Linking ABCC6 Deficiency in Primary Human Dermal Fibroblasts of PXE Patients to p21-Mediated Premature Cellular Senescence and the Development of a Proinflammatory Secretory Phenotype.

Pseudoxanthoma elasticum (PXE) is a rare autosomal-recessive disorder that is mainly caused by mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene. Clinically PXE is characterized by a loss of skin elasticity, arteriosclerosis or visual impairments. It also shares some molecular characteristics with known premature aging syndromes like the Hutchinson-Gilford progeria syndrome (HGPS). However, little is known about accelerated aging processes, especially on a cellular level for PXE now. Therefore, this study was performed to reveal a potential connection between premature cellular aging and PXE pathogenesis by analyzing cellular senescence, a corresponding secretory phenotype and relevant factors of the cell cycle control in primary human dermal fibroblasts of PXE patients. Here, we could show an increased senescence-associated ß-galactosidase (SA-ß-Gal) activity as well as an increased expression of proinflammatory factors of a senescence-associated secretory phenotype (SASP) like interleukin 6 (IL6) and monocyte chemoattractant protein-1 (MCP1). We further observed an increased gene expression of the cyclin-dependent kinase inhibitor (CDKI) p21, but no simultaneous induction of p53 gene expression. These data indicate that PXE is associated with premature cellular senescence, which is possibly triggered by a p53-independent p21-mediated mechanism leading to a proinflammatory secretory phenotype.

[Pseudoxanthoma elasticum revealed by choroidal neovascularization]. / Pseudoxanthome élastique révélé par un néovaisseau choroïdien.

Pseudoxanthoma elasticum is a genetic disease caracterised by calcification and fragmentation of elastic fibers affecting primarily the skin, the eyes and the cardiovascular system. We report a case in which the diagnostic was delayed due to an atypical presentation, allowing us to discuss the clinical signs, especially ocular, as well as the diagnosis criteria of this rare pathology. There is no specific treatment to pseudoxanthoma elasticum. It is essential to diagnose it rapidly in order to avoid potentially dramatic systemic outcomes.

Le pseudoxanthome élastique est une maladie héréditaire caractérisée par la calcification des fibres élastiques du tissu conjonctif touchant particulièrement la peau, les yeux et le système cardiovasculaire. Nous rapportons un cas clinique diagnostiqué plus tardivement suite à sa présentation atypique, ce qui nous permet d'aborder les signes cliniques, particulièrement oculaires, et la prise en charge diagnostique de cette pathologie rare. En effet, il n'existe pas de traitement spécifique du pseudoxanthome élastique. Il est donc essentiel de poser rapidement un diagnostic afin d'éviter la survenue d'atteintes systémiques potentiellement sévères.

[Angioid streaks in systemic disease]. / Szemfenéki angioid csíkok szisztémás betegségekben.

Angioid streaks are defined as the special morphological alteration of the fundus; the most common clinical manifestations are irregular, reddish brownish stripes around the optic nerve head or on the posterior pole. On the basis of histological examination, the cause of this phenomenon is the breaks and continuity deficiencies in the thin layer of Bruch membrane caused by the degeneration of elastic fibers. The aim of this study is to present the ocular complication of this rare entity through the description of three cases, and to draw attention to systemic diseases in the background. In our first and third cases, pseudoxanthoma elasticum (Grönblad-Strandberg syndrome) was in the background, while in our second case, hematological disease was confirmed. In our first and second cases, the ocular complication was the choroidal neovascularization, which we treated with intravitreal anti-VEGF injection. In our third case, the choroidal rupture was the ocular complication, caused by trauma. Angioid streaks on the fundus may be sub-phenomena of systemic diseases, the detection, differential diagnosis and treatment require interdisciplinary collaboration between associate physicians. Orv Hetil. 2019; 160(25): 994-1000.

Alteration of Extracellular Nucleotide Metabolism in Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE) is a rare genetic condition primarily caused by hepatic ABCC6 transporter dysfunction. Most clinical manifestations of PXE are due to premature calcification of elastic fibers. However, the vascular impact of PXE is pleiotropic and remains ill defined. ABCC6 expression has recently been associated with cellular nucleotide export. We studied the impact of ABCC6 deficiency on blood levels of adenosine triphosphate and related metabolites and on soluble nucleotidase activities in PXE patients and Abcc6-/- mice. In addition, we investigated the expression of genes encoding ectocellular purinergic signaling proteins in mouse liver and aorta. Plasma adenosine triphosphate and pyrophosphate levels were significantly reduced in PXE patients and in Abcc6-/- mice, whereas adenosine concentration was not modified. Moreover, 5'-nucleotidase/CD73 activity was increased in the serum of PXE patients and Abcc6-/- mice. Consistent with alterations of purinergic signaling, the expression of genes involved in purine and phosphate transport/metabolism was dramatically modified in Abcc6-/- mouse aorta, with much less impact on the liver. ABCC6 deficiency causes impaired vascular homeostasis and tissue perfusion. Our findings suggest that these alterations are linked to changes in extracellular nucleotide metabolism that are remote from the liver. This opens new perspectives for the understanding of PXE pathophysiology.

Rheumatological complications of beta-thalassaemia: an overview.

Beta-thalassaemia, an autosomal recessive haemoglobinopathy, ranks among the most frequent monogenetic diseases globally. The severe form of the disease, beta-thalassaemia major, is accompanied by progressive involvement of multiple organ systems as a result of the disease pathophysiology as well as iron overload from blood transfusions on a regular basis. Some of the manifestations might also be caused by medications used to manage iron overload. The purpose of this review is to highlight the rheumatological complications of beta-thalassaemia, which include musculoskeletal manifestations, such as arthritis and arthropathies, joint effusions, osteoporosis, bone fractures and myalgias, in addition to CTDs, such as pseudoxanthoma elasticum. Rheumatologists are strongly encouraged to take part in a multidisciplinary approach to the management of this debilitating disease.

Pseudoxanthoma Elasticum-Like in ß-Thalassemia Major, a matter of α-Klotho and Parathyroid Hormone?

Pseudoxanthoma elasticum-like (PXL) condition is one of the complications faced by patients with ß-thalassemia major (ß-TM). Histopathological features include abnormal, mineralized and fragmented elastic fibers in skin, eyes and arterial blood vessels (elastorrhexia). The pathogenesis of PXL lesions in ß-TM is not yet completely understood. This study was aimed at analyzing a possible implication of α-Klotho in the clinical manifestation of PXL in patients with ß-TM (30 with and 78 without PXL). A significant correlation was observed between Klotho, parathyroid hormone (PTH) and serum calcium (Ca). Our analysis seems to indicate α-Klotho and PTH as factors that can affect the development of PXL.

The ABCC6 Transporter: A New Player in Biomineralization.

Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of the pivotal role of ectopic mineralization that is preponderant in the elastin-rich tissues of the skin, eyes and blood vessel walls. After discovery of the causative gene of the disease in 2000, the function of the ABCC6 protein remains elusive. More than 300 mutations have been now reported and the concept of a dermal disease has progressively evolved toward a metabolic disorder resulting from the remote effects caused by lack of a circulating anti-mineralization factor. Very recently, evidence has accumulated that this anti-mineralizing factor is inorganic pyrophosphate (PPi). This leads to decreased PPi/Pi (inorganic phosphate) ratio that results from the lack of extracellular ATP release by hepatocytes and probably renal cells harboring the mutant ABCC6 protein. However, the mechanism by which ABCC6 dysfunction causes diminished ATP release remains an enigma. Studies of other ABC transporters, such as ABCC7 or ABCC1 could help our understanding of what ABCC6 exact function is. Data and a hypothesis on the possible roles of ABCC6 in acquired metabolic diseases are also discussed.

Pseudoxanthoma elasticum associated with vitelliform macular lesion.

The authors describe an uncommon association between pseudoxanthoma elasticum with typical fundus lesions and positive testing for mutation in the ABCC6 gene and the concomitant presence of a large subfoveal vitelliform lesion.

Ectopic calcification in ß-thalassemia patients is associated with increased oxidative stress and lower MGP carboxylation.

A number of beta-thalassemia (ß-thal) patients in the course of the disease exhibit ectopic calcification affecting skin, eyes and the cardiovascular system. Clinical and histopathological features have been described similar to those in pseudoxanthoma elasticum (PXE), although different genes are affected in the two diseases. Cultured dermal fibroblasts from ß-thal patients with and without PXE-like clinical manifestations have been compared for parameters of redox balance and for the expression of proteins, which have been already associated with the pathologic mineralisation of soft connective tissues. Even though oxidative stress is a well-known condition of ß-thal patients, our results indicate that the occurrence of mineralized elastin is associated with a more pronounced redox disequilibrium, as demonstrated by the intracellular increase of anion superoxide and of oxidized proteins and lipids. Moreover, fibroblasts from ß-thal PXE-like patients are characterized by decreased availability of carboxylated matrix Gla protein (MGP), as well as by altered expression of proteins involved in the vitamin K-dependent carboxylation process. Results demonstrate that elastic fibre calcification is promoted when redox balance threshold levels are exceeded and the vitamin K-dependent carboxylation process is affected decreasing the activity of MGP, a well-known inhibitor of ectopic calcification. Furthermore, independently from the primary gene defect, these pathways are similarly involved in fibroblasts from PXE and from ß-thal PXE-like patients as well as in other diseases leading to ectopic calcification, thus suggesting that can be used as markers of pathologic mineralisation.

Nonuremic calciphylaxis associated with histologic changes of pseudoxanthoma elasticum.

Calciphylaxis is a rare condition characterized by medial calcification of small- and medium-sized vessels that subsequently leads to ischemic necrosis. Calciphylaxis most often occurs in patients with end-stage renal disease and secondary hyperparathyroidism. We present a unique case of calciphylaxis in which the patient did not have end-stage renal disease. Instead, primary hyperparathyroidism and/or alcoholic cirrhosis were the more likely causes of her calciphylaxis. In addition, our case demonstrated not only calciphylaxis but also fragmentation and calcification of elastic fibers within the dermis, changes that are most often seen in pseudoxanthoma elasticum. This is the first reported case of calciphylaxis, to our knowledge, with histopathologic changes of pseudoxanthoma elasticum in a patient who is nonuremic.

Acquired pseudoxanthoma elasticum presenting after liver transplantation.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is thought to be a metabolic disorder resulting from mutations in the gene encoding the cellular transporter, ABCC6, which is primarily expressed in liver and kidney. We encountered 3 patients who developed clinical and histopathological evidence of PXE after liver transplantation, suggesting that PXE could have been acquired from the transplanted organ. OBJECTIVE: We sought to delineate the clinical features and screen each patient and samples of donor liver for mutations in the ABCC6 gene. METHODS: Each patient underwent full clinical examination, skin biopsy, and ophthalmologic examination, and whole genome sequencing using standard techniques. Fixed samples of donor liver tissue were available for mutation analysis in two patients and of donor kidney tissue in one. RESULTS: All 3 patients had unequivocal clinical and histopathologic evidence of PXE. No patient (or family member available for screening) had evidence of mutations in ABCC6. Neither liver specimen nor the single available kidney specimen showed evidence of mutations in ABCC6. LIMITATIONS: Liver tissue was not available from one patient and DNA was of poor quality in another, resulting in limited screening. Genetic testing does not detect ABCC6 mutations in 10% of patients with confirmed PXE. CONCLUSION: Although we were unable to demonstrate ABCC6 mutations in limited screening of fixed donor livers, the absence of any PXE mutations in the affected patients, the timing of onset of PXE, and the known acquisition of other metabolic disorders and coagulopathies from donor livers suggest that PXE was likely acquired via liver transplantation.

The natural history of thalassemia intermedia.

The severity of thalassemia intermedia depends on the degree of imbalance between alpha and non-alpha chains as well as other genetic and environmental factors that modify the natural history of the disease. By definition, the patients spontaneously maintain hemoglobin at or above 7 g/dL, sometimes at the price of intense hyperplasia of the bone marrow that is in turn responsible for bone deformities, osteoporosis, and extramedullary erythropoietic masses that often characterize thalassemia intermedia. Transfusion may become necessary with advancing age, during infection and pregnancy, and when hypersplenism develops. Splenectomy is often needed. Iron overload in nontransfused patients is due to increased gastrointestinal absorption and involves mainly the liver. Complications affecting the lives of patients with thalassemia intermedia include pulmonary hypertension, leg ulcers, pseudoxanthoma elasticum, gallstones, hepatocellular carcinoma, and thromboembolic events.

Low serum vitamin K in PXE results in defective carboxylation of mineralization inhibitors similar to the GGCX mutations in the PXE-like syndrome.

Soft-tissue mineralization is a tightly regulated process relying on the activity of systemic and tissue-specific inhibitors and promoters of calcium precipitation. Many of these, such as matrix gla protein (MGP) and osteocalcin (OC), need to undergo carboxylation to become active. This post-translational modification is catalyzed by the gammaglutamyl carboxylase GGCX and requires vitamin K (VK) as an essential co-factor. Recently, we described a novel phenotype characterized by aberrant mineralization of the elastic fibers resulting from mutations in GGCX. Because of the resemblance with pseudoxanthoma elasticum (PXE), a prototype disorder of elastic fiber mineralization, it was coined the PXE-like syndrome. As mutations in GGCX negatively affect protein carboxylation, it is likely that inactive inhibitors of calcification contribute to ectopic mineralization in PXE-like syndrome. Because of the remarkable similarities with PXE, we performed a comparative study of various forms of VK-dependent proteins in serum, plasma (using ELISA), and dermal tissues (using immunohistochemistry) of PXE-like and PXE patients using innovative, conformation-specific antibodies. Furthermore, we measured VK serum concentrations (using HPLC) in PXE-like and PXE samples to evaluate the VK status. In PXE-like patients, we noted an accumulation of uncarboxylated Gla proteins, MGP, and OC in plasma, serum, and in the dermis. Serum levels of VK were normal in these patients. In PXE patients, we found similar, although not identical results for the Gla proteins in the circulation and dermal tissue. However, the VK serum concentration in PXE patients was significantly decreased compared with controls. Our findings allow us to conclude that ectopic mineralization in the PXE-like syndrome and in PXE results from a deficient protein carboxylation of VK-dependent inhibitors of calcification. Although in PXE-like patients this is due to mutations in the GGCX gene, a deficiency of the carboxylation co-factor VK is at the basis of the decreased activity of calcification inhibitors in PXE.

Pseudoxanthoma-elasticum-like syndrome and thalassemia: an update.

Pseudoxanthoma Elasticum (PXE) is an autosomal recessive, multisystem disorder affecting connective tissues. We describe three cases of the acquired PXE-like syndrome that often occurs in association with hemolytic anemias, in particular the hemoglobinopathies, and review the literature on the subject. The pathogenesis of the acquired PXE-like lesions is not yet completely understood. None of the mutations observed in the inherited form has been detected in the syndrome accompanying thalassemia. The cardiovascular complications could be life-threatening. Therefore, an close surveillance of these patients is mandatory.

Pseudoxanthoma elasticum-like lesions in association with thalassaemia major.

A 33-year-old woman with a background of thalassaemia major presented with a 3-month history of yellowish plaques on the back of her neck bilaterally and alterations in the texture of the skin in both axillae. Examination of these lesions showed yellowish cobblestone plaques and coalescing papules in both axillae. Pseudoxanthoma elasticum (PXE)-like lesions were confirmed histopathologically. PXE-like lesions in association with thalassaemia major are an uncommon occurrence. Due to the increase in the survival rate of thalassaemia major patients on treatment, the development of these lesions is likely to increase. The histopathological manifestation of these lesions mimics that of hereditary PXE and is associated with severe vascular complications. This case highlights the importance of recognising this rare disorder and the role dermatologists have in establishing the diagnosis and advising on appropriate screening for complications.

Pseudoxanthoma elasticum in a patient with sickle cell disease: case report.

An 18 year female sickler (HbSS) presented with repeated history of epistaxis and bleeding gums. Features consistent with pseudoxanthoma elasticum were observed, such as hyper-extensile redundant skin folds in the neck, axilla, inguinal areas and abdomen. The skin biopsy showed swollen, clumped and fragmented elastic fibres and calcium deposits in the deep and mid reticular dermis, consistent with pseudoxanthoma elasticum. This is a well recognised complication of sickle cell disease which has not been described in Kenya.

Varied presentations of pseudoxanthoma elasticum in a family.

Pseudoxanthoma elasticum (PXE) is a hereditary disorder of elastic tissue. The characteristic skin changes are asymptomatic yellow papules around the neck and in body folds giving the skin a characteristic cobblestone appearance. The eyes, cardiovascular and gastrointestinal systems are also commonly involved. In this case-series, we present a family of four children, three of whom demonstrated diverse manifestations of PXE. The first child presented with sudden death at age 3 and showed marked coronary and renal arterial intimal fibrosis with prominent fragmentation of the internal elastic lamina, initially attributed to idiopathic arterial calcification. The second child presented with clinical features and histology of the skin typical of PXE at age 11 and the third child, with abnormal, but non-specific cardiological findings at age 8, which raised the possibility of an early stage of PXE. This report emphasizes the importance of considering pseudoxanthoma elasticum in diverse clinical settings, early diagnosis and appropriate screening for asymptomatic family members.

Nephrogenic fibrosing dermopathy and calciphylaxis with pseudoxanthoma elasticum-like changes.

Nephrogenic fibrosing dermopathy (NFD) and calciphylaxis are rare conditions that are associated with chronic kidney disease. Histopathologic changes, including dystrophic dermal calcification, often in association with elastic fibers have been observed in NFD and calciphylaxis. A pattern of dermal elastic fiber calcification that mimics pseudoxanthoma elasticum (PXE) has been previously reported as an incidental finding in the setting of calciphylaxis. Despite a shared association with renal disease and abnormal calcium deposits, however, NFD and calciphylaxis are discrete pathologic processes with distinct clinical and histopathologic features. Criteria for each are reviewed through case presentation of a patient meeting the clinical and histopathologic criteria for both NFD and calciphylaxis with histologic features mimicking PXE.