Clinical performance of a novel chemiluminescent enzyme immunoassay for FGF23

Ito, Nobuaki; Kubota, Takuo; Kitanaka, Susumu; Fujiwara, Ikuma; Adachi, Masanori; Takeuchi, Yasuhiro; Yamagami, Hitomi; Kimura, Takehide; Shinoda, Tomoyasu; Minagawa, Masahiro; Okazaki, Ryo; Ozono, Keiichi; Seino, Yoshiki; Fukumoto, Seiji

doi:10.1007/s00774-021-01250-1

Cited by 20 publications

(25 citation statements)

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“…Patients with histopathological confirmation of PMT who underwent surgery were categorized as having “definite TIO.” Patients with acquired hypophosphatemic osteomalacia with FGF23 >30 pg/mL measured by the Kainos FGF23 assay (Kainos, Tokyo, Japan) or the Determinar CL FGF23 assay (Minaris Medical, Tokyo, Japan) without histopathological confirmation were categorized as “clinically diagnosed TIO,” after excluding intravenous iron preparation‐induced FGF23‐related hypophosphatemic osteomalacia. ( 4,20‐22 )…”

Section: Methodsmentioning

confidence: 99%

“…The following information was collected in the secondary questionnaire: general characteristics (age, sex, date of the first visit to the treating physicians, body height and weight), clinical manifestations on the first visit to the treating physicians, family history of bone diseases, clinical history from onset to the diagnosis of TIO (estimated date of onset, the hospitals and departments the patients visited before the diagnosis of TIO), initial diagnoses other than TIO, laboratory results from onset of the symptoms to the latest visit (albumin, calcium, phosphate, creatinine, alkaline phosphatase, intact FGF23, intact parathyroid hormone [PTH], 25-hydroxyvitamin D [25(OH)D], and 1,25-dihydroxyvitamin D [1,25(OH) 2 D]), dates of the first measurement of phosphate and intact FGF23, physician-assessed efficacy of imaging tests including X-ray, computed tomography (CT), magnetic resonance imaging (MRI), FPET/CT, SRS, and 68 Gallium-DOTATOC-PET/CT for the localization of PMTs, physician-assessed efficacy of SVS (ie, the sampling point with the highest FGF23 value was located near a PMT detected by thin slice CT and/or MRI), bone mineral density, characteristics of the identified PMTs (maximum diameter, location, and histopathology), diagnosis of the primary neoplastic disorders other than PMTs that might overproduce FGF23 (eg, small-cell lung carcinoma, small-cell prostate carcinoma (21,23,24) ), surgical information (date, department, procedure [wide excision, marginal resection, and curettage]), surgical outcomes and information about additional surgery, local recurrence, or distal metastasis, the reasons to avoid surgery, treatment on the latest visit (doses of active vitamin D, oral inorganic phosphate preparation, and burosumab), the existence of metastasis, fractures developed after the diagnosis of TIO, and ambulatory function at the first and the latest visit to the treating physicians. There is no consensus on the criteria for interpreting SVS results; therefore, deciding whether SVS was useful for detecting PMT in this research was solely the physician's discretion.…”

Section: Data Collectionmentioning

confidence: 99%

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Clinical Challenges in Diagnosis, Tumor Localization and Treatment of Tumor-Induced Osteomalacia: Outcome of a Retrospective Surveillance

Hidaka

Koga

Kimura

et al. 2020

Journal of Bone and Mineral Research

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Tumor-induced osteomalacia (TIO) is an acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemic osteomalacia caused by phosphaturic mesenchymal tumors (PMTs) developed in the bone or soft tissue. Diagnostic delay should be addressed, and ideal techniques to localize PMTs and efficient treatment options should be explored to improve the outcomes of this rare disease. To clarify the detailed clinical course and outcomes of TIO patients, retrospective questionnaire surveys were conducted among physicians from the Japanese Society for Bone and Mineral Research (JSBMR) and the Japan Endocrine Society (JES). The primary survey collected the number of TIO patients between January 2007 and December 2018. The secondary survey aimed to obtain the detailed characteristics, laboratory data, and outcomes. Eighty-eight patients (52 males, mean: 52 years old) were included, and 24 patients were clinically diagnosed with TIO without localized PMTs. The median duration from the onset to detection of high FGF23 levels was 3.4 years, with 77 patients being initially misdiagnosed. Among the methods used to detect small, localized PMTs (≤10 mm), fluorine-18-fluorodeoxyglucose-positron emission tomography/ computed tomography and somatostatin receptor scintigraphy were less sensitive than somatostatin receptor positron emission tomography/computed tomography (SRPET/CT). Systemic venous sampling (SVS) of FGF23 was performed in 53 patients; among them, SVS was considered useful for detecting localized PMTs in 45 patients with diverse tumor sizes. Finally, 45 patients achieved biochemical remission by surgery, 39 patients continued pharmaceutical treatment, including burosumab (11 patients), and four patients died. These results encouraged us to further increase the awareness of TIO and to improve the accessibility of SRPET/CT and SVS. Further evidence about the efficacy of new pharmaceutical treatments is awaited.

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Section: Methodsmentioning

confidence: 99%

Section: Data Collectionmentioning

confidence: 99%

Clinical Challenges in Diagnosis, Tumor Localization and Treatment of Tumor-Induced Osteomalacia: Outcome of a Retrospective Surveillance

Hidaka

Koga

Kimura

et al. 2020

Journal of Bone and Mineral Research

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“…Using this method, the reference range of FGF23 is 16.1 to 49.3 pg/mL with cut‐off values for FGF23‐related hypophosphatemia of 30 pg/mL. ( 20,21 )…”

Section: Methodsmentioning

confidence: 99%

“…Using this method, the reference range of FGF23 is 16.1 to 49.3 pg/mL with cut-off values for FGF23-related hypophosphatemia of 30 pg/mL. (20,21) Measurement of plasma PP i Plasma was collected from participants to measure the plasma PP i concentrations. After plasma isolation, samples were filtered through a 30 kDa membrane (PALL, Port Washington, NY, USA) via centrifugation to remove platelets and frozen at À80 C within 1 hour of blood collection for single use.…”

Section: Measurement Of Intact Fgf23mentioning

confidence: 99%

Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early-Onset Osteoporosis

Katô

Ansh

Lester

et al. 2020

Journal of Bone and Mineral Research

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Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77-and 54-year-old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon workup, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536A>G, p.Asn179Ser; case 2, c.1352A>G, p.Tyr451Cys) and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536A>G, p.Asn179Ser and c.1352A>G, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared with that of wildtype ENPP1, respectively. Both variants were therefore categorized as pathogenic loss-of-function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis.

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“…In Japan, once chronic hypophosphatemia with the relevant symptoms of rickets/ osteomalacia is recognized, measurement of serum intact fibroblast growth factor (FGF) 23 (Determinar CL FGF23; Minaris Medical, Tokyo, Japan) is encouraged to determine the etiology of hypophosphatemia, with a cutoff value of 30 pg/mL to discriminate FGF23-related hypophosphatemic rickets/osteomalacia and others, which was revealed to possess high sensitivity and specificity [12][13][14]. Among adult patients with osteomalacia accompanied by FGF23 values of 30 pg/mL or more, diagnosis of XLH is strongly supported by the presence of one or more of the following symptoms: mildly short stature, leg deformity (genu varum, genu vulgus), enthesopathy, or X-linked inheritance of rickets/osteomalacia.…”

Section: Diagnosis Of Adult Xlhmentioning

confidence: 99%

Adult Presentation of X-Linked Hypophosphatemia

Ito

2022

Endocrines

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Adult X-linked hypophosphatemia (XLH) patients present with specific symptoms, including enthesopathies (e.g., ossification of longitudinal ligaments (OPLL), osteophytes around large joints, and enthesopathy in the Achilles tendons), early osteoarthritis, the development of severe secondary and tertiary hyperparathyroidism (SHPT/THPT), and the subsequent progression of chronic kidney disease (CKD). In addition, these patients exhibit the typical phenotypes of osteomalacia, such as pseudofracture and fracture in weight-bearing bones, odontitis, and tooth abscesses. The mechanism underlying enthesopathy development is unknown; however, a common underlying mechanism among XLH and autosomal recessive hypophosphatemic rickets (ARHR1/2) due to mutations in PHEX, DMP1, and ENPP1 is assumed. Clarification of the pathogenesis and drug discovery for this complication is an urgent issue, as many adult XLH patients suffer subsequent debilitating nervous symptoms or impingement syndrome, and existing treatments are ineffective. Severe SHPT and THPT are associated with conventional therapy, including active vitamin D and phosphate supplementation, and complicated and careful adjustment of dosages by experienced clinicians is required to avoid SHPT/THPT. Burosumab is a very effective therapy without risk for the development of SHPT/THPT. However, indications for this drug should be carefully considered, along with cost-effectiveness, guidelines or recommendations, and the health care system of each country.

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Clinical performance of a novel chemiluminescent enzyme immunoassay for FGF23

Cited by 20 publications

References 40 publications

Clinical Challenges in Diagnosis, Tumor Localization and Treatment of Tumor-Induced Osteomalacia: Outcome of a Retrospective Surveillance

Clinical Challenges in Diagnosis, Tumor Localization and Treatment of Tumor-Induced Osteomalacia: Outcome of a Retrospective Surveillance

Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early-Onset Osteoporosis

Adult Presentation of X-Linked Hypophosphatemia

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