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Introduction Tumoral calcinosis (TC) is a difficult-to-treat complication that can occur during several diseases such as dermatomyositis or genetic hyperphosphatemia. It is a painful and disabling condition that can lead to local complications including joint mobility reduction, cutaneous ulceration and superinfection. For the largest lesions, the treatment relies essentially on surgery. Intravenous sodium thiosulfate (STS) is efficient to treat calciphylaxis in patients undergoing hemodialysis. Local injections of STS seem efficient in superficial calcifications. Objective To report the efficacy and safety of intra-lesional injections of STS in tumoral calcinosis. Results We report two cases of successful intra-lesional injections of STS. A 44-year-old woman, with a history of dermatomyositis, presenting large subcutaneous calcifications in the right elbow, and a 42-year-old man, with a history of familial tumoral calcinosis, presenting large intramuscular calcifications in the right buttock, received weekly intra-lesional of 1–3 g STS injections for 12 and 21 months, respectively. In both cases, the treatment relieved pain and greatly reduced the tumoral calcinosis with a very significant functional improvement without specific adverse effects. In case 1, TC size decreased from 28.7*56.0 mm at baseline to 21.5*30.6 mm at M12 treatment (59% reduction). In case 2, TC reduced from 167.5*204.3 mm at baseline to 86.2*85.2 mm at M21 treatment (79% reduction). Conclusion Local injection of STS could be a promising therapeutic strategy for large and deep TC lesions and could therefore be an alternative to surgery.

International audience; In this review we consider diseases associated with pathological mineralization/ossification, namely, ankylosing spondylitis (AS), osteoarthritis (OA), generalized artery calcification of infancy (GACI), vascular calcification as well as chondrocalcinosis (CC) and pseudo gout. Deciphering the key enzymes implicated in the calcification process is an objective of prime importance and the ultimate goal is to synthesize inhibitors of these enzymes in order to provide efficient alternate therapeutic strategies that will slow down the pathologic mineralization and complement the arsenal of anti-inflammatory drugs. One of the difficulties in the definition of diseases associated with pathologic mineralization/ossification lies in the controversial relationship between the type of calcification and the nature of the disease. Here, we propose to clarify this relationship by making a distinction between diseases associated with hydroxyapatite (HA) and calcium pyrophosphate dihydrate (CPPD) deposits. AS, OA, GACI and vascular calcification are usually characterized by mineralization/ossification associated with HA deposits, while CC and pseudo gout are mostly characterized by CPPD deposits. Although both HA and CPPD deposits may occur concomitantly, as in chronic pyrophosphate arthritis or in OA with CPPD, they are formed as a result of two antagonistic processes indicating that treatment of distinct diseases can be only achieved by disease-specific drug therapies. The hydrolysis of PPi, an inhibitor of HA formation, is mostly controlled by tissue non-specific alkaline phosphatase TNAP, while PPi production in the extracellular medium is controlled by ANK, a PPi transporter, and/or NPP1 which generates PPi from nucleotide triphosphates. Low PPi concentration may lead to a preferential deposition of HA while high PPi concentration will favor the formation of CPPD deposits. Thus, HA and CCPD deposition cannot occur concomitantly because they are determined by the Pi/PPi ratio which, in turn, depends on the relative activities of antagonistic enzymes, TNAP hydrolyzing PPi or ANK and NPP1 producing PPi. TNAP inhibitors could prevent HA formation in AS, in late OA, in GACI, as well as in vascular calcifications, while ANK or NPP1 inhibitors could slow down CCPD deposition in CC and pseudo gout.

International audience; Widespread endochondral and intramembranous ectopic bone formation is mediated by extracellular PP(i) deficiency that develops in ank/ank mice. Herein we report on the rapid condensation into chondrogenic nodules of cultured ank/ank bone marrow stromal cells (BMSCs). We compared the roles of increased chondrogenic potential versus altered osteoblast function in the ank/ank phenotype. To do so, we crossbred ank/ank mice with mice lacking Vanin-1 pantetheinase, which inhibits synthesis of the chondrogenesis regulator glutathione, since we observed increased Vanin-1 expression and pantetheinase activity and decreased glutathione in ank/ank BMSCs. Vnn1(-/-) BMSCs demonstrated delayed chondrogenesis mediated by increased glutathione. Moreover, increased chondrogenesis of ank/ank BMSCs and increased chondrogenic transdifferentiation and calcification by ank/ank aortic smooth muscle cells and explants were corrected by Vanin-1 knockout. Osteoblastogenesis was accelerated in ank/ank mesenchymal stem cells. However, in cultured ank/ank osteoblasts, Vanin-1 knockout actually increased specific alkaline phosphatase activity and lowered extracellular PP(i), and did not correct increased calcification. Moreover, Vanin-1 knockout failed to correct the ank/ank skeletal soft tissue phenotype. Therefore, ank/ank periskeletal soft tissue calcification appears more dependent on altered osteoblastic function than enhanced chondrogenic potential and is not dependent on Vanin-1; however, Vanin-1 regulates chondrogenesis via glutathione metabolism and is critical for accelerated chondrogenesis of ank/ank mesenchymal precursors and P(i) donor-driven chondrogenic transdifferentiation and calcification of aortic smooth muscle cells.

International audience; We report a 12-year-old boy who presented with abdominal pain and who was found to have an aneurysm of the abdominal aorta (AAA). The patient was born from a quadruplet pregnancy induced by in vitro fertilization. Postnatal transient respiratory distress required assisted ventilation that had been monitored by two consecutive umbilical arterial catheters (UAC). AAA is a rare condition in childhood. Infection and/or trauma are known to be the most frequent causes. Most of the reported cases have occurred in children in whom a UAC had been placed during the neonatal period. In this patient the delay between UAC placement and diagnosis was considerable. At the time of this report the patient had remained well during a follow-up of 8 years after treatment.

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Background and Purpose— Although intracranial artery calcification (IAC) has been reported to be a risk factor for ischemic stroke, the prognostic implications of IAC in stroke outcome are unknown. The purpose of this study was to determine the association between IAC and risk of vascular events and death in patients with stroke after hospital discharge. Methods— All patients with ischemic stroke over a 1-year period were included (n=302). IAC, assessed by multidetector CT, was defined as hyperdense foci (peak density >130 Hounsfield units) and assessed in the 7 major cerebral arteries. The IAC scores ranged from 0 (no calcification) to 7. Follow-up information on major clinical events (including fatal or nonfatal ischemic stroke, cardiac and peripheral artery events, and all-cause death) was obtained by means of a structured phone interview. Results— IAC was present in 260 patients (83%). With a mean follow-up of 773±223 days, 88 major clinical events occurred in 67 patients (22%): 45 new ischemic vascular events (ischemic stroke: n=22; cardiac event: n=15; peripheral artery event: n=8) and 43 deaths from any cause. Patients with the highest IAC scores had significantly higher rates of death and vascular events than those with the lowest IAC scores (log rank test, P =0.029). In the Cox proportional hazards regression model, the IAC score was significantly associated with major clinical events (hazard ratio, 1.34; 95% CI, 1.11–1.61; P =0.002). Conclusions— In patients with ischemic stroke, IAC detection may constitute a simple marker of a high risk of future major clinical events.

BACKGROUND: Hypertension and chronic renal failure (CRF) are considered models of accelerated arterial stiffening. Arterial stiffness increases further when CRF is associated with hypertension. We hypothesized that, in patients with mild CRF, aortic gene expression profile would include genes involved in arterial calcifications and enlargement. METHOD: We analysed human aorta with the 'GeneChip Microarray' technology, in patients with or without CRF, scheduled for a coronary artery bypass graft. RESULTS: Nine of 25 patients had high-quality RNA and were included in the study. Among the 101 transcripts differentially expressed between CRF patients and controls, 97 transcripts were overexpressed in CRF patients. Two genes had the highest overexpression in CRF patients: lumican (LUM), involved in the regulation of collagen fibrillogenesis; and ornithine decarboxylase (ODC1), involved in polyamine biosynthesis, smooth muscle cell growth and proliferation. Immunohistochemical staining revealed an increased amount of LUM and ODC1 in the vascular smooth muscle cells (VSMCs) of CRF compared to non-CRF aortic sections. Eight genes were implicated in the regulation of the cytoskeleton (including capping protein muscle Z-line 1 alpha and moesin) and cell migration, and five genes were implicated in extracellular matrix function and apoptosis. A trend towards an upregulation of candidate genes involved in arterial calcifications was observed in CRF patients, but did not reach statistical significance. Carotid-femoral pulse wave velocity was not correlated with gene expression level. CONCLUSION: In conclusion, these results show that patients at an early stage of CRF have a specific gene expression profile of aortic tissue and suggest that genes implicated in collagen fibrillogenesis, and VSMCs migration and proliferation, particularly LUM and ODC1, may play a role.

Calcification of arteries is a major risk factor for cardiovascular mortality in humans. Using genetic approaches, we demonstrate here that the transcriptional intermediary factor 1α (TIF1α), recently shown to function as a tumor suppressor in murine hepatocytes, also participates in a molecular cascade that prevents calcifications in arterioles and medium-sized arteries. We further provide genetic evidence that this function of TIF1α is not exerted in hepatocytes. The sites of ectopic calcifications in mutant mice lacking TIF1α resemble those seen in mice carrying an activating mutation of the calcium sensor receptor ( Casr ) gene and, in TIF1 α-deficient kidneys, Casr expression is increased together with that of many other vitamin D receptor (VDR) direct target genes, namely Car2 , Cyp24a1 , Trpv5 , Trpv6 , Calb1 , S100g , Pthlh , and Spp1 . Thus, our data indicate that TIF1α represses the VDR pathway in kidney and suggest that an up-regulation of Casr expression in this organ could account for ectopic calcifications generated upon TIF1 α deficiency. Interestingly, the calcifying arteriopathy of TIF1 α-null mutant mice shares features with the human age-related Mönckeberg's disease and, overall, the TIF1 α-null mutant pathological phenotype supports the hypothesis that aging is promoted by increased activity of the vitamin D signaling pathway.

Context: Hyperostosis-hyperphosphatemia syndrome (HHS) is a rare metabolic disorder characterized by hyperphosphatemia and localized hyperostosis. HHS is caused by mutations in GALNT3, which encodes UDP-N-acetyl-α-d-galactosamine:polypeptide N- acetylgalactosaminyltransferase 3. Familial tumoral calcinosis (TC), characterized by ectopic calcifications and hyperphosphatemia, is caused by mutations in the GALNT3 or fibroblast growth factor 23 (FGF23) genes. Objective: Our objective was to identify mutations in FGF23 or GALNT3 and determine serum FGF23 levels in an HHS patient. Design: Mutation detection in FGF23 and GALNT3 was performed by DNA sequencing, and serum FGF23 concentrations were measured by ELISA. Patients or Other Participants: A 5-year-old French boy with HHS and his family members participated. Results: The patient presented with painful cortical lesions in his leg. Radiographs of the affected bone showed diaphyseal hyperostosis. The lesional tissue comprised trabeculae of immature, woven bone surrounded by fibrous tissue. Biochemistry revealed elevated phosphate, tubular maximum rate for phosphate reabsorption per deciliter of glomerular filtrate, and 1,25-dihydroxyvitamin D levels. The patient was a compound heterozygote for two novel GALNT3 mutations. His parents and brother were heterozygous for one of the mutations and had no biochemical abnormalities. Intact FGF23 level in the patient was low normal, whereas C-terminal FGF23 was elevated, a pattern similar to TC. Conclusion: The presence of GALNT3 mutations and elevated C-terminal, but low intact serum FGF23, levels in HHS resemble those seen in TC, suggesting that HHS and TC are different manifestations of the same disorder. The absence of biochemical abnormalities in the heterozygous individuals suggests that one normal allele is sufficient for secretion of intact FGF23.

Calcific aortic valve stenosis is by far the most common valve disease in developed countries.1 The first clinical symptoms usually appear in the late 60s. Prosthetic aortic valve replacement is the only effective treatment at present.2 The reasons for the occurrence of calcifications of the aortic cusps leading eventually after many years to aortic valve stenosis are unknown. Some risk factors, mainly those already recognised in vascular disease, have been found to be associated with aortic valve stenosis and are considered to cause the disease.3,4 However, these factors are totally non-specific and may be confounded with factors leading to other illnesses. Recently a genetic hypothesis has been proposed after observation of a few familial cases5 but remains largely challenged in the absence of gene determination. The aim of our study was to evaluate whether epidemiological data collected in a selected region of France could provide evidence in favour of this hypothesis. The list of all patients who had undergone aortic valve replacement for calcific aortic valve stenosis in the cardiac surgery department of the Brest University Hospital between January 1996 and June 2003 was obtained from the central computerised registration of medical diagnosis and surgical procedures of the hospital, coded according to the International classification of diseases , 10th revision. This list was compared, and if necessary completed, with the diary registries of all the surgical interventions performed in the cardiac surgery department. For each patient, the following data were collected: name, sex, date of surgery, date of birth, and social security number. The social security number is a 15 digit number allowing identification for sex, year and month of birth, and geographic origin (region and commune). France is administratively divided into 22 provinces, about 100 regions, and 36 000 communes. The commune is the …