Phosphate Wasting Research Articles

New Developments in the Treatment of X-Linked Hypophosphataemia: Implications for Clinical Management.

X-linked hypophosphataemia (XLH) is due to mutations in phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and represents the most common heritable form of rickets. In this condition, the hormone fibroblast growth factor 23 (FGF23) is produced in excessive amounts for still unknown reasons, and causes renal phosphate wasting and suppression of 1,25-dihydroxyvitamin D, leading to low serum phosphate concentrations. Prolonged hypophosphataemia decreases apoptosis of hypertrophic chondrocytes in growth plates (causing rickets) and decreases mineralisation of existing bone (causing osteomalacia). In contrast to historical conventional treatment with oral phosphate supplements and active vitamin D for the last 50 years, the new anti-FGF23 antibody treatment (burosumab) targets the primary pathology by blocking FGF23, thereby restoring phosphate homeostasis. In this review, we describe the changes in treatment monitoring, treatment targets and long-term treatment goals, including future opportunities and challenges in the treatment of XLH in children.

Evaluation of Potential Native Phosphate Solubilizing Bacteria for the Agriculture Practice of okra (Abelmoschus Esculentus) with the Target to Replace Chemical Fertilizer - in a Field Study

Phosphorus (P) is a major growth limiting nutrient. Phosphate Solubilizing Bacteria (PSB) plays an important role in the development of agricultural industry. In this study, the native PSB were isolated from the okra plant root by using Pikovskaya’s medium and potential strains were selected based on the phosphate solubilization efficiency. The potential strains in presence of Rock Phosphate (RP), Tea dust, Eggshells and Bone waste of animal (TEB) were studied as an alternative fertilizer instead of chemical fertilizer. The PSB consortia strains were prepared and inoculated to the plant root. Different growth parameters were studied to determine the effectiveness of strains. In all cases the difference was significant with p<0.05. A decreasing trend of results were recorded among the tested parameters from plants in PSB with RP, PSB with TEB, and PSB with TSP and followed by PSB without fertilizer. The highest results were recorded among plants in PSB with RP for mean shoot length (64cm), mean weight of fruits (29gm), mean length of fruits (23cm), mean number of leaves (13Nos) and chlorophyll content (5.1mg/g). Hence, the present study showed that the application of PSB with the cheap source of nutrients has shown the capability of providing similar or enhanced results based on the various characters expressed by the plant and thus reduce the reliance on synthetic chemical fertilizers.

Gulf X-linked hypophosphatemia preceptorship: July 4–6, 2019, Bicêtre Paris sud hospital, Paris, France

X-linked hypophosphatemia (XLH) is an inherited disorder characterized by low levels of phosphate in the blood. Phosphate levels are low because phosphate is abnormally processed in the kidneys, which causes urinary phosphate wasting and leads to rickets in the young patients and osteomalacia in adults in addition to several other complications thereof. A 3-day conference was hosted by the Rare Diseases Unit of the Bicetre Paris Sud Hospital on July 4–6, 2019. Presentations covered the subject in a comprehensive manner spanning physiology, clinical presentations, disease burden, and the latest in the management of the XLH and its musculoskeletal, neurosurgical, obstetric, and other complications in both children and adults. Several illustrative and challenging cases were presented and discussed. The authors attended the event and would like to present a personal perspective to highlight the proceeding of the conference to extend the benefit to others who did not attend it.

Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency.

ABSTRACTBiallelic ENPP1 deficiency in humans induces generalized arterial calcification of infancy (GACI) and/or autosomal recessive hypophosphatemic rickets type 2 (ARHR2). The latter is characterized by markedly increased circulating FGF23 levels and renal phosphate wasting, but aberrant skeletal manifestations associated with heterozygous ENPP1 deficiency are unknown. Here, we report three adult men with early onset osteoporosis who presented with fractures in the thoracic spine and/or left radius, mildly elevated circulating FGF23, and hypophosphatemia. Total hip bone mineral density scans demonstrated osteoporosis (Z‐score < −2.5) and HRpQCT demonstrated microarchitectural defects in trabecular and cortical bone. Next‐generation sequencing revealed heterozygous loss‐of‐function mutations in ENPP1 previously observed as biallelic mutations in infants with GACI. In addition, we present bone mass and structure data as well as plasma pyrophosphate (PPi) data of two siblings suffering from ARHR2 in comparison to their heterozygous and wild‐type family members indicative of an ENPP1 gene dose effect. The skeletal phenotype in murine Enpp1 deficiency yielded nearly identical findings. Ten‐week‐old male Enpp1 asj/asj mice exhibited mild elevations in plasma FGF23 and hypophosphatemia, and micro‐CT analysis revealed microarchitectural defects in trabecular and cortical bone of similar magnitude to HRpQCT defects observed in humans. Histomorphometry revealed mild osteomalacia and osteopenia at both 10 and 23 weeks. The biomechanical relevance of these findings was demonstrated by increased bone fragility and ductility in Enpp1 asj/asj mice. In summary, ENPP1 exerts a gene dose effect such that humans with heterozygous ENPP1 deficiency exhibit intermediate levels of plasma analytes associated with bone mineralization disturbance resulting in early onset osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

PRO132 DISEASE BURDEN OF X-LINKED HYPOPHOSPHATEMIA

X-linked hypophosphatemia (XLH) is a rare genetic disease, serious, debilitating and deforming condition, characterized by renal phosphate wasting. XLH is caused by loss of function of the PHEX gene resulting in enhanced secretion of the phosphaturic hormone FGF23 and leading defective bone mineralization, leading to rickets and impaired physical function.This disease, which affects 1:20.000 people, results in impaired quality of life (QoL) of patients, since, despite the treatments, suffer progressive and debilitating complications. The main objective of the study was to determine QoL of patients, children and adults suffering XLH, as well as their caregivers. A multicentre, observational and cross-sectional study has been carried out by a scientific committee consisted of 17 health professionals experts in XLH. QoL was assessed with the following EuroQol-5 Dimensions (EQ-5D) questionnaires: the EQ-5D-3L proxy (completed by caregivers or parents of children under 12 years), the EQ-5D-3L (completed by patients aged between 12 and 18 years), and the EQ-5D-5L (completed by adult patients and caregivers). The total number of participants for this project was 50 patients, 21 children and 29 adults, and their corresponding caregivers. Children had mobility problems due to difficulties walking, moderate pain or discomfort, problems doing their daily activities and felt anxious or depressed. In addition, children showed problems washing or dressing themselves. Similarly, a high percentage of adults were unable to walk, suffered extreme pain, showed difficulties to carry out their daily activities, and reported anxiety and depression. Moreover, the results of QoL for caregivers and parents were slightly lower than the general Spanish population. In conclusion, both children and adults, showed an important deterioration in QoL that were worse than the general Spanish population. These findings suggest the need for new treatments, as in many cases, the conventional treatment does not prevent disease complications and the impairment of QoL.

STEM education program: manufacturing mixture of phosphate and potash fertilizer straws and waste of animal bones

STEM educational orientation program is one interdisciplinary approaching way during study which consists of academic terms with principle characteristics combines with lectures in real life. Joining in STEM educational orientation program, students will have practical experience, thus they have opportunities to develop their capabilities including ability to apply knowledge and skills (AAK&S), help students to improve study skills and methods such as planning, analyzing, summarizing information, suggest creative solutions; encourage motivation, benefits and study activities. Based on the foundation of utilizing STEM educational orientation program in teaching, it can be a direction to develop student’s capabilities. In this study, the author instructed students to research “Manufacturing mixture of phosphate and potash fertilizer from straws and waste of animal bones” following STEM educational orientation program in improving abilities and applying Chemistry knowledge to life for the student. The result shows STEM system could handle the theoretical weight situation, help students shape and develop core competencies, specialized Chemistry and especially, the ability to apply knowledge and skills in a systematic and solid manner.

Effectiveness of Monitored Natural Attenuation (MNA) as a Groundwater Remedy for Arsenic in Phosphatic Wastes

AbstractA study was conducted to evaluate monitored natural attenuation (MNA) as a remedy for arsenic in groundwater at a former phosphate mining and manufacturing facility. The mineralogy, speciation, and lability of arsenic in phosphatic wastes present in soils were characterized using sequential extraction procedures, leaching experiments, batch adsorption tests, and microchemical speciation analysis. A PHREEQC‐based reactive transport model was also parameterized using these laboratory results, and it was used to evaluate the importance of identified attenuation mechanisms on arsenic concentrations along a vertical flow path from a shallow, alluvial aquifer to the underlying Floridan aquifer. Arsenic was found to occur in several chemical forms in phosphatic wastes, including unstable sulfide minerals, adsorbed surface complexes, and relatively insoluble phosphate and oxide minerals. Most arsenic was associated with stable minerals. The reactive transport model predicted that historical leaching of solid‐phase waste materials in soils would not have generated enough arsenic to explain the concentrations observed in downgradient groundwater; instead, the source of arsenic to groundwater was likely acidic and saline process water that infiltrated though unlined ponds and ditches during historical manufacturing operations. A key factor affecting the long‐term effectiveness of natural attenuation of arsenic in groundwater is the occurrence and stability of iron oxyhydroxides in aquifer sediments. According to laboratory and reactive transport model results, sufficient levels were found to be present at the site to effectively limit arsenic migration at concentrations exceeding drinking water standards in the future in the Floridan aquifer. This study presents the geochemical evaluations that are needed to satisfy EPA guidelines on determining whether or not MNA is an acceptable remedy for a site. It specifically details the characterization and modeling that were used to demonstrate effectiveness at a site where MNA was ultimately selected as the remedy for arsenic in groundwater.

Eldecalcitol causes FGF23 resistance for Pi reabsorption and improves rachitic bone phenotypes in the male Hyp mouse

X-linked hypophosphatemia (XLH), the most common form of inheritable rickets, is caused by inactivation of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) and leads to fibroblast growth factor (FGF) 23-dependent renal inorganic phosphate (Pi) wasting. In the present study, we investigated whether maintaining Pi homeostasis with a potent vitamin D3 analog, eldecalcitol [1α,25-dihydroxy-2β-(3-hydroxypropyloxy) vitamin D3; ED71], could improve hypophosphatemic rickets in a murine model of XLH, the Hyp mouse. Vehicle, ED71, or 1,25-dihydroxyvitamin D was subcutaneously injected five times weekly in wild-type (WT) and Hyp mice for 4 weeks, from 4 to 8 weeks of age. Injection of ED71 into WT mice suppressed the synthesis of renal 1,25-dihydroxyvitamin D and promoted phosphaturic activity. In contrast, administration of ED71 to Hyp mice completely restored renal Pi transport and NaPi-2a protein levels, although the plasma-intact FGF23 levels were further increased. In addition, ED71 markedly increased the levels of the scaffold proteins, renal sodium-hydrogen exchanger regulatory factor 1, and ezrin in the Hyp mouse kidney. Treatment with ED71 increased the body weight and improved hypophosphatemia, the bone volume/total volume, bone mineral content, and growth plate structure in Hyp mice. Thus, ED71 causes FGF23 resistance for phosphate reabsorption and improves rachitic bone phenotypes in Hyp mice. In conclusion, ED71 has opposite effects on phosphate homeostasis in WT and Hyp mice. Analysis of Hyp mice treated with ED71 could result in an additional model for elucidating PHEX abnormalities.

New advance in hypophosphatemic rickets

Hypophosphatemic rickets(HR) is a bone mineralization disorder caused by phosphate wasting, including hypophosphatemia, bone abnormalities and short stature.X-linked hypophosphatemia(XLH) is the most common inherited disease related to phosphate metabolism, which might result in elevated levels of fibroblast growth factor 23 (FGF23). FGF23 plays an important role in the disease mechanism, so a human anti-FGF23 antibody is developed as a potential treatment for XLH.In many clinical trials, subcutaneous Burosumab increased serum phosphorus levels in pediatric and adult patients with XLH.With the development of phase 1-3 clinical trials of Burosumab in children and adults with XLH, the efficacy and safety of Burosumab is proven to be superior to that of phosphate and calcitriol used in traditional therapy.This review aims to investigate the physiopathology and treatment of HR and to enhance the recognition of HR. Key words: Rickets; Hypophosphatemia; Fibroblast growth factor 23; Osteomalacia; 1, 25(OH)2D

Symptomatic hypophosphataemia after intravenous iron therapy: an underrated adverse reaction

SummaryIron (ferric carboxymaltose) infusion therapy is used to treat severe iron deficiency which is not responding to the first-line oral iron therapy. However, it can also cause severe renal wasting of phosphate resulting in severe hypophosphataemia in some patients. Despite the growing number of case reports, this side effect is not well known to healthcare professionals. The product labelling information sheet does mention that hypophosphataemia can be a side effect, but also says that this side effect is usually transient and asymptomatic. We report a challenging case of a patient who developed severe, symptomatic and prolonged hypophosphataemia after an intravenous iron infusion for severe iron deficiency.Learning points:Clinicians prescribing ferric carboxymaltose (Ferinject®) should be aware of the common side effect of hypophosphataemia, which could be mild, moderate or severe.Patients receiving iron infusion should be educated concerning this potential side effect.Pre-existing vitamin D deficiency, low calcium levels, low phosphate levels or raised parathyroid hormone levels may be risk factors, and these should be evaluated and corrected before administering intravenous iron.Patients may require phosphate and vitamin D replacement along with monitoring for a long period after iron infusion-induced hypophosphataemia.Every incident should be reported to the designated body so that the true prevalence and management thereof can be ascertained.

Functional analysis of a de novo mutation c.1692 del A of the PHEX gene in a Chinese family with X-linked hypophosphataemic rickets.

ObjectivesX-linked hypophosphataemic rickets (XLHR) is a disease of impaired bone mineralization characterized by hypophosphataemia caused by renal phosphate wasting. The main clinical manifestations of the disorder are O-shaped legs, X-shaped legs, delayed growth, and bone pain. XLHR is the most common inheritable form of rickets, with an incidence of 1/20 000 in humans. It accounts for approximately 80% of familial cases of hypophosphataemia and serves as the prototype of defective tubular phosphate (PO43+) transport, due to extra renal defects resulting in unregulated FGF23 activity. XLHR is caused by loss-of-function mutations in the PHEX gene. The aim of this research was to identify the genetic defect responsible for familial hypophosphataemic rickets in a four-generation Chinese Han pedigree and to analyze the function of this mutation.MethodsThe genome DNA samples of all members in the pedigree were extracted from whole blood. We sequenced all exons of the PHEX and FGF23 genes, as well as the adjacent splice site sequence with Sanger sequencing. Next, we analyzed the de novo mutation c.1692 del A of the PHEX gene with an online digital service and investigated the mutant PHEX with SWISS-MODEL, immunofluorescence, and protein stability detection.ResultsThrough Sanger sequencing, we found a de novo mutation, c.1692 del A, in exon 16 of the PHEX gene in this pedigree. This mutation can make the PHEX protein become unstable and decay rapidly, which results in familial XLHR.ConclusionWe have found a de novo loss-of-function mutation, c.1692 del A, in exon 16 of the PHEX gene that can cause XLHR.Cite this article: J. Huang, X. Bao, W. Xia, L. Zhu, J. Zhang, J. Ma, N. Jiang, J. Yang, Q. Chen, T. Jing, J. Liu, D. Ma, G. Xu. Functional analysis of a de novo mutation c.1692 del A of the PHEX gene in a Chinese family with X-linked hypophosphataemic rickets. Bone Joint Res 2019;8:405–413. DOI: 10.1302/2046-3758.88.BJR-2018-0276.R1.

1,25-Dihydroxyvitamin D Maintains Brush Border Membrane NaPi2a and Attenuates Phosphaturia in Hyp Mice.

Phosphate homeostasis is critical for many cellular processes and is tightly regulated. The sodium-dependent phosphate cotransporter, NaPi2a, is the major regulator of urinary phosphate reabsorption in the renal proximal tubule. Its activity is dependent upon its brush border localization that is regulated by fibroblast growth factor 23 (FGF23) and PTH. High levels of FGF23, as are seen in the Hyp mouse model of human X-linked hypophosphatemia, lead to renal phosphate wasting. Long-term treatment of Hyp mice with 1,25-dihydroxyvitamin D (1,25D) or 1,25D analogues has been shown to improve renal phosphate wasting in the setting of increased FGF23 mRNA expression. Studies were undertaken to define the cellular and molecular basis for this apparent FGF23 resistance. 1,25D increased FGF23 protein levels in the cortical bone and circulation of Hyp mice but did not impair FGF23 cleavage. 1,25D attenuated urinary phosphate wasting as early as one hour postadministration, without suppressing FGF23 receptor/coreceptor expression. Although 1,25D treatment induced expression of early growth response 1, an early FGF23 responsive gene required for its phosphaturic effects, it paradoxically enhanced renal phosphate reabsorption and NaPi2a protein expression in renal brush border membranes (BBMs) within one hour. The Na-H+ exchange regulatory factor 1 (NHERF1) is a scaffolding protein thought to anchor NaPi2a to the BBM. Although 1,25D did not alter NHERF1 protein levels acutely, it enhanced NHERF1-NaPi2a interactions in Hyp mice. 1,25D also prevented the decrease in NHERF1/NaPi2a interactions in PTH-treated wild-type mice. Thus, these investigations identify a novel role for 1,25D in the hormonal regulation of renal phosphate handling.

Burosumab Therapy for X-Linked Hypophosphatemia and Therapeutic Implications for CKD.

X-linked hypophosphatemia (XLH) is the most common heritable cause of hypophosphatemic rickets, and it is characterized by hypophosphatemia due to kidney phosphate wasting, deficiency of 1,25-dihydroxyvitamin D [1,25(OH)2D], rickets, and osteomalacia ([1][1]). Clinical features manifest as early as

Continued Beneficial Effects of Burosumab in Adults with X-Linked Hypophosphatemia: Results from a 24-Week Treatment Continuation Period After a 24-Week Double-Blind Placebo-Controlled Period

Burosumab, a fully human monoclonal antibody to FGF23, is the only approved treatment for X-linked hypophosphatemia (XLH), a rare genetic disorder characterized by renal phosphate wasting and substantial cumulative musculoskeletal morbidity. During an initial 24-week randomized, controlled trial, 134 adults with XLH received burosumab 1 mg/kg (n = 68) or placebo (n = 66) every 4 weeks. After 24 weeks, all subjects received open-label burosumab until week 48. This report describes the efficacy and safety of burosumab during the open-label treatment period. From weeks 24–48, serum phosphorus concentrations remained normal in 83.8% of participants who received burosumab throughout and were normalized in 89.4% who received burosumab after placebo. By week 48, 63.1% of baseline fractures/pseudofractures healed fully with burosumab, compared with 35.2% with burosumab after placebo. In both groups, burosumab was associated with clinically significant and sustained improvement from baseline to week 48 in scores for patient-reported outcomes of stiffness, pain, physical function, and total distance walked in 6 min. Rates of adverse events were similar for burosumab and placebo. There were no fatal adverse events or treatment-related serious adverse events. Nephrocalcinosis scores did not change from baseline by more than one grade at either week 24 or 48. These data demonstrate that in participants with XLH, continued treatment with burosumab is well tolerated and leads to sustained correction of serum phosphorus levels, continued healing of fractures and pseudofractures, and sustained improvement in key musculoskeletal impairments.

The Effect of Replacing Fine Silica with Fine Phosphate Waste (Russaifa mine) on the Compressive Strength of Mortar and Concrete: A Case Study in Jordan

It is known that the dumping of Phosphate wastes from Phosphate factories and mines has a negative effect on the environment. In an effort to reduce dumping, this study examines the possible reuse of this waste as a replacement for the fine sand of silica in mortar and concrete. Phosphate waste replaces silica with the following by-weight percentages: 0%, 10%, 25%, 50% and 100%. To check the feasibility of such reuse, 30 mortar cubes, 30 concrete cubes, and 20 concrete cylinders were prepared for testing to achieve a compressive strength of 25 MPa according to ASTM (211.1-81). The tests performed in this paper are conducted to the following samples: (50 * 50 * 50 mm) mortar samples, (150 * 150 * 150 mm) concrete cubes, and (150 * 300 mm) concrete cylinders. The samples were left in curing for a period of 7 days for some samples, and others for 28 days. The results show that the use of Phosphate wastes increased the compressive strength of mortar by 29%. In concrete cubes, the use of Phosphate wastes increased compressive strength by 26%. In concrete cylinders, the use of Phosphate wastes increased the compressive strength by 34%. Subsequently, it is proposed that the stone squanders of Phosphate be utilized as an alternative to fine silica, and they demonstrated their quality through the basic tests of aggregate. The increase in stone strength is attributed to Phosphate waste as it has less absorption. The increase in the strength of Phosphate sand is due to the presence of chemical substances that increase the strength of its cohesion, such as TCP (Tricalcium Phosphate) (40.72%), P2O5 (Phosphate pentoxide) (18.64%), CaO (Calcium oxide) (28.22%) and SiO2 (Silicon dioxide) (44.45%). The percentage of CL (Chlorine) is minimal (0.01%).

Does FGF23 Inhibition Improve Outcomes in X-Linked Hypophosphatemic Rickets?

X-linked hypophosphatemia is the most common genetic cause of rickets and is associated with profound renal phosphate wasting, growth failure, and

Clinical and metabolic features in childhood hypophosphatemic rickets

Background: Hypophosphatemic rickets is a rare disease, related to renal phosphate waste, which cause bone deformities, and lead to walking abnormalities and to the reduction in the quality of life. Clinical recommendations in different countries vary in medications, recommended doses and surgery approach. The main aim was to analyze phosphate metabolism in children with hypophosphatemic rickets and to evaluate results of conservative and surgical therapy. Methods: We analyzed medical histories of 15 children with hypophosphatemic rickets and investigated phosphate metabolism, including the measurement of serum intact fibroblast growth factor 23 and X-ray bone densitometry. Routine biochemical tests were assessed with our laboratory reference data, the level of iFGF-23 in hypophosphatemic children was compared with the same values in 18 healthy children. Results: We investigated 15 girls with hypophosphatemic rickets, aged of from 3 years 9 months to 18 years 7 months. All children were treated with alphacalcidol and inorganic phosphate (in dose from 16.21 to 103.3 mg/kg, during from 1 to 114 months). Eleven (73%) children had surgical correction of bone deformations, starting at the age of from 3 to 12 years. Ten (91%) of them had the relapse of bone deformations. Two of four children undergone to the correction of bone abnormalities on alphacalcidol and phosphate therapy without surgery. The level of iFGF-23 in children with hypophosphatemic rickets was 73.11 pg/ml, and exceed iFGF-23 in control group (22.92 pg/ml), p =0,009. Conclusion: Early surgical treatment of bone deformations is not indicated in hypophosphatemic rickets because of risk of recurrence, observed in 91% of our patients. There could be spontaneous correction of bone deformation during conservative therapy, when it is started early.

Valorization of Phosphate Mine Waste Rocks as Materials for Road Construction

The road construction sector is a worldwide high consumer of natural aggregates. The use of unusual industrial by-products in road techniques can contribute to the conservation of non-renewable natural resources and the reduction of wastes produced by some industries. Phosphate waste rocks could be considered as potential alternative secondary raw materials in road construction. The use and valorization of these wastes is currently limited according to the Moroccan guide for road earthworks (GMTR). The guide has classified these materials as waste products, which consequently, cannot be used in road construction. However, phosphate waste rocks are sedimentary natural rocks which have not been subjected to any transformation other than mechanical fragmentation. The goal of this paper is to discuss key-properties of various phosphate mine waste rocks (PMWR) to be used as road materials. Samples were taken from different stockpiles in the phosphate mine site of Gantour in Morocco. The different waste rocks samples were characterized in terms of their physical, geotechnical, chemical, mineralogical and environmental properties using international testing norms. The obtained results showed that the studied PMWR presented satisfying characteristics; the specific (particle) density: ρs &gt; 26 kN/m3, Los Angeles abrasion: 45% &lt; LA &lt; 58%), methylene blue value MBV &lt; 1 g/100g, organic matter: OM &lt; 1% and plasticity index: PI &lt; 20%. All PMWR were confirmed as possessing the requested geotechnical properties to be used as materials for embankments. Moreover, leaching tests showed that none of them released any contaminants. In field application, these materials have been also successfully used in in situ experimental pilot testing. Therefore, the PMWR have to be classified in the category of natural aggregates that are similar to conventional materials.

MON-340 Concomitant TIO and SIADH in a Patient with Neuroendocrine Tumor

83 year old male patient with remote history of bladder cancer post TURBT, who presented with generalized weakness, poor appetite, and decreased PO intake of one week duration. He was found to have hyponatremia with Na level of 120mmol/L. IV hydration failed to correct his sodium levels. Persistent hyponatremia in the setting of euvolemia and inappropriately elevated urine sodium was suggestive of SIADH (serum Na 126 mmol/l, urine Na 79mmol/l). Lab work was also significant for hypocalcemia (7.4 mg/dl corrected for albumin) and hypophosphatemia (0.9-1.3 mg/dl). PTH was 48.3pg/ml which was inappropriately normal in the setting of hypocalcemia. 25(OH) vitamin D and 1,25(OH)2 Vitamin D levels were measured and were 41 ng/ml and 19.5 pg/ml (19.9-79.3 pg/ml) respectively. Patient was started on calcium and vitamin D replacement. Hypophosphatemia was treated with potassium phosphate supplementation (up to 2 grams a day) with persistently low levels (1.4 mg/dl). 24 hour urine collection was performed and showed urine calcium excretion of 200 mg/24 hrs with a concomitant serum calcium level of 8.2 mg/dl and urine Phosphorus excretion of 684 mg/24hrs with a concomitant serum phosphorus of 1.3 mg/dl (Patient excreted 0.72 g creatinine in 24 hrs which was slightly low). These results were consistent with renal phosphate wasting. The combination of hypocalcemia, hypophosphatemia, renal phosphate wasting along with normal PTH levels is consistent with Oncogenic Osteomalacia. CT scan of the chest abdomen pelvis showed a large mediastinal mass suggestive of primary malignancy in addition to multiple lesions in the liver and adrenal and axillary lymphadenopathy. Liver biopsy was positive for poorly differentiated Neuroendocrine Carcinoma with small cell features. FGF23 level was elevated to 242 RU/ml (Ref range < or = 180 RU/ml) consistent with TIO. Phosphorus level corrected after initiating chemotherapy, as well as 1,25(OH)2 VitD which increased to 51.7 pg/ml. Serum sodium and calcium also normalized. FGF23 was checked again after completing 2 sessions of therapy and was down to 89 RU/ml. Discussion: We report a case of combined TIO and SIADH in the setting of neuroendocrine mediastinal tumor with small cell features. The patient demonstrated hypophosphatemia, hypocalcemia, and hyponatremia due to elevated FGF-23, decreased hydroxylation of 25 OH vitamin D, and inappropriate ADH secretion. All these findings corrected with chemotherapy.

MON-501 A Hemangioma Causing Tumor Induced Osteomalacia

Introduction: TIO (Tumor induced osteomalcia) is a rare paraneoplastic syndrome due to ectopic production of FGF23 (Fibroblast growth factor 23) from a mesenchymal tumor that results in renal phosphate wasting and impaired calcitriol synthesis. We present a case of TIO from a benign hemangioma which is an uncommon occurrence. Clinical case: A 68-year-old female presented with a history of multiple fractures; right pelvic fracture 8 years ago, bilateral pubic rami fractures 3 months ago, left femoral neck fracture and left humeral shaft fracture 1 month ago due to trivial traumas. She also complained of chronic generalized muscle pain and severe fatigue that essentially made her bedbound. Her past medical history was significant for DM type II, hypertension, hyperlipidemia, osteoarthritis and chronic anemia. She was diagnosed with a right inferior parathyroid adenoma after noting high PTH of 281pg/ml [15-65] and increased uptake on a parathyroid scan. Following a right inferior parathyroidectomy, the PTH was 51pg/ml [15-65]. Current workup: Vitamin D 7.4pg/ml [30-80], Calcium 7.0mg/dl [8.6-10.2] (corrected calcium 8.0mg/dl), Phosphorous 1.4mg/dl [2.7-4.5], Magnesium 1.6mg/dl [1.7-2.6], Alkaline phosphatase 222U/l [35-104] , Creatinine 0.6mg/dl [0.5-1.2], PTH 214.4pg/ml [15-65] and normal transaminases. Whole body bone scan showed increased uptake in multiple foci in the bilateral ribs, sternum, both shoulders and left humerus. About 2 weeks following vitamin D and calcium supplementation, serum calcium normalized, vitamin D improved to 15pg/ml [30-80] and PTH trended down to normal limits at 52.4pg/ml [15-65]. But the phosphorous level was never >1.6mg/dl [2.7-4.5] despite vigorous IV and oral replacement. This raised concern for hypophosphatemic osteomalacia. Incidentally, as workup for back pain and acute on chronic anemia, a CT abdomen was done which showed a heterogeneously enhancing right pelvic mass measuring up to 7.5 cm extending into the spinal canal from approximately L4-5 level into the upper sacrum. MRI confirmed the presacral mass. A CT guided biopsy was done and final pathology reported hemangioma by STAT6 immunostain. 1,25 (OH)2 Vitamin D was 24 pg/ml [18-78] and an FGF23 level was very high at 3980 RU/mL [<=180] confirming our diagnosis of TIO. Although surgery would have been curative in TIO, this patient was tired of surgeries and decided to go with medical management. Calcitriol 0.25mcg bid, K-Phos Neutral 1 tablet four times a day at equal intervals throughout the awake hours was recommended. Conclusion: TIO is a rare disorder that is usually caused by benign mesenchymal tumors. Although rare, hemangiomas can cause TIO.