Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia

Colazo, Juan M.; DeCorte, Joseph A.; Gillaspie, Erin A.; Folpe, Andrew L.; Dahir, Kathryn

doi:10.1016/j.bonr.2020.100744

Cited by 6 publications

(9 citation statements)

References 29 publications

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“…In a retrospective study of 144 patients, the initial misdiagnosis rate was 95%; intervertebral disc herniation, spondyloarthritis, and osteoporosis were the most common misdiagnoses [ 3 ]. The mean time between symptom onset and a correct diagnosis of TIO is 2.9 years [ 3 ], and in some cases has been up to 26 years [ 18 ]. Consequently, patients with TIO often cycle through several different medical specialties, including primary care physicians, rheumatologists, orthopedists, neurologists, chronic pain specialists, and psychologists before receiving an accurate diagnosis.…”

Section: Patient Pathwaymentioning

confidence: 99%

Diagnosis and Management of Tumor-induced Osteomalacia: Perspectives From Clinical Experience

Dahir

Zanchetta

Stanciu

et al. 2021

Journal of the Endocrine Society

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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.

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Section: Patient Pathwaymentioning

confidence: 99%

Diagnosis and Management of Tumor-induced Osteomalacia: Perspectives From Clinical Experience

Dahir

Zanchetta

Stanciu

et al. 2021

Journal of the Endocrine Society

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“…Tumor-induced osteomalacia (TIO) is an acquired renal phosphate wasting disorder that has an indolent presentation, usually in adulthood, caused by typically small benign mesenchymal tumors secreting excess FGF23 ( 62 , 63 ). The resulting renal phosphate losses, hypophosphatemia, and low 1,25(OH) 2 D cause myopathy, bone pain, and insufficiency fractures ( 64 ).…”

Section: Introductionmentioning

confidence: 99%

“…The resulting renal phosphate losses, hypophosphatemia, and low 1,25(OH) 2 D cause myopathy, bone pain, and insufficiency fractures ( 64 ). Some causative tumors have an FN1-FGFR1 (fibronectin and fibroblast growth factor receptor 1) transcriptional fusion ( 62 ). The tumors can be difficult to detect despite advanced imaging.…”

Section: Introductionmentioning

confidence: 99%

Approach to Hypophosphatemic Rickets

Ackah

Imel

2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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Hypophosphatemic rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. The most common causes are genetic (such as X-linked hypophosphatemia), and these typically will result in lifelong hypophosphatemia and osteomalacia. Knowledge of phosphate metabolism, including the effects of fibroblast growth factor 23 (FGF23) (an osteocyte produced hormone that downregulates renal phosphate reabsorption and 1,25-dihydroxyvitamin-D (1,25(OH)2D) production), is critical to determining the underlying genetic or acquired causes of hypophosphatemia, and to facilitate appropriate treatment. Serum phosphorus should be measured in any child or adult with musculoskeletal complaints suggesting rickets or osteomalacia. Clinical evaluation incudes thorough history, physical exam, laboratory investigations, genetic analysis (especially in the absence of a guiding family history) and imaging to establish etiology and to monitor severity and treatment course. The treatment depends on the underlying cause, but often includes active forms of vitamin D combined with phosphate salts, or anti-FGF23 antibody treatment (burosumab) for X-linked hypophosphatemia. The purpose of this article is to explore the approach to evaluating hypophosphatemic rickets and its treatment options.

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“…Because of the efficacy of genetic testing, recent emphasis has been placed on using gene panels to accelerate clinicians' diagnosis of phosphate‐wasting disorders. ( 11 , 12 , 13 )…”

Section: Introductionmentioning

confidence: 99%

“…Because FGF23 levels are increased in both XLH and TIO, there exists potential for misdiagnosis of these two disorders. ( 11 ) Moreover, PMTs are notoriously difficult to identify because of their variability in location and small size, but the potential to cure TIO via their resection emphasizes the need for expedient diagnosis and hence distinguishing features for these two disorders. To date, no study has been performed to identify salient differences between TIO and XLH in adults.…”

Section: Introductionmentioning

confidence: 99%

Rare Diseases That Impersonate One Another:X‐LinkedHypophosphatemia andTumor‐InducedOsteomalacia, a Retrospective Analysis of Discriminating Features

et al. 2022

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Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic disease characterized by frequent fractures, bone pain, muscle weakness, and affected gait. The rarity of TIO and similar presentation to other phosphate‐wasting disorders contribute to a high misdiagnosis rate and long time to correct diagnosis. TIO is curable by tumor resection, so accurate diagnosis has significant impact on patients' emotional and economic burden. Current diagnostics for TIO rely on decades‐old literature with poor phenotypic validation. Here, we identify salient clinical differences between rigorously validated cohorts of patients with TIO (n = 9) and X‐linked hypophosphatemia (XLH; n = 43), a frequent misdiagnosis for patients with TIO. The TIO cohort had significantly elevated FGF23 (365 versus 95 RU/mL, p < 0.001) and alkaline phosphatase (282.8 versus 118.5 IU/L, p < 0.01) but significantly reduced phosphorus (1.4 versus 2.2 mg/dL, p < 0.05) and 1,25(OH)2 D (16.6 versus 59.8 pg/mL, p < 0.01). By contrast, total vitamin D was similar between the two groups. Dual‐energy X‐ray absorptiometry (DXA) scans reveal lower Z‐scores in the hip (−1.6 versus 0.050, p < 0.01) and spine (0.80 versus 2.35, p < 0.05). TIO patients were more likely to have prior clinical diagnosis of osteoporosis (67% versus 0%), use assistive devices in daily living (100% versus 14%), and have received a knee arthroplasty (33% versus 7%). TIO patients lost an average of 1.5 cm over their disease course and had sustained an average of 8 fractures each, whereas fractures were rare in XLH. The XLH cohort had higher incidence of osteotomy (19% versus 0%), spinal stenosis (12% versus 0%), secondary dental abnormalities (95% versus 44%, p < 0.001), and depression and anxiety (46.5% versus 11%). These results deepen our understanding of the subtle differences present between diseases of phosphate wasting. They suggest several biochemical, clinical, and historical features that effectively distinguish TIO from XLH. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Hiding in plain sight: Gene panel and genetic markers reveal 26-year undiagnosed tumor-induced osteomalacia of the rib concurrently misdiagnosed as X-linked hypophosphatemia

Cited by 6 publications

References 29 publications

Diagnosis and Management of Tumor-induced Osteomalacia: Perspectives From Clinical Experience

Diagnosis and Management of Tumor-induced Osteomalacia: Perspectives From Clinical Experience

Approach to Hypophosphatemic Rickets

Rare Diseases That Impersonate One Another:X‐LinkedHypophosphatemia andTumor‐InducedOsteomalacia, a Retrospective Analysis of Discriminating Features

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