PVD), cardiovascular disease (CVD), cerebrovascular disease (CeVD), hypertension, and carotid rete mirabile (CRM) in PXE patients as of June 2021. 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.

Purpose To report a case of photoreceptor restitution and vision improvement with pneumatic compaction treatment of acute subfoveal hemorrhage in a patient with angioid streaks associated with pseudoxanthoma elasticum, observed by sequential fundus photography, spectral domain optical coherence tomography, and fundus autofluorescence. Methods Findings on initial and sequential clinical examinations, fundus autofluorescence, and spectral domain optical coherence tomography are presented, before and after pneumatic compaction, demonstrating the course of compaction and resolution of subfoveal hemorrhage and status of the foveal ellipsoid zone and external limiting membrane. Sequential improvements in oxygen and nutrient diffusion are calculated using Fick's law of diffusion. Findings are compared with previous reports regarding the natural history of similar patients. Results Rapid compaction of subfoveal hemorrhage occurred, resulting in an 89% improvement in oxygen diffusion in 15 days. No centrifugal movement of subfoveal hemorrhage occurred, potentially minimizing photoreceptor-shearing injury. Ultimately, resorption of all hemorrhage occurred with reestablishment of the foveal ellipsoid zone and external limiting membrane and minimal juxtafoveal subretinal fibrosis; best-corrected visual acuity improved to 20/40: an advantage over natural history based on published reports. Conclusion Pneumatic compaction in patients with acute subfoveal hemorrhage secondary to angioid streaks associated with pseudoxanthoma elasticum compacts subfoveal hemorrhage, therefore improving oxygen and nutrient diffusion. This potentially spares foveal photoreceptors of ischemic and shearing injury, theoretically reducing subfoveal fibrosis and improving vision prognosis in these patients.

BackgroundBiallelic pathogenic variants in the ATP-binding cassette subfamily C member 6 (ABCC6) gene cause pseudoxanthoma elasticum, a multisystemic ectopic calcification disorder, while heterozygous ABCC6 variants are associated with an increased risk of cardiovascular and cerebrovascular disease. As the prevalence of pathogenic ABCC6 variants in the general population is estimated at ~1%, identifying additional ABCC6-related (sub)clinical manifestations in heterozygous carriers is of the utmost importance to reduce this burden of disease. Here, we present a large Belgian cohort of heterozygous ABCC6 carriers with comprehensive clinical, biochemical and imaging data. Based on these results, we formulate clinical practice guidelines regarding screening, preventive measures and follow-up of ABCC6 carriers.MethodsThe phenotype of 56 individuals carrying heterozygous pathogenic ABCC6 variants was assessed using clinical (eg, detailed ophthalmological examinations), biochemical, imaging (eg, cardiovascular and abdominal ultrasound) and genetic data. Clinical practice guidelines were then drawn up.ResultsWe found that ABCC6 heterozygosity is associated with distinct retinal alterations (‘comet-like’) (24%), high prevalence of hypercholesterolaemia (>75%) and diastolic dysfunction (33%), accelerated lower limb atherosclerosis and medial vascular disease, abdominal organ calcification (26%) and testicular microlithiasis (28%), though with highly variable expression.ConclusionIn this study, we delineated the multisystemic ABCC6 heterozygosity phenotype characterised by retinal alterations, aberrant lipid metabolism, diastolic dysfunction and increased vascular, abdominal and testicular calcifications. Our clinical practice guidelines aimed to improve early diagnosis, treatment and follow-up of ABCC6-related health problems.

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.

Background: Pseudoxanthoma Elasticum is a hereditary disease characterized by calcification of elastic fibers that result in cutaneous, ophthalmologic, and cardiovascular complications. As the pulmonary system contains multiple cell types with abundant elastic fibers, pulmonary manifestations are expected yet not often observed. Objective: To review current literature reporting cases of pulmonary manifestations in patients with pseudoxanthoma elasticum. Methods: A search of the PubMed computerized database limited to English language case reports and cross-sectional cohort studies as of December 2020 was performed using the key words “pseudoxanthoma elasticum”, “PXE”, “pulm*”, and “lung”. Results: A total of 15 patients with clinical, radiologic, or histologic pulmonary manifestations of PXE were identified across four case reports and one cohort study. Patients who did present with pulmonary symptoms were exceedingly rare and reported only progressive exertional dyspnea. Discussion: Histologic and/or radiologic investigation of PXE patients who presented with progressive exertional dyspnea revealed calcification and irregularity of the elastic laminae in the pulmonary vasculature, the alveolar septa or both. Additionally, spirometry and diffusion studies in PXE patients revealed a restrictive pattern of lung disease with significantly decreased absolute total lung capacity compared to controls. Conclusions: PXE patients with pulmonary symptoms severe enough to have clinical impact are exceedingly rare, and thus investigative workup is not often pursued. Further research is needed to elucidate the clinical impact of lung calcification in PXE patients.

Pseudoxanthoma elasticum (PXE)-like papillary dermal elastolysis (PDE) is an acquired, rare, elastic tissue disorder that presents with multiple asymptomatic, nonfollicular yellowish or normochromic papules, coalescing into symmetrical cobblestone plaques, with a predilection for the neck of postmenopausal women. The condition develops slowly, in months to years, and, although clinically similar to PXE, it is devoid of any systemic implication, being only of esthetic concern. The etiology is unknown, but it is speculated that there is a multifactorial pathogenesis, with the contribution of intrinsic aging, exposure to ultraviolet radiation, abnormal elastogenesis, and genetic factors. The diagnosis is confirmed by histopathology, with special stains specific for elastic fibers revealing loss of elastic plexus in the papillary dermis and the presence of melanophages. Its prevalence is probably underestimated, which reinforces the importance of better clinical and histologic identification to distinguish it from inherited PXE and to avoid extensive systemic investigations and unnecessary medical visits for the patient.

Pseudoxanthoma elasticum (PXE), a prototype of heritable ectopic calcification disorders, affects the skin, eyes and the cardiovascular system due to inactivating mutations in the ABCC6 gene. There is no effective treatment for the systemic manifestations of PXE. In this study, the efficacy of INS-3001, an analogue of phytic acid, was tested for inhibition of ectopic calcification in an Abcc6-/- mouse model of PXE. In prevention study, Abcc6-/- mice, at 6 weeks of age, the time of onset of ectopic calcification, were treated with INS-3001 with 0.16, 0.8, 4, 20 or 100 mg/kg/day administered by subcutaneous implantation of osmotic pumps, as well as 4 mg/kg/day by subcutaneous injection thrice weekly or 14, 4 and 0.8 mg/kg/day once weekly subcutaneous injection. Mice were necropsied at 12 weeks of age. Histologic examination and quantitative calcium assay revealed that mice receiving 6 weeks of continuous INS-3001 administration via osmotic pumps showed dose-dependent inhibition of muzzle skin calcification with complete response at 4 mg/kg/day and a minimum effective dose at 0.8 mg/kg/day. INS-3001 plasma concentrations were dose-dependent and largely consistent during treatment for each dose. thrice weekly and once weekly subcutaneous injections of INS-3001 also prevented calcification. In established disease study, 12-week-old Abcc6-/- mice with extensive calcification were continuously administered INS-3001 at 4 mg/kg/day for a follow-up of 12 weeks. INS-3001 treatment was found to stabilize existing calcification that had developed at start of treatment. These results suggest that INS-3001 may provide a promising preventive treatment strategy for PXE, a currently intractable ectopic calcification disorder.

ABCC6 deficiency promotes ectopic calcification; however, circumstantial evidence suggested that ABCC6 may also influence atherosclerosis. The present study addressed the role of ABCC6 in atherosclerosis using Ldlr−/− mice and pseudoxanthoma elasticum (PXE) patients. Mice lacking the Abcc6 and Ldlr genes were fed an atherogenic diet for 16 weeks before intimal calcification, aortic plaque formation and lipoprotein profile were evaluated. Cholesterol efflux and the expression of several inflammation, atherosclerosis and cholesterol homeostasis-related genes were also determined in murine liver and bone marrow-derived macrophages. Furthermore, we examined plasma lipoproteins, vascular calcification, carotid intima-media thickness and atherosclerosis in a cohort of PXE patients with ABCC6 mutations and compared results to dysmetabolic subjects with increased cardiovascular risk. We found that ABCC6 deficiency causes changes in lipoproteins, with decreased HDL cholesterol in both mice and humans, and induces atherosclerosis. However, we found that the absence of ABCC6 does not influence overall vascular mineralization induced with atherosclerosis. Decreased cholesterol efflux from macrophage cells and other molecular changes such as increased pro-inflammation seen in both humans and mice are likely contributors for the phenotype. However, it is likely that other cellular and/or molecular mechanisms are involved. Our study showed a novel physiological role for ABCC6, influencing plasma lipoproteins and atherosclerosis in a haploinsufficient manner, with significant penetrance.

Purpose Generalized Arterial Calcification of Infancy (GACI), characterized by vascular calcifications that are often fatal shortly after birth, is usually caused by deficiency of ENPP1. A small fraction of GACI cases result from deficiency of ABCC6, a membrane transporter. The natural history of GACI survivors has not been established in a prospective fashion. Methods We performed deep phenotyping of 20 GACI survivors. Results Sixteen of twenty subjects presented with arterial calcifications, but only 5 had residual involvement at the time of evaluation. Individuals with ENPP1 deficiency either had hypophosphatemic rickets or were predicted to develop it by 14 years of age; 14/16 had elevated intact FGF23 levels (iFGF23). Blood phosphate levels correlated inversely with iFGF23. For ENPP1-deficient individuals, the lifetime risk of cervical spine fusion was 25%, that of hearing loss was 75%, and the main morbidity in adults was related to enthesis calcification. Four ENPP1-deficient individuals manifested classic skin or retinal findings of PXE. We estimated the minimal incidence of ENPP1 deficiency at ~1 in 200,000 pregnancies. Conclusions GACI appears to be more common than previously thought, with an expanding spectrum of overlapping phenotypes. The relationships among decreased ENPP1, increased iFGF23, and rickets could inform future therapies.

Aim: The physiological ageing process causes significant changes in the extracellular matrix (ECM) of the neck skin, which are the first signs of ageing witness for women. We are inspired by a young woman, who suffers from a rare genetic disorder called pseudoxanthoma elasticum (PXE), which manifests irregular, thickened, fragmented and haphazardly orientated elastic fibers. We herein present a combination of three different therapies (laser skin resurfacing, type I horse collagen boosters and platelet rich plasma)as an approach to ameliorate neck skin sagging. Methods: A 28-year-old Roma woman with a clinically diagnosed PXE, verified by ophthalmologic evidence and skin biopsy, underwent 3 sessions of this combined protocol every 3 weeks. One month after the last treatment session, a new biopsy was taken. During this period, the patient was encouraged for daily topical application of collagen mousse and vitamin C combined with sun block SPF50, along with limited exposure to sunlight. Results: Clinical assessment supported by photographic documentation was performed at each session. Severe changes in hydration and tightening of the neck skin were obvious 3 weeks after the second session, although the verification of the results was substantiated with the pathology of the post treatment skin biopsy obtained 1 month following the completion of the protocol. The elastic fibers in the mid-dermis were dense, non-fragmented and parallel oriented. The aesthetic performance was evident until the final follow-up visit. Conclusions: Nowadays, the primary goal of aesthetic medical research is oriented to the dermis bio-reconstruction, where specific treatments try to improve the dermis quality from the inside to repair imperfections of skin ageing. The key of success is attributed to the best possible treatment combination capable of fibroblast stimulation.

Purpose To investigate whether the extent of Bruch’s membrane (BM) calcification is associated with choroidal neovascularization (CNV) and macular atrophy in patients with pseudoxanthoma elasticum (PXE) by using the extent of angioid streaks as a surrogate marker for the degree of BM calcification. Design; Retrospective cross-sectional study. Methods We investigated 301 PXE patients (median age 52 years, range 9–79) in a tertiary referral center. For both eyes, we graded the extent of angioid streaks, i.e. their distance from the optic disk, into five groups. Imaging was systematically assessed for signs of CNV and macular atrophy. Associations between extent of angioid streaks and CNV or macular atrophy were investigated using regression analysis. Results CNV was present in 148 patients (49%) and retinal atrophy in 71 patients (24%). The extent of angioid streaks was associated with older age (P for trend = 1.92×10-15) and a higher prevalence of CNV and/or macular atrophy (P for trend = 4.22×10-10 and P for trend = 5.17×10-6, respectively). In addition, the extent of angioid streaks was associated with the presence of CNV when adjusted for age and sex (odds ratio (OR) 1.9, 95% CI 1.3 - 2.9) and with more severe macular atrophy (proportional OR 2.3, 95% CI 1.5 - 3.6). Conclusions In PXE patients, longer angioid streaks are associated with an increased risk of CNV and macular atrophy, even after adjustment for age. These findings are relevant when counseling PXE patients on their visual prognosis.

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterised by elastic tissue alterations and caused by mutations in a single gene, ABCC6, on chromosome 16p that includes manifestations that are predominantly cutaneous, ocular and cardiovascular. PXE-like lesions in association with β-thalassemia have previously been reported in the literature in patients with β-thalassaemia intermediate and major, being clinically indistinguishable from classic PXE. The case is presented of a 10-year-old boy with β-thalassaemia minor and characteristic lesions of PXE. It is worth noting the benefit of multimodal imaging in the diagnosis and monitoring of the lesions.

Background: Pseudoxanthoma elasticum (PXE) is a rare, hereditary connective tissue disorder characterized by ectopic calcification of multiple organ systems. Cardiovascular complications secondary to accelerated atherosclerosis are well-documented in published literature; however, there is a paucity of studies that reviews serious neurovascular complications including CVA(cerebral vascular accident), TIA(Transient ischemic attack), and intracranial aneurysm development in PXE patients. Objective: We aim to review current literature reporting cases of serious ischemic and hemorrhagic neurovascular complications in PXE patients as of September 2020 and reexamine current guidelines on anticoagulation and antiplatelet therapy in PXE patients Methods: A search of the PubMed database limited to English language case reports using the key words “pseudoxanthoma elasticum”, “neuro*”, “cerebr*”, “CVA”, “TIA”, and “aneurysm” was performed. Results: A total of 67 cases of cerebral disease were reported; ranging from ages 2-71 years from 12 countries. The most common neurovascular complication seen was ischemic strokes (68.7%) followed by TIAs (20.8%), intracranial aneurysms (6.0%) and lastly hemorrhagic strokes (4.5%). Conclusions: PXE patients have a greater incidence of ischemic strokes compared to the general population. Clinicians should thus carefully weigh the benefits of anticoagulation therapy in patients with known cardiovascular disease against the risk of bleeding.

To characterize morphological changes in the retina and to report the frequency and natural history of non-exudative macular neovascularization (MNV) in a cohort of pseudoxanthoma elasticum (PXE). A single-center, retrospective study was complemented by a cross-sectional examination. Consecutive patients with a definitive genetic and/or clinical diagnosis of PXE, visiting our department between January 2019 and December 2019, and with a minimum follow-up of 6 months were recruited. Baseline data were retrieved from each patient file. Additionally, a cross-sectional examination comprising color fundus photography, spectral-domain optical coherence tomography (SD-OCT), OCT-Angiography (OCT-A), and fundus autofluorescence was performed. The presence of typical PXE-related findings, as well as related complications, was multimodally evaluated. The prevalence and natural history of non-exudative MNV were assessed. All images were graded by two independent graders. Forty-eight eyes from 24 patients (mean age 59.11 ± 18.14) with a median follow-up of 53.00 months were included. Angioid streaks and peau d’orange were observed in 46/48 and 42/48 eyes, while MNV was present in 75.00% of the cohort. The prevalence of non-exudative MNV was 33.33% (6/18). In the 2 eyes that developed exudation, time to conversion was 9.50 ± 4.95 months. No significant difference in visual acuity was found between eyes with non-exudative MNV and those with no signs of MNV. We have shown that non-exudative MNV is a frequent finding in PXE but the majority of eyes did not develop exudation during follow-up. Our results are a clear evidence of the utility of OCT-A in the management of PXE.

Purpose To develop a method of averaging optical coherence tomography (OCT) angiography to improve visualization of choriocapillaris structure. Methods A stack of OCT angiographic data from vascular layers were placed into the red-green-blue channels of a conventional digital color image. The superficial plexus was placed in the blue channel, choriocapillaris in the green, and deep vascular plexus in the red channel. The red-green-blue images derived from nine separate OCT angiographic scans were registered using an automatic registration sequence and the images were averaged. The averaged red-green-blue image was then split into the three averaged component layers. The technique is flexible and any vascular layer, such as macular neovascularization, can be used as well. Results The utility of the imaging method was demonstrated by showing the imaging of two different diseases. A patient with a history of familial amyloidosis, hypertension, kidney failure, kidney transplantation, and prednisone use, followed by central serous chorioretinopathy treated by photodynamic therapy. She had alterations in retinal pigment epithelial pigmentation and widespread abnormalities of autofluorescence. She showed remarkably decreased vascular density and vessel configuration of her choriocapillaris. A patient with pseudoxanthoma elasticum with subretinal drusenoid deposits at an early age also showed marked decreased choriocapillaris density and vascular configuration. These findings were compared with healthy controls of similar age with no abnormalities. Conclusion The detailed method is capable of averaging choriocapillaris OCT angiographic images using a simple automatic method. Image averaging offers opportunity to improve the noisy OCT angiographic images such that actual vascular structure is visible.

Pseudoxanthoma elasticum is a rare cause for ischaemic stroke. Little is known about acute and secondary prevention strategies in these subjects given the increased risk of gastrointestinal and urinary bleedings. Here we present the case of a 62 years old man affected by pseudoxanthoma elasticum who presented with acute ischaemic stroke and was successfully treated with intravenous thrombolysis. Neurological signs improved after intravenous thrombolysis without bleeding complication. To our knowledge, this is the first case of pseudoxanthoma elasticum—related stroke undergoing intravenous thrombolysis.

To evaluate the retinal features of elderly patients affected by pseudoxanthoma elasticum (PXE). This is a retrospective case series of 62 eyes of 31 elderly PXE patients (age > 50 years). Clinical data, ultra-widefield fundus imaging (color, red-free (RF), infra-red imaging (IR), fundus autofluorescence (FAF)), and OCT examinations were collected. Diagnosis was confirmed by genetic testing or skin biopsy. Thirty-one patients (10 males and 21 females (mean age 61.3 years, range 50–74 years)) were included in our study. Visual acuity ranged from 20/20 Snellen equivalent to 20/200. The mean follow-up was 66.4 ± 20.7 months (range 10–88). Pattern dystrophy-like changes (PD) (52 eyes of 26 patients, 83.8%) and atrophy resembling the “diffuse trickling” pattern described in geographic atrophy were present in the majority of patients. Twenty-three eyes of 12 patients (67.6%) had peripapillary atrophy, 9 eyes of 5 patients (26.4%) macular atrophy, 6 eyes of 3 patients (17.6%) displayed posterior pole atrophy and in 6 eyes of 3 patients (17.6%), atrophy could be detected beyond the vascular arcades (mid-peripheral atrophy). End-stage atrophy covered the entire area indicated as “coquille d’oeuf” (eggshell). Choroidal neovascularization occurred in 49 eyes of 26 patients (94.2%) with PD and in 6 eyes of 3 patients (60%) without PD. Genetic examinations were available for 29 patients (29/31, 93.5%). The elderly PXE patients were characterized by pattern dystrophy-like changes with more or less extensive atrophy, progressive over time, which in some cases affected the whole area of the coquille d’oeuf during the course of the disease.

Objective:. Pseudoxanthoma elasticum (PXE) is a multisystem heritable disorder caused by mutations in the Abcc6 gene. The disease is characterized by ectopic mineralization of the skin, eyes, and arterial blood vessels. Previous studies have suggested that cardiovascular complications in patients with PXE are caused in part by premature atherosclerosis. The aim of this study is to determine the effect of an atherogenic diet on ectopic mineralization. Methods:. We used Abcc6 tm1JfK mice (Abcc6 −/− mice) as an established preclinical model of PXE. The offspring at age of 4 weeks were divided into two groups and fed the standard control laboratory diet (control group) and the atherogenic diet. Serum lipid profiles and bile acids were measured, and steatosis and tissue mineralization were evaluated by histopathologic analysis and chemical calcium quantification assay, respectively. Results:. After 50–58 weeks of feeding an atherogenic diet, the concentrations of total cholesterol, low-density lipoprotein/very-low-density lipoprotein cholesterol, and bile acids were significantly higher in the Abcc6 −/− mice on the atherogenic diet (180.9 ± 14.8 g/L, 145.9 ± 12.9 g/L, and 9.7 ± 1.4 μmol/L, respectively) than in Abcc6 −/− mice on a control diet (85.2 ± 4.8 g/L, 25.1 ± 5.5 g/L, and 3.3 ± 0.5 μmol/L, respectively) (P

Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder with ectopic mineralization and fragmentation of elastin fibers. It is caused by mutations of the ABCC6 gene that leads to decreased serum levels of inorganic pyrophosphate (PPi) anti-mineralization factor. The occurrence of severe complications among PXE patients highlights the importance of early diagnosis so that prompt multidisciplinary care can be provided to patients. We aimed to examine dermal connective tissue with nonlinear optical (NLO) techniques, as collagen emits second-harmonic generation (SHG) signal, while elastin can be excited by two-photon excitation fluorescence (TPF). We performed molecular genetic analysis, ophthalmological and cardiovascular assessment, plasma PPi measurement, conventional histopathological examination, and ex vivo SHG and TPF imaging in five patients with PXE and five age- and gender-matched healthy controls. Pathological mutations including one new variant were found in the ABCC6 gene in all PXE patients and their plasma PPi level was significantly lower compared with controls. Degradation and mineralization of elastin fibers and extensive calcium deposition in the mid-dermis was visualized and quantified together with the alterations of the collagen structure in PXE. Our data suggests that NLO provides high-resolution imaging of the specific histopathological features of PXE-affected skin. In vivo NLO may be a promising tool in the assessment of PXE, promoting early diagnosis and follow-up.

PURPOSE OF REVIEW: This review summarizes current understanding of General Arterial Calcification of Infancy (GACI), emphasizing pathophysiology, clinical presentation, and approaches and controversies in management. RECENT FINDINGS: Identification of causative ENPP1 mutations revealed that GACI arises from deficiencies in inorganic pyrophosphate (leading to calcifications) and adenosine monophosphate (leading to intimal proliferation). Identification of genotypic and phenotypic overlap with pseudoxanthoma elasticum and autosomal recessive hypophosphatemic rickets further advanced understanding of GACI as a complex, multisystemic disease. Clinical data is limited to small, retrospective samples; it is therefore unknown whether commonly-used medications, such as bisphosphonates and hypophosphatemia treatment, are therapeutic or potentially harmful. ENPP1-Fc replacement represents a promising approach warranting further study. SUMMARY: Knowledge gaps in natural history place clinicians at high-risk of assigning causality to interventions that are correlated with changes in clinical status. There is thus a critical need for improved natural history studies to develop and test targeted therapies.

The purpose of this series is to highlight a range of rare health conditions. Rare health conditions are those that affect no more and usually fewer than 1 person in every 2000 and many healthcare assistants (HCAs) and nurses will encounter some of these conditions, given the high number of them. This 32nd article will explore four of these conditions: psychogenic nonepileptic seizures (PNES); pseudocyesis (false pregnancy); trisomy 13 syndrome; and pseudoxanthoma elasticum (PXE).

Background and aims: In pseudoxanthoma elasticum (PXE), low levels of inorganic pyrophosphate result in extensive arterial calcification. Recently, the treatment of ectopic mineralization in the PXE (TEMP) trial showed that one year of treatment with etidronate halts progression of femoral artery calcification in PXE patients. The aim of this study was to test the efficacy of etidronate on calcification in different vascular beds. Methods: In this prespecified post-hoc analysis of the TEMP trial, arterial calcification mass was quantified in the carotid siphon, common carotid artery, thoracic and abdominal aorta, coronary arteries, iliac arteries, and the femoropopliteal and crural arteries using CT at baseline and after one year of etidronate treatment or placebo. In addition, a total arterial calcification score was calculated. The difference in calcification progression was compared between the etidronate and placebo group. Results: 74 PXE patients were enrolled and randomized. Etidronate significantly halted progression of calcification in all vascular beds except for the coronary arteries. For the total arterial calcification score, the median absolute increase in mass score was −63.6 (−438.4–42.2) vs. 113.7 (9.4–377.1) (p < 0.01) and the median relative increase was −2.4% (−10.3–3.8) vs. 6.3% (0.2–15.8) (p < 0.01) in the etidronate and placebo arm, respectively. Conclusions: Etidronate treatment halts systemic arterial calcification in PXE. Further research must assess the long term safety and efficacy of etidronate on clinical outcomes in PXE.

Perforating dermatoses are characterized by transepidermal elimination of altered dermal components or foreign particles. Owing to their common clinical presentation as umbilicated papules with a keratotic plug, histopathology and special staining play a very crucial role in the diagnosis. Perforating calcific elastosis, (periumbilical perforating pseudoxanthoma elasticum), an uncommon acquired localized cutaneous dermatoses, is characterized by transepidermal elimination of modified elastic fibres. It is usually seen in middle-aged obese multiparous women as well-defined periumbilical hyperpigmented atrophic plaques. We report a case of a 66-year-old female who presented with a mildly pruritic hyperpigmented periumbilical plaque of 2 years duration. Histopathology studies revealed multiple fragmented, thick, short, and curly eosinophilic fibers; along with granular basophilic material in the dermis, which stained positive for calcium and elastin, thus clinching the diagnosis of perforating calcific elastosis. There were no features of hereditary pseudoxanthoma elasticum. We report this case for its rarity.

Pseudoxanthoma elasticum (PXE) is a rare hereditary disorder occurring due to metabolic defect in the liver and manifesting predominantly in the skin, eyes and arteries. It shows characteristic yellowish papules on the skin around the nape of neck along with looseness of skin over flexural surfaces. PXE shows marked phenotypic heterogeneity. Complications related to arterial wall and retinal Bruchs’ membrane calcification occur later in life; early diagnosis therefore helps keep patient on follow up for development of the same. In Indian patients, classic skin changes may be missed clinically making histopathology pivotal in diagnosis and patient management.

Pseudoxanthoma elasticum (PXE) is a hereditary ectopic calcification disorder affecting the skin, eyes, and blood vessels. Recently, the DNA damage response (DDR), in particular PARP1, was shown to be involved in aberrant mineralization, raising the hypothesis that excessive DDR/PARP1 signaling also contributes to PXE pathogenesis. Using dermal fibroblasts of patients with PXE and healthy controls, (lesional) skin tissue, and abcc6a‒/‒ zebrafish, we performed expression analysis of DDR/PARP1 targets with QRT-PCR, western blot, immunohistochemistry, and enzyme activity assays before and after treatment with the PARP1 inhibitor minocycline. PARP1 and the ATM‒p21‒p53 axis was found to be significantly increased in PXE. In addition, PARP1 downstream targets IL-6, signal transducer and activator of transcription 1/3, TET1, and RUNX2 were upregulated, whereas the RUNX2 antagonist microRNA-204 was decreased. In PXE fibroblasts, DDR/PARP1 signaling increased with advancing ectopic calcification. Minocycline treatment attenuated DDR/PARP1 overexpression and reduced aberrant mineralization in PXE fibroblasts and abcc6a‒/‒ zebrafish. In summary, we showed the involvement of excessive DDR/PARP1 signaling in PXE pathophysiology, identifying a signal transducer and activator of transcription‒driven cascade resulting in increased expression of the epigenetic modifier TET1 and procalcifying transcription factor RUNX2. Minocycline attenuated this deleterious molecular mechanism and reduced ectopic calcification both in vitro and in vivo, fueling the exciting prospect of a therapeutic compound for PXE.

PURPOSE To characterize dark adaptation in patients with pseudoxanthoma elasticum, a systemic disease leading to calcification of elastic tissue including the Bruch membrane. METHODS In this prospective case-control study, dark adaptation thresholds were measured using a Goldmann-Weekers dark adaptometer. Additional assessments included best-corrected visual acuity testing, contrast sensitivity, low luminance deficit, and vision-related quality of life. RESULTS Dark adaptation thresholds were significantly higher, and adaptation periods were prolonged in patients with pseudoxanthoma elasticum (n = 35; 33 with 2 ABCC6 mutations) compared with controls (n = 35). The time to adapt 4 log units (20.6 ± 8.6 vs. 8.0 ± 1.3 minutes) and the mean dark adaptation threshold after 15 minutes (3.5 ± 1.1 vs. 1.8 ± 0.2 log units) were significantly different between patients and controls (both P < 0.001). Low luminance deficits (12.3 ± 6.4 vs. 6.1 ± 4.3 ETDRS letters), contrast sensitivity (1.4 ± 0.3 vs. 1.9 ± 0.1), and low luminance-related quality of life (LLQ score: 1,286 ± 355 vs. 2,167 ± 68) were also significantly worse in patients with pseudoxanthoma elasticum (all, P < 0.001). Two patients were treated with high-dose vitamin A which partially reversed impaired dark adaptation. CONCLUSION Patients with pseudoxanthoma elasticum often have impaired dark adaptation. Positive effects of vitamin A supplementation may indicate restricted retinal access of vitamin A through the Bruch membrane as one possible underlying pathogenic factor.

Chronic low back pain is a highly prevalent health condition intricately linked to intervertebral disc degeneration. One of the prominent features of disc degeneration that is commonly observed with aging is dystrophic calcification. ATP-binding cassette sub-family C member 6 (ABCC6), a presumed ATP efflux transporter, is a key regulator of systemic levels of the mineralization inhibitor pyrophosphate (PPi). Mutations in ABCC6 result in pseudoxanthoma elasticum (PXE), a progressive human metabolic disorder characterized by mineralization of the skin and elastic tissues. The implications of ABCC6 loss-of-function on pathological mineralization of structures in the spine, however, are unknown. Using the ABCC6-/- mouse model of PXE, we investigated age-dependent changes in the vertebral bone and intervertebral disc. ABCC6-/- mice exhibited diminished trabecular bone quality parameters at 7-months which remained significantly lower than the wild-type mice at 18 months-of-age. ABCC6-/- vertebrae showed increased TRAP staining along with decreased TNAP staining, suggesting an enhanced bone resorption as well as decreased bone formation. Surprisingly, however, loss of ABCC6 resulted only in a mild, aging disc phenotype without evidence of dystrophic mineralization. Finally, we tested the utility of oral K3Citrate to treat the vertebral phenotype since it is shown to regulate hydroxyapatite mechanical behavior. The treatment resulted in inhibition of osteoclastic response and an early improvement in mechanical properties of the bone underscoring the promise of potassium citrate as a therapeutic agent. Our data suggest that although ectopic mineralization is tightly regulated in the disc, loss of ABCC6 compromises vertebral bone quality and dysregulates osteoblast-osteoclast coupling.Author SummaryInherited mutations in the ABCC6 transporter gene results in mineralization, often in the form of hydroxyapatite, of connective tissues throughout the body, predominantly affecting the skin, eyes, and blood vessels. Functional loss of ABCC6 causes reduced levels of the potent mineralization inhibitor pyrophosphate (PPi) in blood resulting in these pathologies. Pathological mineralization is also a prominent feature of intervertebral disc degeneration, but the role of ABCC6 and systemic PPi levels and its correlation to disc mineralization and vertebral bone health has remained unexplored. In this study, we show for the first time that loss of ABCC6 in mice results in significant decline in vertebral bone quality and mild age-related disc degeneration without increased incidence of abnormal mineralization. Importantly, treatment of ABCC6 deficient mice with K3Citrate resulted in restoration of early cellular changes which drive bone loss and mechanical function of the vertebrae. In summary, our data reveal that ABCC6 is dispensable for mineralization prevention in the intervertebral disc. Unexpectedly, we found that vertebral bone quality and bone cell activities are linked to ABCC6 function.

Pseudoxanthoma elasticum (PXE) is a rare, autosomal recessive connective tissue disease that manifests primarily in the skin, eyes, vasculature, and gastrointestinal tract. Most cases occur in women and are present in the third decade of life. Diagnosis is confirmed via skin biopsy or by genetic testing that reveals a variant ABCC6 gene. We present the case of a 68-year-old woman who came to the clinic to discuss her daughter’s diagnosis of PXE, specifically, what testing she and her family should pursue. A family pedigree revealed a strong family history of abdominal aortic aneurysm (AAA). Although PXE has not been directly related to AAA, this raised concern for familial connective tissue disease. It was recommended that all family members undergo AAA screening with ultrasound, but that not all family members warranted genetic testing. Patients diagnosed with PXE should establish care with specialists to monitor for adverse outcomes.

A 34-year-old female presented to us with complaints of decreased vision in her left eye for 1 month. Best-corrected visual acuity was 20/20 in the right eye and 20/60 in the left eye. Anterior segment examination was normal in both the eyes. Fundus examination showed angioid streaks and comet tail lesions in both eyes. The left eye in addition showed a choroidal neovascular membrane (CNVM) at the macula. Systemic examination revealed skin lesions on the neck with a plucked chicken appearance and multiple papules. Biopsy from the lesions provided histopathological confirmation of pseudoxanthoma elasticum (PXE). CNVM in the left eye was treated successfully with a single dose of intravitreal bevacizumab injection with no further recurrence. No cardiovascular association was found in our case. This case report describes the pathognomonic fundus lesions seen in PXE. This case also emphasizes the need for thorough systemic evaluation, including biopsy from skin lesions for histopathological confirmation of the diagnosis in all cases with ocular features of PXE.

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.

Cells : open access journal 10(8), 2097 (2021). doi:10.3390/cells10082097 special issue: "Special Issue "Research on Vascular Calcification in Cardiovascular Disease" / Special Issue Editors: Prof. Dr. Leon Schurgers, Guest Editor; Dr. Peter Stenvinkel, Guest Editor", Published by MDPI, Basel

Pseudoxanthoma elasticum, or Gronblad-Strandberg syndrome, is an inherited disorder that involves multiple organ systems. The characteristic degeneration and calcification of the elastic fibers caused by this disease were first observed by Ferdinand Jean Darrier in 1896. We report a case of a 27-year-old female who was diagnosed with pseudoxanthoma elasticum based on a skin biopsy prior to her presentation to our ophthalmology outpatient clinic. The past ocular history of the patient was unremarkable for any previous eye complaint or surgery. Her ocular and fundus examination showed pigmented grayish irregular post choroidal crack-like linear dehiscence, forming a network-like pattern, originating at the optic disc and extending radially involving the macular area and the posterior pole in both eyes, representing bilateral angioid streaks. There were no clinical or optical coherent tomographic signs of choroidal neovascularization. Periodic follow up for patients with pseudoxanthoma elasticum is recommended to detect choroidal neovascularization which is a sight-threatening complication. Ophthalmologists should be aware of this association as early recognition and treatment are vital to prevent irreversible visual loss.

Introduction: Pseudoxanthoma elasticum (PXE), an ectopic mineralization disorder caused by pathogenic ABCC6 variants, is characterized by skin, ocular and cardiovascular (CV) symptoms. Due to striking phenotypic variability without genotype-phenotype correlations, modifier genes are thought to play a role in disease variability. In this study, we evaluated the collective modifying effect of rare variants on the cardiovascular phenotype of PXE.Materials and Methods: Mixed effects of rare variants were assessed by Whole Exome Sequencing in 11 PXE patients with an extreme CV phenotype (mild/severe). Statistical analysis (SKAT-O and C-alpha testing) was performed to identify new modifier genes for the CV PXE phenotype and enrichment analysis for genes significantly associated with the severe cohort was used to evaluate pathway and gene ontology features.Results Respectively 16 (SKAT-O) and 74 (C-alpha) genes were significantly associated to the severe cohort. Top significant genes could be stratified in 3 groups–calcium homeostasis, association with vascular disease and induction of apoptosis. Comparative analysis of both analyses led to prioritization of four genes (NLRP1, SELE, TRPV1, and CSF1R), all signaling through IL-1B.Conclusion This study explored for the first time the cumulative effect of rare variants on the severity of cardiovascular disease in PXE, leading to a panel of novel candidate modifier genes and disease pathways. Though further validation is essential, this panel may aid in risk stratification and genetic counseling of PXE patients and will help to gain new insights in the PXE pathophysiology.

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.

We describe a 14-year-old boy with Wilson disease (WD) who first developed pseudo-pseudoxanthoma elasticum (PPXE) after 4.5 years of treatment with D-penicillamine. Although previously reported cases have occurred in adults following at least a decade of high-dose D-penicillamine use, this case demonstrates that D-penicillamine-induced PPXE can present in children with shorter treatment courses. Upon this diagnosis, the patient was switched from D-penicillamine to trientine, with adequate cupriuresis and stabilization of the skin lesion. Prompt diagnosis and management of PPXE in children can limit systemic progression and prevent long-term complications.

Pseudoxanthoma elasticum-like papillary dermal elastolysis is an acquired elastic tissue disorder clinically similar to pseudoxanthoma elasticum in the absence of systemic involvement. Histopathologically, special staining of elastic fibers demonstrates a total or partial band-like loss of elastic fibers in the papillary dermis. Although ultraviolet radiation seems to be one of the main etiological factors in this entity, we report a case of pseudoxanthoma elasticum-like papillary dermal elastolysis on the neck of a woman who wore hijab.