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

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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Fibroblast Growth Factor 23 (FGF23) and Klotho Protein in Beta-Thalassemia

Hormone and Metabolic Research ◽

10.1055/a-1104-5326 ◽

2020 ◽

Vol 52 (03) ◽

pp. 194-201

Author(s):

Dimitrios Stefanopoulos ◽

Narjes Nasiri-Ansari ◽

Ismene Dontas ◽

Andromachi Vryonidou ◽

Antonis Galanos ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Iron Chelation ◽

Thalassemia Major ◽

The Body ◽

Beta Thalassemia ◽

Fibroblast Growth ◽

Control Subjects ◽

Number Of Patients

AbstractDerangements in phosphate and calcium homeostasis are common in patients with beta-thalassemia. Fibroblast growth factor 23 (FGF23) is among the main hormones regulating phosphate levels, while several studies underline an interplay between iron (Fe) and FGF23. Herein, we investigated, for the first time, the serum intact molecule (iFGF23) and the carboxyl-terminal fragment (C-FGF23) and Klotho levels simultaneously in patients with beta-thalassemia major receiving iron chelation regimens in comparison to healthy control subjects. We also correlated them with the body iron burden. The observational case-control study included 81 subjects (40 thalassemic patients and 41 healthy controls). Serum iFGF23, C-FGF23 and Κlotho were measured by ELISA. Parathormone, 25-hydroxycholecalciferol, calcium, and phosphorus were measured in blood and/or urine. The degree of hemosiderosis was evaluated by assessing the serum ferritin levels and performing T2* MRI measurements. Serum C-FGF23 levels were significantly lower in patients compared to control subjects (p=0.04), while iFGF23 and Klotho levels did not differ. Serum C-FGF23 levels were negatively correlated with ferritin (r=–0,421, p=0.018), whereas there were no significant correlations of each of the three factors with the iron chelation therapy. Decreased serum C-FGF23 levels were found in βTh patients which may be attributed to inhibition of proteolytic cleavage of iFGF23. Further studies in a greater number of patients will shed more light on the disturbances of the iFGF23, Klotho and C-FGF23 in thalassemia and their possible role in bone disease of such patients.

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

Cardiorenal Medicine ◽

10.1159/000449476 ◽

2016 ◽

Vol 7 (1) ◽

pp. 60-65 ◽

Cited By ~ 1

Author(s):

George T. Georges ◽

O. Nájera ◽

Kurt Sowers ◽

James R. Sowers

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Genetic Mutations ◽

Fibroblast Growth ◽

Male College Student ◽

Mesenchymal Tumors ◽

Vitamin D Metabolism ◽

Male College ◽

Systemic Symptoms

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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Tumour-induced Osteomalacia Secondary to a Sarcoma

European Endocrinology ◽

10.17925/ee.2016.12.02.104 ◽

2016 ◽

Vol 12 (2) ◽

pp. 104 ◽

Cited By ~ 2

Author(s):

Karla Victoria Rodriguez-Velver ◽

◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Rare Case ◽

Bone Fractures ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Biochemical Characteristics ◽

History Of ◽

Benign Tumours

Tumour-induced osteomalacia (TIO), is a rare paraneoplasatic syndrome found in >95% of benign tumours that secrete fibroblast growth factor 23 - a phosphaturic circulating hormone. A rare case of a TIO secondary to a sarcoma, in a 21-year old man with history of bone fractures and distinctive physical and biochemical characteristics is presented and discussed.

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Upstream Regulators of Fibroblast Growth Factor 23

Frontiers in Endocrinology ◽

10.3389/fendo.2021.588096 ◽

2021 ◽

Vol 12 ◽

Author(s):

Danielle M. A. Ratsma ◽

M. Carola Zillikens ◽

Bram C. J. van der Eerden

Keyword(s):

Growth Factor ◽

Iron Deficiency ◽

Fibroblast Growth Factor ◽

Mineral Metabolism ◽

Fibroblast Growth Factor 23 ◽

Treatment Options ◽

The Body ◽

Fibroblast Growth ◽

Mineral Homeostasis ◽

Upstream Regulators

Fibroblast growth factor 23 (FGF23) has been described as an important regulator of mineral homeostasis, but has lately also been linked to iron deficiency, inflammation, and erythropoiesis. FGF23 is essential for the maintenance of phosphate homeostasis in the body and activating mutations in the gene itself or inactivating mutations in its upstream regulators can result in severe chronic hypophosphatemia, where an unbalanced mineral homeostasis often leads to rickets in children and osteomalacia in adults. FGF23 can be regulated by changes in transcriptional activity or by changes at the post-translational level. The balance between O-glycosylation and phosphorylation is an important determinant of how much active intact or inactive cleaved FGF23 will be released in the circulation. In the past years, it has become evident that iron deficiency and inflammation regulate FGF23 in a way that is not associated with its classical role in mineral metabolism. These conditions will not only result in an upregulation of FGF23 transcription, but also in increased cleavage, leaving the levels of active intact FGF23 unchanged. The exact mechanisms behind and function of this process are still unclear. However, a deeper understanding of FGF23 regulation in both the classical and non-classical way is important to develop better treatment options for diseases associated with disturbed FGF23 biology. In this review, we describe how the currently known upstream regulators of FGF23 change FGF23 transcription and affect its post-translational modifications at the molecular level.

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Predictors of intact and C-terminal fibroblast growth factor 23 in Gambian children

Endocrine Connections ◽

10.1530/ec-13-0070 ◽

2014 ◽

Vol 3 (1) ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Vickie Braithwaite ◽

Kerry S Jones ◽

Shima Assar ◽

Inez Schoenmakers ◽

Ann Prentice

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Local Community ◽

Iron Status ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Normal Range ◽

Hydroxyvitamin D ◽

Fgf23 Concentration ◽

History Of

Elevated C-terminal fibroblast growth factor 23 (C-FGF23) concentrations have been reported in Gambian children with and without putative Ca-deficiency rickets. The aims of this study were to investigate whether i) elevated C-FGF23 concentrations in Gambian children persist long term; ii) they are associated with higher intact FGF23 concentrations (I-FGF23), poor iron status and shorter 25-hydroxyvitamin D half-life (25OHD-t1/2); and iii) the persistence and predictors of elevated FGF23 concentrations differ between children with and without a history of rickets. Children (8–16 years, n=64) with a history of rickets and a C-FGF23 concentration >125 RU/ml (bone deformity (BD), n=20) and local community children with a previously measured elevated C-FGF23 concentration (LC+, n=20) or a previously measured C-FGF23 concentration within the normal range (LC−, n=24) participated. BD children had no remaining signs of bone deformities. C-FGF23 concentration had normalised in BD children, but remained elevated in LC+ children. All the children had I-FGF23 concentration within the normal range, but I-FGF23 concentration was higher and iron status poorer in LC+ children. 1,25-dihydroxyvitamin D was the strongest negative predictor of I-FGF23 concentration (R2=18%; P=0.0006) and soluble transferrin receptor was the strongest positive predictor of C-FGF23 concentration (R2=33%; P≤0.0001). C-FGF23 and I-FGF23 concentrations were poorly correlated with each other (R2=5.3%; P=0.07). 25OHD-t1/2 was shorter in BD children than in LC− children (mean (s.d.): 24.5 (6.1) and 31.5 (11.5) days respectively; P=0.05). This study demonstrated that elevated C-FGF23 concentrations normalised over time in Gambian children with a history of rickets but not in local children, suggesting a different aetiology; that children with resolved rickets had a shorter 25OHD-t1/2, suggesting a long-standing increased expenditure of 25OHD, and that iron deficiency is a predictor of elevated C-FGF23 concentrations in both groups of Gambian children.

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