scholarly journals Diagnosis and Management of Tumor-Induced Osteomalacia: Perspectives from Clinical Experience

2021 ◽  
Author(s):  
Kathryn Dahir ◽  
María Belén Zanchetta ◽  
Irinel Stanciu ◽  
Cemre Robinson ◽  
Janet Y Lee ◽  
...  
Keyword(s):  
Fibroblast Growth Factor 23 ◽  
Delayed Diagnosis ◽  
Medical Community ◽  
Endocrine Tumors ◽  
Multiple Fractures ◽  
Laboratory Assessment ◽  
Vitamin D Metabolism ◽  
Treatment Pathways ◽  
Dihydroxyvitamin D ◽  
Anatomical Imaging

Abstract Purpose Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of abnormal phosphate and vitamin D metabolism caused by typically small endocrine tumors that secrete fibroblast growth factor 23 (FGF23). TIO is characterized clinically by progressive musculoskeletal pain, fatigue, proximal muscle weakness, and multiple fractures, leading to long-term disability. Misdiagnosis and delayed diagnosis are common because of the non-specific symptoms, and several years may elapse before patients receive an accurate diagnosis and appropriate treatment. Thus, it is vital that awareness of the appropriate recognition and management of TIO is increased among healthcare professionals who may encounter patients with suspected TIO. Methods A roundtable meeting was held on 10 January 2020 in Dallas, TX, USA to gather perspectives on the diagnosis and treatment of TIO. The following topics were considered: clinical presentation, patient history, differential diagnosis, laboratory assessment, imaging, venous sampling, and treatment. Results This report provides a summary of our collective experiences in the management of TIO. Main conclusions Laboratory tests are mandatory to expedite TIO diagnosis and should include measurement of fasting serum phosphorus, renal phosphate reabsorption, serum 1,25-dihydroxyvitamin D, and serum FGF23 levels. Functional and anatomical imaging are essential to locate the FGF23-secreting tumor(s) causing TIO. Surgical resection is often a curative treatment when the tumor can be localized; however, better management of non-operable patients with targeted therapies is needed. Further efforts to increase awareness of TIO within the medical community, and education on recommended diagnostic and treatment pathways are required to improve the management of this debilitating disease.

scholarly journals Dietary and Serum Phosphorus Regulate Fibroblast Growth Factor 23 Expression and 1,25-Dihydroxyvitamin D Metabolism in Mice

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5358-5364 ◽  
Author(s):  
Farzana Perwad ◽  
Nasreen Azam ◽  
Martin Y. H. Zhang ◽  
Takeyoshi Yamashita ◽  
Harriet S. Tenenhouse ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Fold Increase ◽  
Mrna Abundance ◽  
Fibroblast Growth ◽  
Calvarial Bone ◽  
Vitamin D Metabolism ◽  
Dihydroxyvitamin D ◽  
Fgf 23

Fibroblast growth factor-23 (FGF-23) is a novel circulating peptide that regulates phosphorus (Pi) and vitamin D metabolism, but the mechanisms by which circulating FGF-23 itself is regulated are unknown. To determine whether the serum FGF-23 concentration is regulated by dietary intake of Pi, we fed wild-type (WT), Npt2a gene-ablated (Npt2a−/−), and Hyp mice diets containing varying Pi contents (0.02–1.65%). In WT mice, increases in dietary Pi intake from 0.02–1.65% induced a 7-fold increase in serum FGF-23 and a 3-fold increase in serum Pi concentrations. Across the range of dietary Pi, serum FGF-23 concentrations varied directly with serum Pi concentrations (r2 = 0.72; P < 0.001). In Npt2a−/− mice, serum FGF-23 concentrations were significantly lower than in WT mice, and these differences could be accounted for by the lower serum Pi levels in Npt2a−/− mice. The serum concentrations of FGF-23 in Hyp mice were 5- to 25-fold higher than values in WT mice, and the values varied with dietary Pi intake. Fgf-23 mRNA abundance in calvaria was significantly higher in Hyp mice than in WT mice on the 1% Pi diet; in both groups of mice, fgf-23 mRNA abundance in calvarial bone was suppressed by 85% on the low (0.02%) Pi diet. In WT mice fed the low (0.02%) Pi diet, renal mitochondrial 1α-hydroxylase activity and renal 1α-hydroxylase (P450c1α) mRNA abundance were significantly higher than in mice fed the higher Pi diets and varied inversely with serum FGF-23 concentrations (r2 = 0.86 and r2 = 0.64; P < 0.001, respectively). The present data demonstrate that dietary Pi regulates the serum FGF-23 concentration in mice, and such regulation is independent of phex function. The data suggest that genotype-dependent and dietary Pi-induced changes in the serum FGF-23 concentration reflect changes in fgf-23 gene expression in bone.

scholarly journals Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniela Egli-Spichtig ◽  
Martin Y. H. Zhang ◽  
Alfred Li ◽  
Eva Maria Pastor Arroyo ◽  
Nati Hernando ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Actin Polymerization ◽  
Fibroblast Growth Factor 23 ◽  
Wild Type ◽  
Vitamin D Metabolism ◽  
Endocrine Hormone ◽  
Dnase 1 ◽  
Sodium Dependent ◽  
Renal Tubular ◽  
High Phosphate

AbstractFibroblast growth factor 23 (FGF23) is a bone-derived endocrine hormone that regulates phosphate and vitamin D metabolism. In models of FGF23 excess, renal deoxyribonuclease 1 (Dnase1) mRNA expression is downregulated. Dnase-1 is an endonuclease which binds monomeric actin. We investigated whether FGF23 suppresses renal Dnase-1 expression to facilitate endocytic retrieval of renal sodium dependent phosphate co-transporters (NaPi-IIa/c) from the brush border membrane by promoting actin polymerization. We showed that wild type mice on low phosphate diet and Fgf23−/− mice with hyperphosphatemia have increased renal Dnase1 mRNA expression while in Hyp mice with FGF23 excess and hypophosphatemia, Dnase1 mRNA expression is decreased. Administration of FGF23 in wild type and Fgf23−/− mice lowered Dnase1 expression. Taken together, our data shows that Dnase1 is regulated by FGF23. In 6-week-old Dnase1−/− mice, plasma phosphate and renal NaPi-IIa protein were significantly lower compared to wild-type mice. However, these changes were transient, normalized by 12 weeks of age and had no impact on bone morphology. Adaptation to low and high phosphate diet were similar in Dnase1−/− and Dnase1+/+ mice, and loss of Dnase1 gene expression did not rescue hyperphosphatemia in Fgf23−/− mice. We conclude that Dnase-1 does not mediate FGF23-induced inhibition of renal tubular phosphate reabsorption.

Vitamin D

2005 ◽  
Vol 289 (1) ◽  
pp. F8-F28 ◽  
Author(s):  
Adriana S. Dusso ◽  
Alex J. Brown ◽  
Eduardo Slatopolsky
Keyword(s):  
Vitamin D ◽  
Target Genes ◽  
Endocrine System ◽  
Target Cells ◽  
Vitamin D Metabolism ◽  
Diverse Range ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Single Receptor ◽  
Recent Developments

The vitamin D endocrine system plays an essential role in calcium homeostasis and bone metabolism, but research during the past two decades has revealed a diverse range of biological actions that include induction of cell differentiation, inhibition of cell growth, immunomodulation, and control of other hormonal systems. Vitamin D itself is a prohormone that is metabolically converted to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]. This vitamin D hormone activates its cellular receptor (vitamin D receptor or VDR), which alters the transcription rates of target genes responsible for the biological responses. This review focuses on several recent developments that extend our understanding of the complexities of vitamin D metabolism and actions: the final step in the activation of vitamin D, conversion of 25-hydroxyvitamin D to 1,25(OH)2D in renal proximal tubules, is now known to involve facilitated uptake and intracellular delivery of the precursor to 1α-hydroxylase. Emerging evidence using mice lacking the VDR and/or 1α-hydroxylase indicates both 1,25(OH)2D3-dependent and -independent actions of the VDR as well as VDR-dependent and -independent actions of 1,25(OH)2D3. Thus the vitamin D system may involve more than a single receptor and ligand. The presence of 1α-hydroxylase in many target cells indicates autocrine/paracrine functions for 1,25(OH)2D3in the control of cell proliferation and differentiation. This local production of 1,25(OH)2D3is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases.

Cellular Origins of Endometriosis: Towards Novel Diagnostics and Therapeutics

2020 ◽  
Vol 38 (02/03) ◽  
pp. 201-215
Author(s):  
Caitlin E. Filby ◽  
Luk Rombauts ◽  
Grant W. Montgomery ◽  
Linda C. Giudice ◽  
Caroline E. Gargett
Keyword(s):  
Clinical Care ◽  
Diagnostic Delay ◽  
Delayed Diagnosis ◽  
Disease Recurrence ◽  
Diagnostic Tools ◽  
Unknown Etiology ◽  
Treatment Pathways ◽  
Retrograde Menstruation ◽  
Personalized Diagnosis ◽  
New Research

AbstractEndometriosis remains an enigmatic disease of unknown etiology, with delayed diagnosis and poor therapeutic options. This review will discuss the cellular, physiological, and genomic evidence of Sampson's hypothesis of retrograde menstruation as a cause of pelvic endometriosis and as the basis of phenotypic heterogeneity of the disease. We postulate that collaborative research at the single cell level focused on unlocking the cellular, physiological, and genomic mechanisms of endometriosis will be accompanied by advances in personalized diagnosis and therapies that target unique subtypes of endometriosis disease. These advances will address the clinical conundrums of endometriosis clinical care—including diagnostic delay, suboptimal treatments, disease recurrence, infertility, chronic pelvic pain, and quality of life. There is an urgent need to improve outcomes for women with endometriosis. To achieve this, it is imperative that we understand which cells form the lesions, how they arrive at distant sites, and what factors govern their ability to survive and invade at ectopic locations. This review proposes new research avenues to address these basic questions of endometriosis pathobiology that will lay the foundations for new diagnostic tools and treatment pathways.

scholarly journals Transgenic Mice Overexpressing Human Fibroblast Growth Factor 23 (R176Q) Delineate a Putative Role for Parathyroid Hormone in Renal Phosphate Wasting Disorders

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5269-5279 ◽  
Author(s):  
Xiuying Bai ◽  
Dengshun Miao ◽  
Jiarong Li ◽  
David Goltzman ◽  
Andrew C. Karaplis
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Transgenic Mice ◽  
Fibroblast Growth Factor ◽  
Calcium Homeostasis ◽  
Fibroblast Growth Factor 23 ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism ◽  
Dihydroxyvitamin D3 ◽  
Circulating Levels

Abstract Fibroblast growth factor 23 (FGF23) is a recently characterized protein likely involved in the regulation of serum phosphate homeostasis. Increased circulating levels of FGF23 have been reported in patients with renal phosphate-wasting disorders, but it is unclear whether FGF23 is the direct mediator responsible for the decreased phosphate transport at the proximal renal tubules and the altered vitamin D metabolism associated with these states. To examine this question, we generated transgenic mice expressing and secreting from the liver human FGF23 (R176Q), a mutant form that fails to be degraded by furin proteases. At 1 and 2 months of age, mice carrying the transgene recapitulated the biochemical (decreased urinary phosphate reabsorption, hypophosphatemia, low serum 1,25-dihydroxyvitamin D3) and skeletal (rickets and osteomalacia) alterations associated with these disorders. Unexpectantly, marked changes in parameters of calcium homeostasis were also observed, consistent with secondary hyperparathyroidism. Moreover, in the kidney the anticipated alterations in the expression of hydroxylases associated with vitamin D metabolism were not observed despite the profound hypophosphatemia and increased circulating levels of PTH, both major physiological stimuli for 1,25-dihydroxyvitamin D3 production. Our findings strongly support the novel concept that high circulating levels of FGF23 are associated with profound disturbances in the regulation of phosphate and vitamin D metabolism as well as calcium homeostasis and that elevated PTH levels likely also contribute to the renal phosphate wasting associated with these disorders.

scholarly journals Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

2018 ◽  
Vol 29 (10) ◽  
pp. 2583-2592 ◽  
Author(s):  
Cassianne Robinson-Cohen ◽  
Traci M. Bartz ◽  
Dongbing Lai ◽  
T. Alp Ikizler ◽  
Munro Peacock ◽  
...  
Keyword(s):  
Vitamin D ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Genetic Variants ◽  
Fibroblast Growth Factor 23 ◽  
Phosphate Transport ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism ◽  
Genome Wide ◽  
Fgf23 Concentration

BackgroundFibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.MethodsWe performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m2 to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log–transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.ResultsWe discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (P=3.0×10−24), lies upstream of CYP24A1, which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within RGS14 and upstream of SLC34A1 (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within ABO, the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.ConclusionsCommon genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.

scholarly journals Acute presentation of intestinal malrotation in adults: a report of two cases

2010 ◽  
Vol 92 (7) ◽  
pp. e15-e18 ◽  
Author(s):  
Thomas Hanna ◽  
Jacob A Akoh
Keyword(s):  
Case Reports ◽  
Delayed Diagnosis ◽  
Adult Life ◽  
Intestinal Malrotation ◽  
Unusual Complication ◽  
Fetal Life ◽  
Diagnostic Challenge ◽  
Multiple Fractures ◽  
Diagnostic Uncertainty ◽  
First Case

Introduction Intestinal malrotation is a rare developmental abnormality occurring as a result of incomplete rotation during fetal life. It usually presents in the first few weeks of life, but may persist unrecognised into adult life. We report two interesting cases in elderly patients both characterised by a significant diagnostic challenge due to atypical clinical and radiological signs and in one case an unusual complication following laparotomy. Case Reports The first case was a 64-year-old man initially treated for diverticulitis but at laparotomy was found to have malrotation of the midgut and a perforated left-sided appendicitis. The second case was a 76-year-old woman admitted with multiple fractures and increasing abdominal distension following a fall. Ten days after admission, she underwent right hemicolectomy to treat faecal peritonitis due to multiple caecal perforations complicating volvulus in the presence of midgut malrotation. Conclusions These cases illustrate challenges associated with managing patients with undiagnosed intestinal malrotation. Delayed diagnosis is a common feature in several case reports describing atypical presentation of appendicitis in patients with malrotation. While abdominal CT scan can remove much of the diagnostic uncertainty, the diagnosis of malrotation can be missed unless there is a high index of suspicion.

Biological variation of intact fibroblast growth factor 23 measured on a fully automated chemiluminescent platform

2019 ◽  
Vol 56 (3) ◽  
pp. 381-386 ◽  
Author(s):  
Antonín Jabor ◽  
Zdenek Kubíček ◽  
Jitka Komrsková ◽  
Tereza Vacková ◽  
Jiří Vymětalík ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Growth Factor 23 ◽  
Biological Variation ◽  
Fibroblast Growth ◽  
Vitamin D Metabolism ◽  
Automated Assay ◽  
Reference Change Value ◽  
Index Of Individuality ◽  
Non Gaussian

Background Fibroblast growth factor 23 (FGF23), a potent regulator of phosphate and vitamin D metabolism, is a new biomarker of kidney, bone and cardiovascular disorders. The aim of this study was to assess the biological variation of intact fibroblast growth factor 23 (iFGF23). Methods The within-subject (CVI) and between-subject (CVG) biological variations were assessed in 14 healthy volunteers in a six-week protocol (seven samples). Imprecision (CVA) was assessed by duplicate measurements and the EP15-A2 protocol. Intact FGF23 was measured using a fully automated chemiluminescent assay (Liaison XL, DiaSorin S.p.A., Saluggia, Italy). Two methods with different sensitivities to non-Gaussian distribution were used to estimate the CVI, SD ANOVA and CV ANOVA methods. We calculated the index of individuality (II) and reference change values. Results Depending on the statistical method used, the CVI and CVA were 14.2 and 3.7% (SD ANOVA) or 12.5 and 3.9% (CV ANOVA), respectively. The corresponding reference change values were 40.5 and 36.4%, respectively. The CVG was 13.4% (SD ANOVA was the only option), and the total imprecision (EP15-A2) was less than 7%. Conclusions The measurement of iFGF23 demonstrated a CVA less than 4% during the experimental estimation of biological variation. The total imprecision was less than 7% in the EP15-A2 experiment. The CVI values of iFGF23 in healthy persons were 14.2 (SD ANOVA) and 12.5% (CV ANOVA), respectively. The CVG was 13.4%, and the resulting index of individuality was 1.06. The reference change value was less than 41%. The availability of this automated assay for iFGF23 with well-characterized biological variation data delivers opportunities for improved availability and application of this assay clinically.

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