Tumor-induced Osteomalacia Research Articles

OR13-1 Long-Term Burosumab Therapy Provides Sustained Benefit in Patients with Tumor-Induced Osteomalacia: End of Study Findings From the Pivotal Phase 2 Study

Abstract Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome wherein small tumors secrete excess fibroblast growth factor 23 (FGF23) leading to hypophosphatemia, osteomalacia, bone pain, fractures, and muscle weakness. Burosumab is an anti-FGF23 monoclonal antibody approved for treatment of TIO. We report end of study (EOS) data from the open-label phase 2 UX023T-CL201 trial (NCT02304367) of burosumab in adults with TIO. In UX023T-CL201, participants received burosumab (0.3–2.0 mg/kg) by subcutaneous injection every 4 weeks for 48 weeks with an extension up to 300 weeks (∼6 years). Co-primary endpoints were change in serum phosphorus at Week 24 and change in excess osteoid by trans-iliac crest bone biopsy at Week 48. Additional endpoints included changes in bone biomarkers, activity on radionucleotide bone scan representing fractures/pseudofractures, patient-reported outcomes, and safety measures. This analysis included 14/17 UX023T-CL201 participants; excluding those with other diagnoses (n=3). Mean (SD) serum phosphorus improved from 1.6 (0.5) mg/dL at baseline to 2.3 (0.5) mg/dL when averaged across the mid-point of the dose interval through Week 24 (co-primary endpoint). Levels further improved (2.6 [0.4] mg/dL; n=7) to within the normal range (2.5–3.6 mg/dL) at Week 240. Most measures of osteomalacia improved at Week 48 (co-primary endpoint), including osteoid/bone volume, osteoid thickness, and mineralization lag time. However, osteoid surface/bone surface showed no change. Bone biomarkers (P1NP, CTx, BALP) followed similar trends. Upon initiation of burosumab, markers briefly increased by Week 24 as bone healing began, then gradually decreased with further treatment, reaching normal (P1NP, CTx) or near-normal (BALP) ranges by Week 240. At baseline, 249 areas of increased radionucleotide uptake indicating fracture activity were detected across 14 participants. By Week 144, 36% (72/201) and 13% (26/201) regions of abnormal uptake were fully or partially restored, respectively. By EOS, further reduction of active fractures and fewer new areas of uptake were observed. New fractures at Week 144 were observed in a single participant (considered a burosumab partial responder) and between Week 144 and EOS in another participant unrelated to burosumab (car accident). Participants reported sustained mean reduction from baseline pain at Week 240 per Brief Pain Inventory and significantly per SF-36 Bodily Pain score. Significant reductions in baseline fatigue at Week 240 were reported per Brief Fatigue Inventory and SF-36 Vitality scores. SF-36 physical health (Role Physical, Bodily Pain, Component Score) and mental health (Social Function, Vitality) significantly improved from baseline at Week 240. The observed safety profile of long-term burosumab in participants with TIO was consistent with the known safety profile of burosumab and similar to patients with XLH. Long-term burosumab therapy was associated with improved serum phosphorus, osteomalacia, bone turnover, fracture incidence and healing, health-related quality of life, and reductions in pain and fatigue in adults with TIO. Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

Treating 'osteoporosis': a near miss in an unusual case of FGF-23-mediated hypophosphataemic osteomalacia.

We present the case of a 60-year-old female who developed repeated atraumatic stress fractures. She was initially diagnosed with osteoporosis based on her dual-energy X-ray absorptiometry (DXA) scan bone mineral density (BMD) T-scores and started on denosumab therapy. Secondary osteoporosis screen revealed abnormal myeloma screen and low serum phosphate levels. It was thought that the patient had multiple myeloma with associated Fanconi-related tubular dysfunction. However, fibroblast growth factor-23 (FGF-23) levels were grossly elevated, making Fanconi syndrome unlikely. The patient was subsequently diagnosed with two separate conditions, namely cardiac amyloid light-chain (AL) amyloidosis and FGF-23-related hypophosphataemia, likely due to tumour-induced osteomalacia. This case highlights the importance of excluding osteomalacia as a cause of low BMD and checking FGF-23 levels in the workup for hypophosphataemia. Tumour-induced osteomalacia is a difficult diagnosis as the tumour is often small and slow growing. Imaging may fail to identify a tumour, and treatment therefore consists of calcitriol and phosphate replacement. Tumour-induced osteomalacia should be suspected in the adult presenting with new-onset hypophosphataemia, elevated FGF-23 levels and isolated renal phosphate wasting. Serum phosphate is not part of the routine chemistry panels. Routinely checking phosphate levels prior to initiating antiresorptive therapy is warranted. DXA cannot distinguish low bone mineral density due to osteoporosis from osteomalacia. Antiresorptive therapy should be avoided in osteomalacia due to the risk of clinical and radiographic deterioration.

PSAT222 Muscle Weakness, Bone Pain, and Stress Fractures: When a Fracture is NOT JUST a Fracture: A Case Report

Abstract Case A previously healthy 46-year-old male presented to orthopedic clinic with bilateral hip pain, and progressive weakness without history of trauma requiring cane for ambulation. X-ray and MRI evaluation revealed stress fractures of left subtrochanteric femur and right basicervical femoral neck, both requiring surgery. In hospital blood work revealed elevated total alkaline phosphatase 167 units/L, mild hypocalcemia 8.5 mg/dL, and low 25-hydroxy Vitamin D 18 ng/mL. The patient was started on calcium/vitamin D supplements upon discharge. Initial endocrinology outpatient work-up revealed low phosphorus level of 2.1 mg/dl and low 1, 25 OH vitamin D of 5.9 pg/ml (19.9–79.3). Bone mineral density revealed normal spine bone density, and 1/3 radius osteopenia (T score -1.1). Physical exam revealed profound proximal weakness with inability to rise independently from sitting position. Follow-up of low phosphorous level demonstrated an elevated FGF-23 level of 186 RU/mL (normal < 180) and elevated fractional excretion of phosphorus 16% (expect < 5% with hypophosphatemia), indicating inappropriate renal phosphate wasting. The patient was started on Calcitriol and phosphorus. Before above evaluation was completed the patient had an ED visit with complaint of small mass just below left knee associated with mild pain and warmth. Ultrasound and MRI showed a complex cyst which was aspirated and showed cystic appearing mass suggestive of hematoma. This was treated with antibiotic course. Due to suspicion of tumor-induced osteomalacia, octreotide scan (Indium-111 pentetreotide) performed showed focal increased activity in the medial left knee. MRI showed a 26 mm cystic lesion within the subcutaneous tissue along the inferomedial aspect of the left knee, which correlated with the site of radiotracer uptake on the octreotide scan. The patient underwent left knee soft tissue tumor resection, and pathology demonstrated phosphaturic mesenchymal tumor. Follow-up several weeks postoperatively showed normalization of phosphorus and FGF-23 level. The patient's mobility and weakness improved significantly within a few months. Discussion Tumor-induced osteomalacia is a rare paraneoplastic condition characterized by chronic hypophosphatemia secondary to excessive tumoral FGF 23 production. Typical presenting symptoms are profound muscle weakness, bone pain, and fractures. Diagnosis is often delayed for several years, as phosphorus levels are not included in a routine metabolic panel. Considering high morbidity of this condition including significant mobility limitation requiring use of assistive devices, healthcare provider vigilance is paramount as this condition is potentially curable if the offending tumor is detectable and amenable to surgical resection. This case illustrates the importance of consideration of an underlying metabolic bone disease in patients with unexplained atraumatic fractures and hypophosphatemia. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Tumour-induced osteomalacia (TIO).

Not required for Clinical Vignettes.

Persistently Augmented FGF-23 Serum Values in a Surgically Resolved Oncogenic Osteomalacia Patient with No Tumor and Inflammatory Activity

Objective: Oncogenic osteomalacia is a paraneoplastic syndrome characterized by severe hypophosphatemia, hyperphosphaturia, and osteomalacia subordinated to renal loss of phosphate. It is caused by overproduction of phosphatonin fibroblast growth factor-23 by benign mesenchymal tumors which, when surgically eliminated, returns to basal levels. Methods: We report a case of a patient with oncogenic osteomalacia from a sacrum mesenchymal tumor whose FGF-23 levels remain elevated two years after successful surgical treatment. Results: A 53-year-old man with severe difficulty to walk and stand, severe hypophosphatemia, hyperphosphaturia, and raised levels of alkaline phosphatase and FGF-23 was diagnosed with oncogenic osteomalacia after a thorough process of elimination of causes of hyphosphatemia were excluded. Despite systemic chemotherapy, surgical removal of sacrum, primary mesenchymal tumor, phosphate and calcium supplementation, and no evidence of tumor recurrence, the serum concentration of FGF-23 remains elevated two years after discharge. Conclusions: The possible underlying mechanisms of sustained FGF-23 serum concentrations in this patient suggest the presence of molecular alterations in the FGF/FGFR signaling pathway.

High prevalence of vertebral deformity in tumor-induced osteomalacia associated with impaired bone microstructure.

Patients with tumor-induced osteomalacia (TIO) often suffer from irreversible height loss due to vertebral deformity. However, the prevalence of vertebral deformity in TIO patients varies among limited studies. In addition, the distribution and type of vertebral deformity, as well as its risk factors, remain unknown. This study aimed to identify the prevalence, distribution, type and risk factors for vertebral deformity in a large cohort of TIO patients. A total of 164 TIO patients were enrolled in this retrospective study. Deformity in vertebrae T4-L4 by lateral thoracolumbar spine radiographs was evaluated according to the semiquantitative method of Genant. Bone microstructure was evaluated by trabecular bone score (TBS) and high-resolution peripheral QCT (HR-pQCT). Ninety-nine (99/164, 60.4%) patients had 517 deformed vertebrae with a bimodal pattern of distribution (T7-9 and T11-L1), and biconcave deformity was the most common type (267/517, 51.6%). Compared with patients without vertebral deformity, those with vertebral deformity had a higher male/female ratio, longer disease duration, more height loss, lower serum phosphate, higher bone turnover markers, lower TBS, lower areal bone mineral density (aBMD), lower peripheral volumetric BMD (vBMD) and worse microstructure. Lower trabecular vBMD and worse trabecular microstructure in the peripheral bone and lower spine TBS were associated with an increased risk of vertebral deformity independently of aBMD. After adjusting for the number of deformed vertebrae, we found little difference in clinical indexes among the patients with different types of vertebral deformity. However, we found significant correlations of clinical indexes with the number of deformed vertebrae and the spinal deformity index. We reported a high prevalence of vertebral deformity in the largest cohort of TIO patients and described the vertebral deformity in detail for the first time. Risk factors for vertebral deformity included male sex, long disease duration, height loss, abnormal biochemical indexes and bone impairment. Clinical manifestation, biochemical indexes and bone impairment were correlated with the number of deformed vertebrae and degree of deformity, but not the type of deformity.

Tumor-induced osteomalacia.

Tumor-induced osteomalacia.

39-Year-Old Woman With Severe Weakness

39-Year-Old Woman With Severe Weakness

Novel Therapeutic Agents for Rare Diseases of Calcium and Phosphate Metabolism.

The last decade has been revolutionary regarding the management of rare bone diseases caused by impaired calcium and phosphate metabolism. Elucidation of the underlying genetic basis and pathophysiologic alterations has been the determinant factor for the development of new, disease-specific treatment agents. The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) possesses a critical role in the pathogenesis of various hypophosphatemic disorders. Among them, the genetic disorder of X-linked hypophosphatemia and the acquired syndrome of tumor-induced osteomalacia, although very rare, have attracted the scientific community's attention towards designing an FGF23-inhibitor as a potential specific therapy. The monoclonal antibody burosumab was approved for the treatment of children and adult patients with X-linked hypophosphatemia and recently for tumor-induced osteomalacia patients, demonstrating benefits regarding their symptoms, biochemical profile and bone mineralization status. Asfotase alfa is a hydroxyapatite-targeted recombinant alkaline phosphatase, an enzymatic replacement therapy, substituting the defective activity of tissue non-specific alkaline phosphatase, in patients suffering from hypophosphatasia. Promising data regarding its favorable effect on survival rate, bone quality, fracture healing, muscle strength, mobility, respiratory function, and general quality of life have led to the approval of the drug for the treatment of childhood-onset hypophosphatasia. Given the high costs of treatment for both agents and their limited clinical use until now, more data are needed to define patients' characteristics that make them ideal candidates for therapy. Long-term safety issues also need to be clarified.

Reconstruction With a 3D-Printed Megaprosthesis With Ankle Arthrodesis After Distal Tibial Tumor Resection.

Reconstruction after en bloc resection of the distal tibia has remained an unsettled issue despite many attempts with bone grafts or prostheses in the past. Failures of the previous methods have been attributed to inadequate mechanical strength, poor articular stability, failed osseointegration, and poor soft tissue coverage. To overcome these shortcomings, we designed and applied a 3D-printed megaprosthesis with ankle arthrodesis. A total of 13 patients underwent resection of a distal tibial tumor and reconstruction with a 3D-printed distal tibial megaprosthesis between January 2017 and November 2020. Mean age was 14.9±6.5 years. Diagnoses included 11 cases of osteosarcoma and 1 case each of low-grade phosphaturic mesenchymal tumor and rhabdomyosarcoma. Baseline characteristics, operative data, complication profiles, and oncologic, and functional outcomes were reviewed and analyzed. All 13 cases attained a wide or marginal resection. During a mean follow-up of 26.8±10.6 months, 1 patient experienced local recurrence and distant metastasis, whereas 3 other patients only developed distant metastasis. Periprosthetic infection subsequent to paronychia occurred in 1 patient 24 months after the operation. No other complications were observed. By the last follow-up, the mean MSTS-93 score was 28.0±1.5. In this relatively small cohort with short-term follow-up, reconstruction with the 3D-printed megaprosthesis with ankle arthrodesis was found to be a safe and efficacious method after resection of a distal tibial malignancy.

Burosumab Treatment for Autosomal Recessive Hypophosphatemic Rickets Type 1 (ARHR1).

Autosomal recessive hypophosphatemic rickets (ARHR) are rare, heritable renal phosphate-wasting disorders that arise from overexpression of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) leading to impaired bone mineralization (rickets and osteomalacia). Inactivating mutations of Dentin matrix protein 1 (DMP1) give rise to ARHR type 1 (ARHR1). Short stature, prominent bowing of the legs, fractures/pseudofractures, and severe enthesopathy are prominent in this patient population. Traditionally, treatment consists of oral phosphate replacement and the addition of calcitriol but this approach is limited by modest efficacy and potential renal and gastrointestinal side effects. The advent of burosumab (Crysvita), a fully humanized monoclonal antibody to FGF23 for the treatment of X-linked hypophosphatemia and tumor-induced osteomalacia, offers a unique opportunity to evaluate its safety and efficacy in patients with ARHR1. Monthly administration of burosumab to 2 brothers afflicted with the disorder resulted in normalization of serum phosphate, healing of pseudofracture, diminished fatigue, less bone pain, and reduced incapacity arising from the extensive enthesopathy and soft tissue fibrosis/calcification that characterizes this disorder. No adverse effects were reported following burosumab administration. The present report highlights the beneficial biochemical and clinical outcomes associated with the use of burosumab in patients with ARHR1.

Infigratinib Reduces Fibroblast Growth Factor 23 (FGF23) and Increases Blood Phosphate in Tumor‐Induced Osteomalacia

ABSTRACTTumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by ectopic production of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMTs). Acting on renal tubule cells, excess FGF23 decreases phosphate reabsorption and 1,25‐dihydroxy‐vitamin D (1,25D) production, leading to hypophosphatemia, impaired bone mineralization, pain, and fractures. Fibronectin 1‐fibroblast growth factor receptor 1 (FN1‐FGFR1) gene fusions have been identified as possible drivers in up to 40% of resected PMTs. Based on the presumptive role of FGFR1 signaling by chimeric FN1‐FGFR1 proteins, the effectiveness of infigratinib, a FGFR1‐3 tyrosine kinase inhibitor, was studied in an open‐label, single‐center, phase 2 trial. The primary endpoint was persistent normalization of blood phosphate and FGF23 after discontinuation. Four adults with TIO (two nonlocalized, two nonresectable PMTs) were treated with daily infigratinib for up to 24 weeks. All patients had a favorable biochemical response that included reduction in intact FGF23, and normalization of blood phosphate and 1,25D. However, these effects disappeared after drug discontinuation with biochemistries returning to baseline; no patients entered biochemical remission. In the two patients with identifiable tumors, 68Gallium (68Ga)‐DOTATATE and 18Fluoride (18F)‐Fluorodeoxyglucose (FDG) PET/CT scans showed a decrease in PMT activity without change in tumor size. Patients experienced mild to moderate, treatment‐related, dose‐limiting adverse events (AEs), but no serious AEs. Three patients had dose interruptions due to AEs; one patient continued on a low dose for the entire 24 weeks and one patient stopped therapy at 17 weeks due to an AE. The study closed early due to a failure to meet the primary endpoint and a higher‐than‐expected incidence of ocular AEs. Infigratinib treatment lowered FGF23, increased blood phosphate, and suppressed PMT activity, confirming the role of FGFR signaling in PMT pathogenesis. However, treatment‐related AEs at efficacy doses and disease persistence on discontinuation support restricting the use of infigratinib to patients with life‐limiting metastatic PMTs. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Identification of Small-Molecule Inhibitors of Fibroblast Growth Factor 23 Signaling via In Silico Hot Spot Prediction and Molecular Docking to α-Klotho.

Fibroblast growth factor 23 (FGF23) is a therapeutic target for treating hereditary and acquired hypophosphatemic disorders, such as X-linked hypophosphatemic (XLH) rickets and tumor-induced osteomalacia (TIO), respectively. FGF23-induced hypophosphatemia is mediated by signaling through a ternary complex formed by FGF23, the FGF receptor (FGFR), and α-Klotho. Currently, disorders of excess FGF23 are treated with an FGF23-blocking antibody, burosumab. Small-molecule drugs that disrupt protein/protein interactions necessary for the ternary complex formation offer an alternative to disrupting FGF23 signaling. In this study, the FGF23:α-Klotho interface was targeted to identify small-molecule protein/protein interaction inhibitors since it was computationally predicted to have a large fraction of hot spots and two druggable residues on α-Klotho. We further identified Tyr433 on the KL1 domain of α-Klotho as a promising hot spot and α-Klotho as an appropriate drug-binding target at this interface. Subsequently, we performed in silico docking of ∼5.5 million compounds from the ZINC database to the interface region of α-Klotho from the ternary crystal structure. Following docking, 24 and 20 compounds were in the final list based on the lowest binding free energies to α-Klotho and the largest number of contacts with Tyr433, respectively. Five compounds were assessed experimentally by their FGF23-mediated extracellular signal-regulated kinase (ERK) activities in vitro, and two of these reduced activities significantly. Both these compounds were predicted to have favorable binding affinities to α-Klotho but not have a large number of contacts with the hot spot Tyr433. ZINC12409120 was found experimentally to disrupt FGF23:α-Klotho interaction to reduce FGF23-mediated ERK activities by 70% and have a half maximal inhibitory concentration (IC50) of 5.0 ± 0.23 μM. Molecular dynamics (MD) simulations of the ZINC12409120:α-Klotho complex starting from in silico docking poses reveal that the ligand exhibits contacts with residues on the KL1 domain, the KL1-KL2 linker, and the KL2 domain of α-Klotho simultaneously, thereby possibly disrupting the regular function of α-Klotho and impeding FGF23:α-Klotho interaction. ZINC12409120 is a candidate for lead optimization.

FGF23 tumor induced osteomalacia

Tumor induced osteomalacia is a rare acquired disease. The cause is a mesenchymal tumor secreting fibroblast growth factor 23 (FGF23). An excessive amount of FGF 23 disrupts the metabolism of phosphorus and vitamin D, which leads to severe paraneoplastic syndrome, manifested in the form of multiple fractures, severe pain in the bones and generalized myopathy. With oncogenic osteomalacia, a complete cure is possible with radical resection of the tumor. Unfortunately, localization, small size of formations and rare frequency of occurrence lead to the fact that the disease remains unrecognized for a long time and leads to severe, disabling consequences. A step-by-step approach to diagnosis improves treatment outcomes. First, a thorough anamnesis is collected, then functional visualization is performed and the diagnosis is confirmed by anatomical visualization of the tumor. After that, the method of choice is a surgical treatment. If resection is not possible, then conservative therapy with active metabolites of vitamin D and phosphorus salts is indicated. New therapeutic approaches, such as the antibody to FGF23 or the pan-inhibitor of receptors to FGF, are actively developing. This article provides an overview of modern approaches to the diagnosis and treatment of this disease.

Tumor-induced osteomalacia characterized by “painful knee joint with difficulty in moving”: a case report

BackgroundTumor-related osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. The diagnosis of TIO can be very difficult because of its nonspecific nature of clinical manifestations. Here we reported a case of young TIO patient with “painful knee joint with difficulty in moving” to improve the clinical diagnosis and treatment levels.Case presentationThe patient’s clinical features were consistent with TIO. A tumor was successfully located in left tibial by 68Ga-DOTATATE PET/CT, and then was surgically resected. Upon pathologic assessment, the tumor was diagnosed as phosphaturia stromal tumor (PMT) with positive Vim staining. After the surgery, serum phosphate level rapidly recovered and symptoms significantly improved.ConclusionTIO should be considered in patients with chronically hypophosphorus osteomalacia in the setting of no family history. Early removal of the responsible tumors is clinically essential for the treatment, and imaging examination is of great significance for tumor localization.

Malignancy mimics- diagnostic perplexities for oral and maxillofacial pathologists.

In pathology practice, one frequently encounters benign lesions which superficially resemble malignancy clinically and histopathologically. The diagnostic pitfalls can be avoided if the approach exemplified in the present study is followed. We expect that familiarity of these cases will be helpful for pathologists at the beginning of their career. Clinical case records of all the pathological specimens reported in our laboratory from January 2018 to September 2019 were queried. Cases displaying pseudotumor features were reviewed along with the special stains were performed and immunohistochemistry (IHC) studies. A working classification of pseudotumors presenting in the oral cavity was proposed. Immunoglobulin G4-related disease, nodular fasciitis, fibrolipoma, odontogenic keratocyst with giant cell granuloma, juvenile ossifying fibroma with central giant cell granuloma and tumor-induced osteomalacia were the most common diagnoses where the tissue specimens resembled malignancies on routine clinicoradiological evaluation and light microscopy of tissue specimens. Their differential diagnosis and the pathological diagnostic dilemmas are explained. We have also highlighted the importance of correlating clinical, radiological and microscopic details with the findings deduced from advanced pathological aids to establish the final diagnosis. Pathologists should be aware of the conditions where the diagnosis of malignancy needs stricter evaluation to rule out malignant mimics. In such scenarios, correlation of light microscopy findings with clinical and radiological details cannot be overemphasized. Advanced pathological aids such as IHC, where necessary are often indispensable for reaching the accurate diagnosis in these cases.

Tumour-induced osteomalacia

Phosphate is important for normal mineralisation of bone. Phosphate is important in its own right for neuromuscular function, and profound hypophosphataemia can be accompanied by encephalopathy, muscle weakness and cardiomyopathy. Hypophosphataemia can be due to intracellular uptake of phosphate

Pathogenesis of FGF23-Related Hypophosphatemic Diseases Including X-linked Hypophosphatemia

Since phosphate is indispensable for skeletal mineralization, chronic hypophosphatemia causes rickets and osteomalacia. Fibroblast growth factor 23 (FGF23), which is mainly produced by osteocytes in bone, functions as the central regulator of phosphate metabolism by increasing the renal excretion of phosphate and suppressing the production of 1,25-dihydroxyvitamin D. The excessive action of FGF23 results in hypophosphatemic diseases, which include a number of genetic disorders such as X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia (TIO). Phosphate-regulating gene homologous to endopeptidase on the X chromosome (PHEX), dentin matrix protein 1 (DMP1), ectonucleotide pyrophosphatase phosphodiesterase-1, and family with sequence similarity 20c, the inactivating variants of which are responsible for FGF23-related hereditary rickets/osteomalacia, are highly expressed in osteocytes, similar to FGF23, suggesting that they are local negative regulators of FGF23. Autosomal dominant hypophosphatemic rickets (ADHR) is caused by cleavage-resistant variants of FGF23, and iron deficiency increases serum levels of FGF23 and the manifestation of symptoms in ADHR. Enhanced FGF receptor (FGFR) signaling in osteocytes is suggested to be involved in the overproduction of FGF23 in XLH and autosomal recessive hypophosphatemic rickets type 1, which are caused by the inactivation of PHEX and DMP1, respectively. TIO is caused by the overproduction of FGF23 by phosphaturic tumors, which are often positive for FGFR. FGF23-related hypophosphatemia may also be associated with McCune-Albright syndrome, linear sebaceous nevus syndrome, and the intravenous administration of iron. This review summarizes current knowledge on the pathogenesis of FGF23-related hypophosphatemic diseases.

GRM1 Immunohistochemistry Distinguishes Chondromyxoid Fibroma From its Histologic Mimics.

Chondromyxoid fibroma (CMF) is a rare benign bone neoplasm that manifests histologically as a lobular proliferation of stellate to spindle-shaped cells in a myxoid background, exhibiting morphologic overlap with other cartilaginous and myxoid tumors of bone. CMF is characterized by recurrent genetic rearrangements that place the glutamate receptor gene GRM1 under the regulatory control of a constitutively active promoter, leading to increased gene expression. Here, we explore the diagnostic utility of GRM1 immunohistochemistry as a surrogate marker for GRM1 rearrangement using a commercially available monoclonal antibody in a study of 230 tumors, including 30 CMF cases represented by 35 specimens. GRM1 was positive by immunohistochemistry in 97% of CMF specimens (34/35), exhibiting moderate to strong staining in more than 50% of neoplastic cells; staining was diffuse (>95% of cells) in 25 specimens (71%). Among the 9 CMF specimens with documented exposure to acid decalcification, 4 (44%) exhibited diffuse immunoreactivity (>95%) for GRM1, whereas all 15 CMF specimens (100%) with lack of exposure to decalcification reagents were diffusely immunoreactive ( P =0.003). High GRM1 expression at the RNA level was previously observed by quantitative reverse transcription polymerase chain reaction in 9 CMF cases that were also positive by immunohistochemistry; low GRM1 expression was observed by quantitative reverse transcription polymerase chain reaction in the single case of CMF that was negative by immunohistochemistry. GRM1 immunohistochemistry was negative (<5%) in histologic mimics of CMF, including conventional chondrosarcoma, enchondroma, chondroblastoma, clear cell chondrosarcoma, giant cell tumor of the bone, fibrous dysplasia, chondroblastic osteosarcoma, myoepithelial tumor, primary aneurysmal bone cyst, brown tumor, phosphaturic mesenchymal tumor, CMF-like osteosarcoma, and extraskeletal myxoid chondrosarcoma. These results indicate that GRM1 immunohistochemistry may have utility in distinguishing CMF from its histologic mimics.

Unusual Presentation and Surgical Treatment of a Phosphaturic Mesenchymal Tumor in a Knee.

A 30-year-old woman presented to our hospital with an 11-year history of gradually enlarging masses around the left knee and 2-year history of progressively worsening bone pain. Tumor-induced osteomalacia (TIO), a rare paraneoplastic syndrome caused by phosphaturic mesenchymal tumors (PMTs) was suspected, but the postoperative pathology of her two operations was both reported as tenosynovial giant cell tumor (TGCT), making its diagnosis confusing. The possibility of hypophosphatemia, insufficient blood supply, innervation of the left lower limbs, as well as the unclear pathology, make it unreasonable to perform tumor-type knee prosthesis replacement directly. Finally, we placed static polymethylmethacrylate (PMMA) spacer at first, then when the concentration of blood phosphorus level rose to the normal range, the pathology was confirmed to be TIO, the blood supply and innervation was satisfying, tumor-type knee prosthesis replacement was performed. She was discharged post operative day 15 after the prothesis implantation without incident. One and a half years after her surgery, the concentration of blood phosphorus was still in the normal range, the symptom of systemic bone pain had improved significantly, the prosthesis was still in a good position and no recurrence was caught.