Fibroblast Growth Factor 23 and Hypophosphatemia: A Case of Hypophosphatemia along the Rickets-Osteomalacia Spectrum

Phosphorus is a key component of bone, and a deficiency results in poor mineralization along with other systemic symptoms of hypophosphatemia. Various causes of hypophosphatemia with renal wasting of phosphorus have been identified. These include the Fanconi syndrome, various genetic mutations of fibroblast growth factor 23 (FGF23) handling and the sodium/phosphate cotransporter, and those due to FGF23 secretion by mesenchymal tumors. Depending on the cause, vitamin D metabolism may also be impaired, which may amplify the deficiency in phosphorus and render treatment more challenging. Here, we report a case of hypophosphatemia and multiple stress fractures in a 20-year-old male college student living with chronic bone pain and anxiety about suffering further fractures. We further review the literature regarding this spectrum.

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Fibroblast Growth Factor 23 and Disordered Vitamin D Metabolism in Chronic Kidney Disease: Updating the “Trade-off” Hypothesis: Figure 1.

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.02640310 ◽

2010 ◽

Vol 5 (9) ◽

pp. 1710-1716 ◽

Cited By ~ 91

Author(s):

Orlando M. Gutiérrez

Keyword(s):

Chronic Kidney Disease ◽

Vitamin D ◽

Growth Factor ◽

Kidney Disease ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Vitamin D Metabolism ◽

Trade Off

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The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune?Albright syndrome

Journal of Bone and Mineral Metabolism ◽

10.1007/s00774-004-0589-9 ◽

2005 ◽

Vol 23 (3) ◽

pp. 231-237 ◽

Cited By ~ 47

Author(s):

Takehisa Yamamoto ◽

Yasuo Imanishi ◽

Eiichi Kinoshita ◽

Yoshiko Nakagomi ◽

Nobuhiko Shimizu ◽

...

Keyword(s):

Vitamin D ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Vitamin D Metabolism ◽

Mccune Albright Syndrome ◽

Albright Syndrome ◽

Mccune Albright

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

Endocrinology ◽

10.1210/en.2004-0233 ◽

2004 ◽

Vol 145 (11) ◽

pp. 5269-5279 ◽

Cited By ~ 241

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.

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Quantitative ELISA-Like Immunohistochemistry of Fibroblast Growth Factor 23 in Diagnosis of Tumor-Induced Osteomalacia and Clinical Characteristics of the Disease

Disease Markers ◽

10.1155/2016/3176978 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

Fangke Hu ◽

Chengying Jiang ◽

Qiang Zhang ◽

Huaiyin Shi ◽

Lixin Wei ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Clinical Features ◽

Fibroblast Growth Factor 23 ◽

The Body ◽

Fibroblast Growth ◽

Mesenchymal Tumors ◽

History Of ◽

Paraneoplastic Disorder ◽

Formalin Fixed

Tumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder and fibroblast growth factor 23 (FGF23) plays a key role in its pathogenesis. This study was conducted to describe a novel FGF23 detecting procedure and describe clinical features of the disease. Fourteen TIO cases were retrieved and FGF23 expression was measured by quantitative ELISA-like immunohistochemistry using formalin-fixed and paraffin-embedded tissues. As summarized from 14 TIO cases, clinical features of TIO were long-standing history of osteomalacia, hypophosphatemia, and urinary phosphate wasting. The associated tumors were mostly benign phosphaturic mesenchymal tumors mixed connective tissue variant (PMTMCT) which could be located anywhere on the body, and most of them could be localized by conventional examinations and octreotide scanning. By quantitative ELISA-like immunohistochemistry, all the 14 TIO cases had high FGF23 expression (median 0.69, 25%–75% interquartile 0.57–1.10, compared with 26 non-TIO tumors of median 0.07, 25%–75% interquartile 0.05–0.11,p<0.001). The quantitative ELISA-like immunohistochemistry was a feasible and reproducible procedure to detect the high FGF23 expression in formalin-fixed and paraffin-embedded biopsies or specimens. Since TIO was often delay-diagnosed or misdiagnosed, clinicians and pathologists should be aware of TIO and PMTMCT, respectively.

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Genetic Variants Associated with Circulating Fibroblast Growth Factor 23

Journal of the American Society of Nephrology ◽

10.1681/asn.2018020192 ◽

2018 ◽

Vol 29 (10) ◽

pp. 2583-2592 ◽

Cited By ~ 12

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.

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

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563219826161 ◽

2019 ◽

Vol 56 (3) ◽

pp. 381-386 ◽

Cited By ~ 1

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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