Successful Treatment of Tumoral Calcinosis by Lanthanum Carbonate.

Tumoral calcinosis (TC) is a rare benign but aggressive disorder with variable response rates and high recurrence rates despite medical or surgical treatments. We herein report a case of a 28-year-old woman with underlying systemic lupus erythematosus (SLE) who developed diffuse tumoral calcinosis that was successfully treated by lanthanum carbonate. The formation of tumoral calcinosis depends on the supersaturation of calcium and phosphate. Lanthanum carbonate not only has an excellent phosphate-lowering ability but also low gastro-intestinal calcium absorption. It can be considered an effective alternative treatment for tumoral calcinosis if surgical treatment is not feasible.

Magnesium intake is inversely associated with coronary artery calcification: the Framingham Heart Study.

OBJECTIVES: The aim of this study was to examine whether magnesium intake is associated with coronary artery calcification (CAC) and abdominal aortic calcification (AAC). BACKGROUND: Animal and cell studies suggest that magnesium may prevent calcification within atherosclerotic plaques underlying cardiovascular disease. Little is known about the association of magnesium intake and atherosclerotic calcification in humans. METHODS: We examined cross-sectional associations of self-reported total (dietary and supplemental) magnesium intake estimated by food frequency questionnaire with CAC and AAC in participants of the Framingham Heart Study who were free of cardiovascular disease and underwent Multi-Detector Computed Tomography (MDCT) of the heart and abdomen (n = 2,695; age: 53 ± 11 years), using multivariate-adjusted Tobit regression. CAC and AAC were quantified using modified Agatston scores (AS). Models were adjusted for age, sex, body mass index, smoking status, systolic blood pressure, fasting insulin, total-to-high-density lipoprotein cholesterol ratio, use of hormone replacement therapy (women only), menopausal status (women only), treatment for hyperlipidemia, hypertension, cardiovascular disease prevention, or diabetes, as well as self-reported intake of calcium, vitamins D and K, saturated fat, fiber, alcohol, and energy. Secondary analyses included logistic regressions of CAC and AAC outcomes as cut-points (AS >0 and AS ≥90th percentile for age and sex), as well as sex-stratified analyses. RESULTS: In fully adjusted models, a 50-mg/day increment in self-reported total magnesium intake was associated with 22% lower CAC (p < 0.001) and 12% lower AAC (p = 0.07). Consistent with these observations, the odds of having any CAC were 58% lower (p trend: <0.001) and any AAC were 34% lower (p trend: 0.01), in those with the highest compared to those with the lowest magnesium intake. Stronger inverse associations were observed in women than in men. CONCLUSIONS: In community-dwelling participants free of cardiovascular disease, self-reported magnesium intake was inversely associated with arterial calcification, which may play a contributing role in magnesium's protective associations in stroke and fatal coronary heart disease.

Dietary phosphate restriction normalizes biochemical and skeletal abnormalities in a murine model of tumoral calcinosis.

Mutations in the GALNT3 gene cause tumoral calcinosis characterized by ectopic calcifications due to persistent hyperphosphatemia. We recently developed Galnt3 knockout mice in a mixed background, which had hyperphosphatemia with increased bone mineral density (BMD) and infertility in males. To test the effect of dietary phosphate intake on their phenotype, Galnt3 knockout mice were generated in the C57BL/6J strain and fed various phosphate diets: 0.1% (low), 0.3% (low normal), 0.6% (normal), and 1.65% (high). Sera were analyzed for calcium, phosphorus, alkaline phosphatase, creatinine, blood urine nitrogen, 1,25-dihydroxyvitamin D, osteocalcin, tartrate-resistant acid phosphatase 5b, and fibroblast growth factor 23 (Fgf23). Femurs were evaluated by dual-energy x-ray absorptiometry, dynamic histomorphometry, and/or microcomputed tomography. Galnt3 knockout mice in C57BL/6J had the same biochemical phenotype observed in our previous study: hyperphosphatemia, inappropriately normal 1,25-dihydroxyvitamin D level, decreased alkaline phosphatase activity, and low intact Fgf23 concentration but high Fgf23 fragments. Skeletal analyses of their femurs revealed significantly high BMD with increased cortical bone area and trabecular bone volume. On all four phosphate diets, Galnt3 knockout mice had consistently higher phosphorus levels and lower alkaline phosphatase and intact Fgf23 concentrations than littermate controls. The low-phosphate diet normalized serum phosphorus, alkaline phosphatase, and areal BMD but failed to correct male infertility in Galnt3 knockout mice. The high-phosphate diet did not increase serum phosphorus concentration in either mutant or control mice due to a compensatory increase in circulating intact Fgf23 levels. In conclusion, dietary phosphate restriction normalizes biochemical and skeletal phenotypes of Galnt3 knockout mice and, thus, can be an effective therapy for tumoral calcinosis.

Extensive coronary calcification: a clinically unrecognised condition.

Atheroma calcification is a common feature of advanced atherosclerosis, however with the advent of CT scanning it has become possible to detect extensive coronary calcification in the absence of flow-limiting lesions. While this phenomenon is known in renal disease, it also exists in some patients with exertional angina. Vascular pathology suggests biomineralisation associated with development of osteoblast-like cells in the arterial wall. While some conventional risk factors are shared with atheroma formation, others such as ethnicity and medications appear more specific to extensive calcification and may mirror those for osteoporosis. Similarly an atherogenic diet can predispose to both conditions while some elements promote or inhibit coronary calcification but not atheroma formation. The immune and endocrine systems contribute to both conditions but not necessarily in the same way, with vitamins D and K more related to calcification than atheroma formation. Finally, statins significantly lower low density lipoprotein (LDL) cholesterol and reduce atheroma formation but are largely powerless against extensive calcification. Although investigations into the exact cause of extensive coronary calcification are in their infancy, early results suggest that it is sufficiently different in nature from atheroma formation to be considered as a separate condition. Further research would yield a greater understanding, which would aid management and the development of specific biomarkers to reduce the cost and radiation risk of CT scanning.

Dietary magnesium, not calcium, prevents vascular calcification in a mouse model for pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by ectopic calcification of connective tissue in skin, Bruch's membrane of the eye, and walls of blood vessels. PXE is caused by mutations in the ABCC6 gene, but the exact etiology is still unknown. While observations on patients suggest that high calcium intake worsens the clinical symptoms, the patient organization PXE International has published the dietary advice to increase calcium intake in combination with increased magnesium intake. To obtain more data on this controversial issue, we examined the effect of dietary calcium and magnesium in the Abcc6(-/-) mouse, a PXE mouse model which mimics the clinical features of PXE. Abcc6(-/-) mice were placed on specific diets for 3, 7, and 12 months. Disease severity was measured by quantifying calcification of blood vessels in the kidney. Raising the calcium content in the diet from 0.5% to 2% did not change disease severity. In contrast, simultaneous increase of both calcium (from 0.5% to 2.0%) and magnesium (from 0.05% to 0.2%) slowed down the calcification significantly. Our present findings that increase in dietary magnesium reduces vascular calcification in a mouse model for PXE should stimulate further studies to establish a dietary intervention for PXE.

High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease.

BACKGROUND: Dent's disease, an X-linked renal tubular disorder, is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. Dent's disease results from mutations of the voltage-gated chloride channel CLC-5. METHODS: We studied the effect of zero and high citrate diet on renal function of ClC-5 knockout mice and wild-type mice. The mice were placed in metabolic cages from which the urine was collected. Mice were sacrificed to obtain serum and tissues for analysis. RESULTS: ClC-5 knockout mice fed zero or high citrate diet had significantly increased urinary calcium excretion compared with wild-type mice fed the same diets. Nine-month-old ClC-5 knockout mice on a zero citrate diet had significantly decreased glomerular filtration rate (GFR), whereas 9-month-old ClC-5 knockout mice on a high citrate diet had normal renal function. ClC-5 knockout mice fed a zero citrate diet had significantly increased tubular atrophy, interstitial fibrosis, cystic changes, and nephrocalcinosis compared to ClC-5 knockout mice fed a high citrate diet. Transforming growth factor-beta1 (TGF-beta1) was significantly increased in 9-month-old ClC-5 knockout mice on zero citrate diet compared to 9-month-old wild-type mice on the same diet. CONCLUSION: High citrate diet preserved renal function and delayed progression of renal disease in ClC-5 knockout mice even in the apparent absence of stone formation. We conclude from this that long-term control of hypercalciuria is an important factor in preventing renal failure in these mice.

Calcinosis involving multiple paws in a cat with chronic renal failure and in a cat with hyperthyroidism.

Calcinosis of multiple paws is described in two cats. A metastatic pathogenesis was supported by the laboratory findings of hyperphosphataemia and a calcium x phosphorus solubility product > 7 g/L. Hyperparathyroidism could not be confirmed because a valid feline parathyroid hormone assay was not available at the time. One cat was diagnosed with chronic renal failure and presented initially with an irregular nodular calcification on the chin. Dietary and medical management was unsuccessful and ultimately the animal was euthanased. Hyperthyroidism was diagnosed in another cat by laboratory findings and scintigraphic imaging. In addition, the cat had a hyperphosphataemia in the absence of azotaemia. Intravenous administration of radioactive iodine as (131)I was accompanied by reduction and normalization in serum total thyroxine and phosphorus concentrations and resulted in resolution of calcification in the paws.

Epilepsy, occipital calcifications, and oligosymptomatic celiac disease in childhood.

The association of epilepsy, occipital calcifications, and celiac disease has been recognized as a distinct syndrome. The objective of this study was to present the clinical, electrophysiologic, and neuroradiologic features in a series of patients with this syndrome. Thirty-two patients with the constellation of epilepsy, occipital calcifications, and celiac disease were identified in our epilepsy clinic. The mean age was 11 years and the mean length of follow-up was 7.4 years. The 1990 criteria of the European Society of Pediatric Gastroenterology and Nutrition were used to diagnose celiac disease. The Kruskal-Wallis statistics test was employed with a signficance of P < .05. Thirty-one patients had partial seizures, 21 of them with symptoms related to the occipital lobe. In most patients, the epilepsy was controlled or the seizures were sporadic. Three developed severe epilepsy. Occipital calcifications were present in all cases. Computed tomography in 7 patients showed hypodense areas in the white matter around calcifications, which decreased or disappeared after a period of gluten-free diet in 3 patients. A favorable outcome of epilepsy was detected in patients with the earliest dietary therapy. This study presents the largest series of children with this syndrome outside Italy. White-matter hypodensities surrounding calcifications are rarely reported. A prompt diagnosis of celiac disease might improve the evolution of the epilepsy and may improve cognitive status.

Epilepsy, cerebral calcifications and clinical or subclinical coeliac disease. Course and follow up with gluten-free diet.

We have studied four patients (three male, one female, age range 15-25 years) with epilepsy, bilateral occipital calcifications and latent coeliac disease (CD). The epilepsy started at mean age 7 years, in three cases there were partial seizures and in one case generalized seizure. Three cases had symptoms suggesting malabsorptive syndrome during infancy and one case was diagnosed CD before the onset of seizures. In all cases serologic markers of CD were found, especially antiendomisium antibody, and intestinal biopsy indicated several grades of atrophy. The electroencephalograph (EEG) findings pointed to focal abnormalities in three patients and generalized abnormalities in one patient. In all cases computer tomography (CT) showed bilateral, almost symmetrical occipital calcifications in the cortical subcortical layers. The enhanced CT were unremarkable and magnetic resonance images (MRI) were normal. After diagnosis of CD, all patients followed a gluten-free diet and in three patients a significant reduction in seizure frequency was observed. CD should be ruled out in all cases of epilepsy, cerebral calcifications of unexplained origin and malabsorption syndrome in infancy.

Increasing intake of soybean protein or casein, but not cod meal, reduces nephrocalcinosis in female rats.

Female weanling rats were fed diets with soybean protein, casein or cod meal at 171, 342 or 513 mmol nitrogen/100 g for 3 wk. The diets were isonitrogenous and balanced for fat, cholesterol, calcium, magnesium and phosphorus. Cod meal feeding at 171 and 342 mmol nitrogen/100 g diet produced lower kidney calcium concentrations than the feeding of either soybean protein or casein. Increasing protein intakes were associated with reduced kidney calcium concentrations in the rats fed either soybean protein or casein but not in those fed cod meal. The anti-nephrocalcinogenic effect of increasing intakes of soybean protein may relate to the lowering of urinary phosphorus concentration. Increasing intakes of casein probably inhibited nephrocalcinogenesis by lowering urinary pH and raising urinary magnesium concentration. Increasing cod meal concentrations in the diet lowered urinary pH and raised urinary magnesium and calcium concentrations, but the effects on nephrocalcinogenesis of these changes probably counteracted each other.

Celiac disease, posterior cerebral calcifications and epilepsy.

Ten patients (5 males) affected by epilepsy with cerebral calcifications of unknown etiology mainly located in the posterior regions were subjected to a battery of tests including an intestinal biopsy. Our aim was to establish whether or not the patients also suffered from celiac disease. Celiac diseases was found in 6 patients. This result and the individual cases reported in the literature suggest that this triad of diseases (celiac disease, posterior cerebral calcifications and epilepsy) are casually related. The same HLA phenotype was found in all 10 patients, i.e., including the cases without celiac disease, suggesting an underlying disorder of the immune system. Our results emphasize that particular attention should be paid to a search for celiac disease in all patients with epilepsy and posterior cerebral calcifications.

Self-limited neonatal familial hyperparathyroidism associated with hypercalciuria and renal tubular acidosis in three siblings.

Three siblings with neonatal familial hyperparathyroidism diagnosed at age 4 months, 2 months, and 5 days, respectively, were treated. Hypercalciuria, nephrocalcinosis, and renal tubular acidosis were present in each child. In all three, there were higher responses of serum parathyroid hormone to serum calcium and higher elevation of serum calcium with oral calcium loading. The metabolism of vitamin D and calcitonin seemed to be intact. Hypercalcemia associated with the abnormal response of parathyroid hormone secretion disappeared when the children passed the age of approximately 2 years, although renal tubular acidosis and nephrocalcinosis remained. An autosomal recessive inheritance seems likely.

Tumoral calcinosis. Case report with treatment failure.

Periarticular calcifications are the hallmark of a rare entity: tumoral calcinosis. We have followed for 90 months a nine-year-old black girl with involvement of both shoulders. Seven initial local excisions of the mass on the right shoulder were attempted without complete removal and prompt recurrence after each attempt. The entire lesion on the right side, including a cutaneous ulceration, was managed by en masse surgical excision. Preoperative inpatient medical management in the form of low calcium and low phosphorus diet was unsuccessful. Postoperatively, she has remained free of ulceration; however, after two and a half years, the right mass has again increased in size with compression of the brachial plexus. This recurrence occurred despite strict dietary control starting immediately postoperatively. Although there are many advocates of surgical excision of these lesions and, more recently, several cases reported of successful medical management, we find that often a combination approach is necessary to effectively treat tumoral calcinosis and reduce the rate of recurrence.

Effects of the acute subcutaneous administration of synthetic salmon calcitonin in tumoral calcinosis.

We examined the effects of the acute administration of salmon calcitonin on phosphate metabolism in tumoral calcinosis. On two different days, 200 MRC U of the synthetic hormone were administered sc to a 38-year-old patient, either as twice daily 100 MRC U injections, or as a continuous sc infusion via a portable pump. Both ways of calcitonin administration elicited a phosphaturic effect and a lowering of serum phosphate level comparable with that observed after an iv infusion of calcitonin. 1,25 dihydroxyvitamin D level, which was in the normal range during a control study, increased after calcitonin administration. In our patient, long term therapy with diet, a phosphate-binding agent and calcitonin prevented the occurrence of new ectopic calcifications. Owing to its phosphaturic activity, synthetic salmon calcitonin may be a useful adjunct to diet and aluminium-containing antacids in long-term management of tumoral calcinosis.

Tumoral calcinosis: serial images to monitor successful dietary therapy.

Tumoral calcinosis involves formation of periarticular calcified soft tissue masses. Experimental evidence suggests a metabolic etiology with dietary restriction of calcium and phosphorus as beneficial therapy. We prospectively monitored serum levels of calcium, phosphorous, alkaline phosphatase, and erythrocyte sedimentation rate (ESR) while successfully treating a patient with tumoral calcinosis. The values were compared with changes on serial radiographic and radionuclide bone and gallium images. Our work suggests using serial serum phosphate levels and the ESR as the most sensitive indications of progress in dietary treatment of tumoral calcinosis.

Phosphate depletion therapy in two ectopic calcification syndromes.

Ectopic calcification may be a complication of a wide variety of pathologic conditions. Subcutaneous calcification frequently results in restriction of motion at joints in addition to cosmetic deformity. Parenchymal tissue calcification may result in decreased organ function. Dietary phosphate restriction and total body phosphate depletion with aluminum containing antacids were used in an attempt to decrease the deposition of subcutaneous calcium phosphate which occurs with two separate syndromes. Two subjects with hyperphosphatemic tumoral calcinosis were studied by metabolic balance, by long-term clinical evaluation, and routine laboratory and radiographic techniques before and after 1 year of phosphate depletion. One patient with a newly described syndrome--normocalcemic, hypercalciuric, subcutaneous calcification--was similarly studied. The etiology of this disorder is unknown. No consistent clinically significant evidence of regression of the lesions was noted in either syndrome, although one patient with tumoral calcinosis did demonstrate some regression of his lesions. It is not clear if this response failure was due to the intrinsic nature of the diseases or to failure of patient compliance secondary to a relatively unpalatable diet.