Spatial Atlas for Mapping Vascular Microcalcification Using 18F-NaF PET/CT: Application in Hyperphosphatemic Familial Tumoral Calcinosis.

BACKGROUND: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals. METHODS: To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCSmean and mCSmax were computed to compare microcalcification score levels at predefined vascular segments within subjects. RESULTS: Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment. CONCLUSIONS: This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.

Hyperphosphatemia-Related False-Positive 99m Tc-Pyrophosphate Myocardial Scan: A Case Report With Endomyocardial Biopsy Result.

ABSTRACT: With documented high specificity, 99m Tc-pyrophosphate (PYP) scan enables the diagnosis of transthyretin cardiomyopathy to be made reliably without endomyocardial biopsy in patients who do not have monoclonal gammopathy. We report a case with extensive myocardial uptake of Perugini 3 score in the 3-hour 99m Tc-PYP myocardial SPECT that suggested transthyretin cardiac amyloidosis. However, a followed endomyocardial biopsy revealed no amyloid deposition. In this case, hyperphosphatemia was the most likely and presumptive cause of the false-positive 99m Tc-PYP scan. With this case, our experiences of the potential causes of false-positive results of 99m Tc-PYP are further expanded.

Recurrence of tumoral calcinosis: a case report.

We describe radiographic, contrast-enhanced MDCT and MRI findings with pathologic correlations of an unusual recurrence of tumoral calcinosis, also called Teutschlander disease. The disease was silent in the first decade of life, when it appeared with elbows recurring lesions, until the seventh decade of life, when a left hip active growth lesion developed. A review about tumoral calcinosis pathogenesis, clinical course and imaging differential diagnosis is reported. (www.actabiomedica.it).

Hyperphosphatemic familial tumoral calcinosis secondary to fibroblast growth factor 23 (FGF23) mutation: a report of two affected families and review of the literature.

Hyperphosphatemic familial tumoral calcinosis (HFTC), secondary to fibroblast growth factor 23 (FGF23) gene mutation, is a rare genetic disorder characterized by recurrent calcified masses. We describe young Lebanese cousins presenting with HFTC, based on a retrospective chart review and a prospective case study. In addition, we present a comprehensive review on the topic, based on a literature search conducted in PubMed and Google Scholar, in 2014 and updated in December 2017. While the patients had the same previously reported FGF23 gene mutation (homozygous c.G367T variant in exon 3 leading to a missense mutation), they presented with variable severity and age of disease onset (at 4 years in patient 1 and at 23 years in patient 2). A review of the literature revealed several potential patho-physiologic pathways of HFTC clinical manifestations, some of which may be independent of hyperphosphatemia. Most available treatment options aim at reducing serum phosphate level, by stimulating renal excretion or by inhibiting intestinal absorption. HFTC is a challenging disease. While the available medical treatment has a limited and inconsistent effect on disease symptomatology, surgical resection of calcified masses remains the last resort. Research is needed to determine the safety and efficacy of FGF23 replacement or molecular therapy, targeting the specific genetic aberration. Hyperphosphatemic familial tumoral calcinosis is a rare genetic disorder characterized by recurrent calcified masses, in addition to other visceral, skeletal, and vascular manifestations. It remains a very challenging disease.

Dialysis as a Treatment Option for a Patient With Normal Kidney Function and Familial Tumoral Calcinosis Due to a Compound Heterozygous FGF23 Mutation.

Primary tumoral calcinosis is a rare autosomal recessive disorder characterized by ectopic calcified tumoral masses. Mutations in 3 genes (GALNT3, FGF23, and KL) have been linked to this human disorder. We describe a case of a 28-year-old man with a history of painful firm masses over his right and left gluteal region, right clavicle region, knees, and left elbow. Biochemical analysis disclosed hyperphosphatemia (phosphate, 9.0 mg/dL) and normocalcemia (calcium, 4.8 mg/dL), with normal kidney function and fractional excretion of phosphate of 3%. Parathyroid hormone was suppressed (15 pg/mL), associated with a low-normal 25-hydroxyvitamin D (26 ng/mL) concentration but high 1,25-dihydroxyvitamin D concentration (92 pg/mL). Serum intact FGF-23 (fibroblast growth factor 23) was undetectable. Genetic analysis revealed tumoral calcinosis due to a compound heterozygous mutation in FGF23, c.201G>C (p.Gln67His) and c.466C>T (p.Gln156*). Due to lack of other treatment options and because the patient was facing severe vascular complications, we initiated a daily hemodialysis program even in the setting of normal kidney function. This unusual therapeutic option successful controlled hyperphosphatemia and reduced metastatic tumoral lesions. This is a report of a new mutation in FGF23 in which dialysis was an effective treatment option for tumoral calcinosis with normal kidney function.

Clinical Characteristics of Seven Patients with Lanthanum Phosphate Deposition in the Stomach.

Objective To analyze the clinical characteristics and endoscopic features of patients with lanthanum deposition in the stomach. Patients We retrospectively reviewed seven patients with lanthanum deposition in the stomach who were diagnosed at Okayama Saiseikai General Hospital. We investigated the patient sex, age at diagnosis, medical and medication histories, gastrointestinal symptoms, complications, presence or absence of gastric atrophy, and outcome. We also investigated any changes in the endoscopic features if previous endoscopic images were available. Results Seven patients (six males and one female) had lanthanum deposition. The median age was 65 years (range, 50-79 years). All patients had been undergoing dialysis (continuous ambulatory peritoneal dialysis in one patient, hemodialysis in six patients). The dialysis period ranged from 16 to 73 months (median, 52 months). The patients had all been taking lanthanum carbonate for a period ranging from 5 to 45 months (median, 27 months). Gastric atrophy was noted in 6 patients (85.7%). One patient had difficulty swallowing, and 1 other patient had appetite loss. The other 5 patients were asymptomatic. Endoscopic features included annular whitish mucosa (n = 4), diffuse whitish mucosa (n = 3), and whitish spots (n = 2). Five patients underwent multiple esophagogastroduodenoscopy. The endoscopic features were unchanged in 2 patients, whereas the whitish mucosa became apparent and spread during the course in 3 patients. Conclusion We identified 7 patients with lanthanum deposition in the stomach. All patients showed whitish lesions macroscopically. Although the pathogenicity of gastric lanthanum deposition is uncertain, lanthanum-related lesions in the stomach progressed during continuous lanthanum phosphate intake in several patients.

Increased technetium-99 m hydroxy diphosphonate soft tissue uptake on bone scintigraphy in chronic kidney disease patients with secondary hyperparathyroidism: correlation with hyperphosphataemia.

In bone scan patients with dialysis-treated chronic kidney disease (CKD) and hyperparathyroidism, soft tissue accumulation of technetium-99 m hydroxy/methylene diphosphonate (Tc-99 m-HDP/MDP) has been reported primarily in case reports and usually explained by hypercalcaemia and/or hyperphosphataemia. As human vascular smooth muscle cells produce hydroxyapatite during cell culture with increased phosphate levels and as Tc-99 m-HDP/MDP primarily binds to hydroxyapatite, we hypothesized that soft tissue accumulation would be found in patients with hyperphosphataemia. We identified 63 CKD patients diagnosed with secondary hyperparathyroidism admitted for Tc-99 m-HDP bone scan. Baseline characteristics and mean concentrations of biochemical markers (including P-calcium and P-phosphate) taken 0-3 months prior to the bone scans were collected. Soft tissue uptake was detected on bone scans in 37 of 63 (59%) patients. Primary locations were in the heart (27/37 = 73%), muscles (12/37 = 32%), lung (9/37 = 24%) and gastrointestinal tract (6/37 = 16%), and 13 of 37 (35%) patients had simultaneous uptake in more than one location. Regarding biochemical markers, patients with soft tissue uptake only differed from patients without in terms of plasma phosphate levels (1·95 ± 0·15 (n = 37) versus 1·27 ± 0·08 (n = 26), P = 0·0012). All patients with myocardial uptake (n = 27) had a coronary arteriography-verified history of coronary artery disease (CAD), whereas CAD was only present in six of the 36 patients without myocardial uptake. In conclusion, dialysis-treated CKD patients with secondary hyperparathyroidism have a high incidence of soft tissue uptake, and this finding is strongly correlated with elevated phosphate, but not calcium values.

Establishment and characterization of a rat model of hyperphosphatemia.

We established a rat model of hyperphosphatemia and investigated the systemic effects of high phosphorus (P). Sprague Dawley rats were randomly divided into high (HP), low (LP), and normal (NP) P groups (N = 12 each), which received injections of fructose diphosphate sodium, or were fed self-manufactured low phosphorus or normal diets, respectively. In each group, 4 rats were sacrificed at the first, third, and sixth week to detect the serum (Scr) and urinary creatinine and P, and calcium (Ca) levels. The HP group's serum P and intact parathyroid hormone (iPTH) were significantly higher than those in the other groups at the first, third, and sixth weeks, (P < 0.05); the LP group's serum P was lower than the NP group's at the third week (P < 0.05), while at the sixth week, the serum P and iPTH were lower (P < 0.05). No significant differences were detected for blood Ca+ (P > 0.05). The HP group's Scr increased (P < 0.01), whereas the fractional excretion decreased (P < 0.05) significantly. Thighbone and lumbar spine bone densities differed significantly between groups in the third week (P < 0.05); LP group densities were lower than NP group measures (P < 0.05). Crystallized stones were not observed microscopically following hematoxylin and eosin staining of the kidney. We successfully established a hyperphosphatemia rat model, and high blood P was found to significantly influence renal function and bone density. These results might provide a foundation to study the effects of hyperphosphatemia in rats.

Hyperphosphatasemia in an adult. Clinical, conventional roentgenographic, and CT findings.

A 47-year-old Saudi deaf lady with short stature presented being unable to walk. She had long standing diffuse skeletal deformities, and progressive head enlargement. She had markedly elevated serum alkaline phosphatase. The radiographic changes were those of hyperphosphatasemia, and the CT scanning of the skull, which was not studied before, further elicited the extensive calvarial and basilar changes. The various entities of hyperphosphatasemia with and without bony changes are reviewed.

Hyperphosphatemic tumoral calcinosis: a 10-year follow-up.

OBJECTIVE: To report a case of primary hyperphosphatemic tumoral calcinosis (TC) and its long-term 10-year follow-up. PATIENT: The patient was an 18-year-old male, who had been diagnosed with TC at the age of 8 years. In spite of nine surgeries for tumoral resection and medical treatments (i.e., aluminum hydroxide, non-steroidal anti-inflammatory agents) the lesions continued to progress. Physical examination showed calcified masses on shoulders, hip, elbows and right foot. PTH, calcitonin, 25(OH) vitamin D, 1,25(OH)2 vitamin D, renal and liver function, electrolytes, alkaline phosphatase, calcium and magnesium were normal. Serum phosphorus was elevated. FGF-23 (C-terminal): 1960 RU/mL (<180) Radiological and histological studies were compatible with TC. CONCLUSION: This long-term follow-up illustrates the morbidity and difficulty in treating these patients due to the progressive and recurrent nature of the calcified masses, for which there is no effective treatment as yet. The discovery of FGF-23 as the factor responsible for the hyperphosphatemic type of TC paves the way for forthcoming therapies.

Recurrent primary hyperphosphatemic tumoral calcinosis: a case report.

BACKGROUND: Tumoral calcinosis (TC) is a special form of idiopathic calcinosis that affects adolescents and young adults. It is characterized by extensive nonosseous calcification, especially in the periarticular soft tissue regions of major joints. CASE: A young girl presented with recurrent subcutaneous swellings over both infrascapular regions and left hip. The patient had elevated serum phosphorus levels while the serum calcium levels were normal. The clinical and radiologic features were suggestive of TC, and the same was confirmed by cytologic and histopathologic study. Positive von-Kossa stain further confirmed that the deposits were of calcium and thus the diagnosis of TC. CONCLUSION: TC is a disorder of obscure etiology with typical clinical, radiologic, cytologic and histopathologic features.

Familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are different manifestations of the same disease: novel missense mutations in GALNT3.

OBJECTIVE: To report on the biochemistry and clinical and genetic findings of two siblings, the younger sister presenting with recurrent bone pain of the radius and ulna, and medullary sclerosis, and the older brother with soft tissue calcific deposits (tumoral calcinosis) but who later developed bone pain. Both were found to be hyperphosphaturic. MATERIALS AND METHODS: The index family comprised four individuals (father, mother, brother, sister). The affected siblings were the offspring of a non-consanguineous Indian family of Tamil origin. Bidirectional sequencing was performed on the DNA from the index family and on 160 alleles from a population of 80 unrelated unaffected control individuals of Tamil extraction and 72 alleles from individuals of non-Tamil origin. RESULTS: Two symptomatic siblings were found to harbour previously unreported compound heterozygous missense UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3) mutations in exon 4 c.842A>G and exon 5 c.1097T>G. This sequence variation was not detected in the control DNA. This is the first report of siblings exhibiting stigmata of familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome with documented evidence of autosomal recessive missense GALNT3 mutations. CONCLUSION: The findings from this family add further evidence to the literature that familial tumoral calcinosis and hyperostosis-hyperphosphataemia syndrome are manifestations of the same disease and highlight the importance of appropriate metabolic and genetic investigations.

Hyperostosis and hyperphosphataemia syndrome: a diagnostic dilemma.

The syndrome of hyperostosis and hyperphosphataemia (HHS) is very rare. It can mimic bone infections and tumours. A nine-year-old girl presented with pain in her left lower leg. Radiographs showed patchy sclerosis in the tibial diaphysis. Investigations were normal except for hyperphosphataemia. Open biopsy showed chronic inflammation. Bacterial cultures were negative. Four months later, she had pain in the other leg. On evaluation for hyperphosphataemia, there was increased renal reabsorption of phosphates. She responded to analgesics. In patients between six and 16 years of age, HHS must be considered when there is painful diaphyseal swelling of long bones associated with isolated hyperphosphataemia. The painful episodes can recur. Surgical decompression can be considered if conservative treatment methods are ineffective.