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Background: Osteoporosis (OP) and osteomalacia (OM) are metabolic bone diseases characterized by mineral and matrix density changes. Quantitative bone matrix density differentiates OM from OP. MRI is a noninvasive and nonionizing imaging technique that can measure bone matrix density quantitatively in ex vivo and in vivo., Purpose: To demonstrate water + fat suppressed 1 H MRI to compute bone matrix density in ex vivo rat femurs in the preclinical model., Study Type: Prospective., Animal Model: Fifteen skeletally mature female Sprague-Dawley rats, five per group (normal, ovariectomized (OVX), partially nephrectomized/vitamin D (Vit-D) deficient), 250-275 g, ∼15 weeks old., Field Strength/sequence: 7T, zero echo time sequence with water + fat (VAPOR) suppression capability, μCT imaging, and gravimetric measurements., Assessment: Cortical and trabecular bone segments from normal and disease models were scanned in the same coil along with a dual calibration phantom for quantitative assessment of bone matrix density., Statistical Tests: ANOVA and linear regression were used for data analysis, with P-values <0.05 statistically significant., Results: The MRI-derived three-density PEG pellet densities have a strong linear relationship with physical density measures (r 2  = 0.99). The Vit-D group had the lowest bone matrix density for cortical bone (0.47 ± 0.16 g cm -3 ), whereas the OVX had the lowest bone matrix density for trabecular bone (0.26 ± 0.04 g cm -3 ). Gravimetry results confirmed these MRI-based observations for Vit-D cortical (0.51 ± 0.07 g cm -3 ) and OVX trabecular (0.26 ± 0.03 g cm -3 ) bone groups., Data Conclusion: Rat femur images were obtained using a modified pulse sequence and a custom-designed double-tuned ( 1 H/ 31 P) transmit-receive solenoid-coil on a 7T preclinical MRI scanner. Phantom experiments confirmed a strong linear relation between MRI-derived and physical density measures and quantitative bone matrix densities in rat femurs from normal, OVX, and Vit-D deficient/partially nephrectomized animals were computed., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 2., (© 2024 International Society for Magnetic Resonance in Medicine.)

Background: Phosphaturic mesenchymal tumor (PMT) is a rare tumor that causes tumor-induced osteomalacia. Patients present with non-specific symptoms secondary to renal phosphate wasting and decreased bone mineralization. We sought to assess: (1) What are the common presenting features, laboratory and imaging findings, histologic findings of phosphaturic mesenchymal tumors? (2) What are the available treatment strategies for phosphaturic mesenchymal tumors and their long-term outcomes in terms of local recurrence and symptom control after treatment?, Methods: We retrospectively identified patients with a histologic diagnosis of PMT located in the axial or appendicular skeleton, or surrounding soft tissues. A total of 10 patients were finally included in our study., Results: Median tumor size was 1.9 cm (range, 1.1 to 6.1) and median time from symptom onset to diagnosis was 3 years (range, 0.5 to 15 years). All patients but one presented with hypophosphatemia (median 1.9 mg/dL, range 1.2 to 3.2). Pre-operative FGF-23 was elevated in all cases (median 423.5 RU/mL, range 235 to 8950). Six patients underwent surgical resection, three were treated percutaneously (radiofrequency ablation or cryoablation), and one refused treatment. Only one patient developed local recurrence and no patients developed metastatic disease. At last follow-up, nine patients showed no evidence of disease and one was alive with disease., Conclusion: Phosphaturic mesenchymal tumor is a rare tumor presenting with non-specific symptoms. Surgery is the standard treatment when negative margins can be achieved without significant morbidity. In patients with small tumors in surgically-inaccessible areas, radiofrequency ablation or cryoablation can be performed successfully., (© 2024. The Author(s), under exclusive licence to International Skeletal Society (ISS).)

Introduction: This study explores tumor-induced osteomalacia (TIO) through a case series and literature review, assessing the diagnostic potential of 18 F-AlF-NOTA-octreotide ( 18 F-OC) positron emission tomography/computed tomography (PET/CT)., Methods: We analyzed TIO patients who underwent 18 F-OC PET/CT. Parameters such as tumor dimension, the maximum standardized uptake value (SUVmax), the mean standardized uptake value (SUVmean) and metabolic tumor volume (MTV) were meticulously assessed. Clinical features and imaging characteristics pertinent to TIO were reviewed., Results: 6 patients with clinical suspicion of TIO exhibited hypophosphatemia (0.25 to 0.64 mmol/L), elevated alkaline phosphatase (ALP) levels (142 to 506 U/L), and increased parathyroid hormone (PTH) levels (92.9 to 281.7 pg/mL). Of these patients, two underwent FGF-23 testing, with results of 3185.00 pg/ml and 17.56 pg/ml, respectively. Conventional imaging modalities depicted widespread osteoporosis, with several cases demonstrating fractures indicative of osteomalacic and associated pathological fractures. Subsequent 18 F-OC PET/CT facilitated the accurate localization of causative tumors, with histopathological examination confirming the diagnosis of phosphaturic mesenchymal tumor (PMT). The interval from initial clinical presentation to definitive TIO diagnosis spanned approximately 2.5 years (range: 1 - 4 years), with tumors varying in size (maximum diameter: 7.8 to 40.0 mm), SUVmax (5.47 to 25.69), SUVmean (3.43 to 7.26), and MTV (1.27 to 18.59 cm 3 )., Conclusion: The implementation of whole-body 18 F-OC PET/CT imaging emerges as a critical tool in the identification of occult tumors causing TIO. Future investigations incorporating a broader cohort are imperative to further delineate the diagnostic and therapeutic implications of 18 F-OC PET/CT in managing TIO., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li.)

Tumor-induced osteomalacia (TIO) poses a significant diagnostic challenge, leading to increased disease duration and patient burden also by missing clinical suspicion. Today, diagnosis of osteomalacia relies on invasive iliac crest biopsy, if needed. Therefore, a noninvasive method would be beneficial for patients with severe osteomalacia, such as TIO, to inform their clinical management and address specific needs, like estimating the regeneration capacity at high osteoid volumes (OVs) or the potential of a hungry bone syndrome after tumor removal. Furthermore, given the lack of comprehensive histological characterization of TIO, there is a need for additional tissue characterization. Therefore, our assessment encompassed iliac crest biopsies that were examined using quantitative electron backscattered microscopy, Raman spectroscopy, micro-computed tomography, and histology to analyze the biopsy tissue. Our clinical assessment encompassed DXA and high-resolution peripheral quantitative computed tomography (HR-pQCT) alongside with biochemical analyses and clinical evaluations. Combining imaging and clinical data, we established a model to predict the OV. We compared 9 TIO patients with 10 osteoporosis (OPO) patients and 10 healthy controls. Histological analyses confirmed a pronounced OV in TIO patients (OPO: 1.20% ± 1.23% vs TIO: 23.55% ± 12.23%, P < .0005), and spectroscopy revealed lower phosphate levels in TIO biopsies. By combining HR-pQCT and laboratory diagnostics, we developed a linear regression model to noninvasively predict the OV revealing significantly higher modeled OV/BVmodel values of 24.46% ± 14.22% for TIO compared to the control group (5.952% ± 3.44%, P ≤ .001). By combining laboratory diagnostics, namely, ALP and Tt.BMDRadius measured by HR-pQCT, we achieved the calculation of the virtual osteoid volume to bone volume ratio (OV/BVmodel) with a significant correlation to histology as well as reliable identification of TIO patients compared to OPO and control. This novel approach is potentially helpful for predicting OV by noninvasive techniques in diagnostic procedures and improving the clinical management of TIO., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Abstract: A 61-year-old man underwent a resection of tumor in the left tibia that caused osteomalacia 11 years ago. Postoperative bone pain and fatigue symptoms were briefly relieved but then recurred. To identify potential recurrent tumors, 99m Tc-HYNIC-TOC scintigraphy was performed. Images revealed an osteolytic lesion in the right tibia with increased uptake. The lesion was subsequently resected, which pathologically proved a brown tumor. Symptoms of bone pain and weakness caused by osteomalacia did not relieve 4 months after the operation. Here, we present a rare case of brown tumor with high activity on 99m Tc-HYNIC-TOC SPECT/CT, mimicking a culprit tumor of osteomalacia., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Neoplasms that cause tumor-induced osteomalacia are very rarely located in the lung. A 27-year-old man underwent a surgery in the right femoral head to remove the tumor that induced osteomalacia 8 years ago with complete symptomatic relief. However, his bone pain occurred again recently, which lead to suspicion of a recurrent tumor-induced osteomalacia. 68 Ga-DOTATATE PET/CT images showed a pulmonary nodule with mildly increased uptake along with increased activity in the left foot. The pulmonary nodule was subsequently resected and was pathologically confirmed as a phosphaturic mesenchymal tumor. The symptoms were completely relieved postsurgery., Competing Interests: Conflicts of interest and sources of funding: This work was supported by National High Level Hospital Clinical Research Funding (grant number: 2022-PUMCH-B-071). The authors have no conflicts to report., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Tumor-induced rickets/osteomalacia (TIR/O) severely impairs bone microarchitecture and bone strength. However, no study has described the microarchitectural quality of bone in adolescent patients with TIR/O. TIR/O affects bone quality more severely than the inherited causes of hypophosphatemia, the most common form of which is X-linked hypophosphatemia (XLH). Nevertheless, differences of the microarchitectural quality of the bone between TIR/O and XLH have never been clarified. Therefore, in this study, we used high-resolution peripheral quantitative computed tomography to assess bone microarchitecture in five Chinese adolescent TIR/O patients, and these were compared with 15 age- and gender-matched XLH patients as well as 15 age- and gender-matched healthy controls. Compared with the healthy controls, the TIR/O patients presented with significantly lower volumetric bone mineral densities (vBMDs), severely affected bone microarchitecture, and profoundly weaker bone strength. The distal tibia was more severely affected than the distal radius. Compared with the XLH patients, the TIR/O patients showed deteriorated bone quality notably at the distal tibia and in the cancellous compartment, reflected by 45.9% lower trabecular vBMD ( p = 0.029), 40.2% lower trabecular fraction ( p = 0.020), 40.6% weaker stiffness ( p = 0.058), and 42.7% weaker failure load ( p = 0.039) at the distal tibia. The correlation analysis showed that a higher level of serum FGF23 and a lower level of serum phosphate were associated with a poorer bone microarchitecture and a weaker estimated bone strength in the hypophosphatemic patients of our study. In conclusion, our study demonstrated significantly lower vBMDs, severely impaired bone microarchitecture, and profoundly weaker bone strength in Chinese adolescent patients with TIR/O, notably at the distal tibia, compared with the same parameters in age- and sex-matched healthy controls and XLH patients, which was possibly caused by excessive FGF23 production and secretion, chronically severe hypophosphatemia, and weak mechanical stimulus at the lower extremities. These findings further our understanding of the impact of different kinds of hypophosphatemic rickets/osteomalacia on bone quality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiajue, Ni, Jin, Yu, Huo, Wu, Liu, Jin, Lv, Zhou, Xia, Chi, Cui, Pang, Li, Jiang, Wang, Li, Xing, Meng and Xia.)

Phosphaturic mesenchymal tumors (PMTs) are neoplasms associated with tumor-induced osteomalacia. Patients typically present with pathologic fractures in the setting of chronic hypophosphatemic hyperphosphaturic osteomalacia, as well as gradual muscle weakness, bone pain, and difficulty walking. Because of their rarity and nonspecific symptomatology, phosphaturic mesenchymal tumors often go undiagnosed for years. Even when discovered on imaging, the tumors can be diagnostically challenging for radiologists. Phosphaturic mesenchymal tumors often tend to be small and can be located nearly anywhere in the body, and, therefore, can mimic many other tumors. This case highlights the imaging and pathologic markers of a phosphaturic mesenchymal tumor, often found in a patient with tumor-induced osteomalacia., (© 2022 by American Journal of Neuroradiology.)

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Previous studies have revealed generalized mineralization defects and low areal bone mineral density (aBMD) in TIO. However, data on the bone microarchitecture in TIO are limited. In this study, we evaluated the microarchitecture in the peripheral (distal radius and tibia) and axial (lumbar spine) skeleton using high-resolution peripheral quantitative computed tomography (HR-pQCT) and trabecular bone score (TBS) and investigated related factors in a large cohort of Chinese patients with TIO. A total of 186 patients with TIO who had undergone dual-energy X-ray absorptiometry (DXA) or HR-pQCT scans were enrolled. Compared with age-, sex-, and body mass index (BMI)-matched healthy controls, TIO patients (n = 113) had lower volumetric BMD, damaged microstructure, and reduced bone strength in the peripheral skeleton, especially at the tibia. The average TBS obtained from 173 patients was 1.15 ± 0.16. The proportion of patients with abnormal TBS (<1.35) was higher than that with low L 1 to L 4 aBMD Z-score (Z ≤ -2) (43.9% versus 89.6%, p < 0.001). Higher intact fibroblast growth factor 23 (iFGF23), intact parathyroid hormone (iPTH), alkaline phosphatase, and β-isomerized C-terminal telopeptide of type I collagen (β-CTx) levels, more severe mobility impairment, and a history of fracture were associated with poorer HR-pQCT parameters but not with lower TBS. However, greater height loss and longer disease duration were correlated with worse HR-pQCT parameters and TBS. Moreover, TBS was correlated with both trabecular and cortical HR-pQCT parameters in TIO. In conclusion, we revealed impaired bone microarchitecture in the axial and peripheral skeleton in a large cohort of Chinese TIO patients. HR-pQCT parameters and TBS showed promising advantages over aBMD for assessing bone impairment in patients with TIO. A longer follow-up period is needed to observe changes in bone microarchitecture after tumor resection. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Background: Tumor-induced osteomalacia is a rare, acquired paraneoplastic syndrome, including hypophosphatemia, high serum alkaline phosphatase, reduced active vitamin D, suboptimal bone mineral density, bone pain, fragility fractures, and muscle weakness., Case Presentation: We report a case of 74-year-old male of mixed ancestry with hypophosphatemia resistant to treatment despite optimal compliance, associated with profound reduction of bone mineral density and multiple nontraumatic fractures, including bilateral rib fractures, lower-thoracic (T11, T12) vertebrae, and two fractures involving the surgical and anatomical neck of the right humerus. We discuss an approach to identifying the underlying cause of hypophosphatemia associated with fragility fractures, and options for management of this rare condition., Conclusion: Although rare, tumor-induced osteomalacia can be diagnosed if a logical stepwise approach is implemented. Surgery could be curative if the tumor is properly located and is resectable., (© 2022. The Author(s).)

Phosphaturic mesenchymal tumors (PMTs) are rare mesenchymal neoplasms of soft tissue or bone origin that can give rise to a challenge in diagnostic imaging. These tumors are frequently associated with tumor-induced osteomalacia, also called oncogenic osteomalacia, which is a rare paraneoplastic syndrome characterized by ectopic secretion of fibroblast growth factor 23, a hormone that regulates serum phosphate level. PMTs show polymorphic features on both radiological findings and histological examination, causing problems in diagnosis owing to their similarity with other mesenchymal tumors. Thus, this paper aims to describe radiological aspects of PMTs and suggest an imaging pathway for accurate diagnosis throughout the evidence from the literature review., (© 2021. The Author(s).)

Context: Tumor-induced osteomalacia (TIO) is a paraneoplastic disorder, usually caused by benign mesenchymal tumors that produce high levels of fibroblast growth factor 23. The only curative therapy is resection of the causative tumors., Objective: This research was conducted to evaluate the efficacy of 18F-AlF-NOTA-octreotide (18F-OC) positron emission tomography/computed tomography (PET/CT) in detecting TIO and its impact on patient management., Methods: Retrospective analysis was conducted of 17 patients with hypophosphatemic osteomalacia suspected to be TIO. A  18F-OC PET/CT study was performed in all 17 patients to localize the tumor and 68Ga-DOTATATE PET/CT was performed in 4 out of 17 patients; both studies were performed within 1 week of each other. Both studies were interpreted blindly without the knowledge of other imaging findings. The image findings were compared with the results of histopathological examinations and clinical follow-ups., Results: The 18F-OC PET/CT scans were positive in 14 patients. Furthermore, 4 of 14 patients were scanned with both 18F-OC and 68Ga-DOTATATE PET/CT. Both studies were able to localize the tumor in all 4 patients. In total, 14 patients had surgery to remove the lesions. Postsurgical pathological examination confirmed causative tumors in these patients, whose symptoms diminished promptly. Serum phosphate levels normalized, confirming the diagnosis of TIO. 18F-OC PET/CT sensitivity, specificity, and accuracy were 87.5%, 100%, and 88.2% respectively. 18F-OC PET/CT findings affected patient management in 88.2% of cases., Conclusion: 18F-OC PET/CT scan is useful in the detection of tumors causing TIO. Further studies with larger patient populations are needed to validate the result., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale: Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm causing oncogenic osteomalacia. Surgery remains the definitive treatment for PMT, and radiotherapy is seldom employed. However, surgery for PMT involving the head and neck is often difficult due to the local invasion and complicated anatomy. We report the first case of PMT, which was successfully treated with the combination of radiotherapy and supplementation of activated vitamin D., Patient Concerns: A 55-year-old woman suffered from pain in the hip and bilateral femur. Serum phosphate and calcium decreased to abnormal levels. Serum alkaline phosphatase and fibroblast growth factor 23 increased to abnormal levels. The hearing loss of the right ear had continued and a middle ear tumor was revealed., Diagnoses: Subsequent biopsy provided the diagnosis of PMT that caused oncogenic osteomalacia. These clinical and pathological characteristics were consistent with and provided the final diagnosis of benign PMT., Interventions: Surgery of the PMT was difficult and the patient underwent radiotherapy. The prescribed dose was 36 Gy in 10 fractions. Simultaneously, the patient started supplementation of 1,25-dihydroxyvitamin D3 (1-2 μg/day) and continued for 2 years., Outcomes: Near-complete resolution of the symptoms was achieved and abnormal laboratory values recovered. At 5 years of follow-up, the irradiated tumor showed no regrowth. Severe hearing loss of the right ear was not observed., Lessons: Radiotherapy was effective for the PMT and could be an important treatment option for inoperable cases., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by chronic hypophosphatemia and osteomalacia. We present case of a patient with a protracted clinical course of TIO. TIO profoundly affected every aspect of his life with subsequent profound physical and psychosocial disabilities. Method. The review of a complex clinical presentation, serial laboratory investigations, and imaging modalities of a patient with TIO caused by a mesenchymal tumor. Results. The patient presented with chronic lower back pain, severe bilateral leg weakness, and multiple pathological fractures due to severe osteoporosis. His investigations revealed hypophosphatemia, low 1,25 dihydroxyvitamin D, phosphaturia and normal serum calcium, and parathyroid hormone. Elevated fibroblast growth factor 23 (FGF23) confirmed the diagnosis of TIO and 68 Ga-DOTATATE-positron emission tomography/computed tomography (PET/CT) imaging correctly identified a tumor in the left femoral head. His clinical features and biochemical abnormalities promptly recovered after successful surgical resection of the mesenchymal tumor. Conclusion. The present case demonstrated the need to extensively investigate causes of generalized bone pain in patients with hypophosphatemia, as TIO is highly curable. Importantly, 68 Ga-DOTATATE PET/CT imaging successfully identified the FGF23 producing tumor, which was undetectable by conventional imaging, favoring its early use in suspected TIO presentation. The present report highlights the importance of timely diagnosis of this complex medical condition, aiming to improve general awareness and enable better clinical outcomes for this rare disorder., (© 2021 Huajing (Jing) Ni et al., published by Sciendo.)

Sinonasal type hemangiopericytoma is a rare soft tissue tumor. Oncogenic osteomalacia (tumor-induced osteomalacia) is a rare syndrome that develops especially due to benign mesenchymal tumors. Nonspecific general bone pain and weakness delay the diagnosis and treatment of oncogenic osteomalacia, and it is difficult to determine the localization of the primary tumor causing oncogenic osteomalacia. A 43-year-old male patient with nasal hemangiopericytoma with symptoms of oncogenic osteomalacia is presented. The patient had musculoskeletal complaints at first and was diagnosed with lumbar disc herniation and surgery was performed. When his complaints recurred 1 year later, he was re-evaluated and diagnosed with hypophosphatemic osteomalacia. Despite the various treatments he received, his complaints did not decrease but increased, so a detailed examination was decided. When the positive PHEX mutation and very high fibroblast growth factor 23 level were detected, PET-CT imaging was performed with a pre-diagnosis of possible oncogenic osteomalacia, but no finding was found. Then he was evaluated with Ga-68 DOTATATE, and the soft tissue mass filling the right ethmoidal sinus was detected. Due to the relation of the mass with surrounding structures, it was considered unsuitable for total excision and incomplete surgical excision was performed. Pathologic evaluation revealed sinonasal type hemangiopericytoma (glomangiopericytoma). A significant remission in the patient's complaints was observed after the operation. Young patients with osteomalacia with unknown causes should be evaluated for malignancy, and screening and further examinations should be performed., (Copyright © 2021. Published by Elsevier Inc.)

Atraumatic fractures of femur, although not as common as traumatic fractures, are frequently encountered in the clinical practice. They present with non-specific symptoms and can be occult on initial imaging making their diagnosis difficult, sometimes resulting in complications. Overlapping terminologies used to describe these fractures may hamper effective communication between the radiologist and the clinician. In this article, we review various atraumatic fractures of femur, terminologies used to describe them, their imaging findings and differential diagnosis. The article also describes the aetiology, pathophysiology and relevant biomechanics behind these fractures. An approach to atraumatic femoral fractures has been outlined.

Objective: To assess and compare the performance of fluorine-18-labeled fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET/ CT) and gallium-68-labeled tetraazacyclododecanetetraacetic acid-DPhe1-Tyr3-octreotate ( 68 Ga- DOTATATE) PET/CT in the targeted imaging of culprit tumors causing osteomalacia., Methods: This was a clinical retrospective analysis. We analyzed 13 patients (five men, eight women; mean age, 49 years; range, 19-55 years) with suspicion of tumor-induced osteomalacia (TIO) between March 2017 and October 2019. All patients underwent two functional imaging methods to locate the culprittumors. Studies were performed on a PET/CT scanner. The injection doses of 18 F- FDG and 68 Ga-DOTATATE were 0.5mCi/kg and approximately 5.0mCi, respectively. In the two scans, the whole body was captured from head to toe 45 to 60 min after intravenous tracer injection. 68 Ga-DOTATATE PET/CT and 18 F-FDG PET/CT imaging results locate culprit tumors according to the following criteria: (i) abnormal foci uptake concentration was observed locally, and the uptake level was higher than the background level of the right lobe of the liver; (ii) combined CT showed or did not have obvious abnormal density changes; and (iii) non-specific ingestion lesions due to fracture, arthritis, necrosis of femoral head are excluded. Compared with the results of pathological examination and clinical follow-up, the sensitivity, specificity and accuracy of 68 Ga-DOTATATE PET/CT imaging and 18 F-FDG PET/CT imaging for TIO were analyzed., Results: All patients had symptoms of osteomalacia and hypophosphatemia. The lag time (symptoms to PET diagnosis) ranged from 2 to 12 years. There were eight cases of TIO patients and five cases of non-TIO patients confirmed by surgery, pathology and follow-up. Among the eight TIO patients, there were six cases (75.0%) of PMTs, one case (12.5%) of giant cell tumor, one case (12.5%) of hemangiopericutoma. Most (n = 6, 75.0%) of the confirmed tumors in our patient population were in the lower extremities, followed by craniofacial regions (n = 1, 12.5%), and torso (n = 1, 12.5%), respectively. Among the five non-TIO patients, there were two cases of Fanconi syndrome, one case of rickets, and two cases of sporadic osteomalacia hypophosphorus. The culprit tumors could be located either in the bone (n = 5, 62.5%) or the soft tissue (n = 3, 37.5%). 18 F-FDG PET/CT was able to localize the tumor in six (6/13, 46.1%) patients. 68 Ga-DOTATATE PET/CT detected tumor in 8 (83.3%) of 13 patients. The sensitivity of 68 Ga-DOTATATE PET/CT imaging and 18 F-FDG PET/CT imaging in the evaluation of TIO in our patient population were 100% (8/8) vs 75% (6/8). The specificity of the two different methods was 80% (4/5). The overall accuracy was 92.3% (12/13) vs 76.9% (10/13)., Conclusions: 68 Ga-DOTATATE PET/CT is very effective in assessing hypophosphatemia patients with TIO typical symptoms compared with 18 F-FDG. Therefore, in clinically suspected cases of hypophosphatemic osteomalacia, 68 Ga-DOTATATE PET/CT should be preferred as an imaging modality investigation to avoid delay in the treatment of this disease., (© 2021 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Tumor-induced osteomalacia (TIO) is a vanishingly rare paraneoplastic syndrome which is usually caused by phosphaturic mesenchymal tumors (PMTs). The conventional treatment for PMTs is total resection, and ultrasound-guided radiofrequency ablation (RFA) can also be used for the treatment of PMTs patients, especially for patients in whom complete resection may lead to serious complications. We report two cases with PMT who presented syndrome with progressive musculoskeletal complaints and performed ultrasound-guided biopsy and RFA. Ultrasound-guided RFA, which is a safe and effective minimally invasive treatment option, appears to be a valuable alternative to surgery for patients presenting with PMT. We are the first reported case of RFA guided by ultrasonography in the treatment of PMT.

Objective: This paper looks to broaden the methodological possibilities for diagnosing osteomalacia in archaeological bone using micro-CT analysis. Increasing the identification of osteomalacia in paleopathology will provide support for important interpretive frameworks., Materials: Nine embedded and two unembedded rib fragments were sourced from St. Martin's Birmingham and Ancaster, UK, and Lisieux Michelet, France. Of the 11 samples, nine were previously confirmed as osteomalacic, and presented with varying levels of diagenesis and two were non-osteomalacic controls, one of which exhibits diagenetic change., Methods: Micro-CT, backscattered scanning electron microscopy, and light microscopy were employed. Micro-CT images were evaluated for osteomalacic features using corresponding microscopic images., Results: Micro-CT images from osteomalacic samples demonstrated the presence of defective mineralization adjacent to cement lines, areas of incomplete mineralization, and resorptive bays/borders, three key diagnostic features of osteomalacia. Diagenetic change was also detectable in micro-CT images, but did not prevent the diagnosis of osteomalacia., Conclusions: Micro-CT analysis is a non-destructive method capable of providing microstructural images of osteomalacic features in embedded and unembedded samples. When enough of these features are present, micro-CT images are capable of confirming a diagnosis of osteomalacia., Significance: Vitamin D deficiency has important health consequences which operate throughout the life course. Increasing the ability to detect cases of vitamin D deficiency provides researchers with a greater understanding of health and disease in past communities., Limitations: Only adult rib samples were used., Suggestions for Further Research: Paleopathologists should look to test the utility of micro-CT analysis in diagnosing active rickets in subadult individuals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: None

Competing Interests: Competing interests: None declared.

Background: Tumor-induced osteomalacia (TIO) is often misdiagnosed as hypophosphatemia that is not valued. The aim of this study was to analyze the diagnostic value of 68Ga-DOTA-TATE PET/CT imaging for TIO., Methods: Clinical data was retrospectively collected for 56 patients with suspected TIO at the Affiliated Hospital of Southwest Medical University between January 2016 and December 2019, where patients were examined by 68Ga-DOTA-TATE PET/CT and 99mTc-HYNIC-TOC SPECT. Based on the results of the patient's surgery, the diagnostic efficacy of the two imaging techniques on TIO were analyzed., Results: Of the 56 patients, 41 were diagnosed with TIO, with phosphorus levels ranging from 0.25 to 0.75 mmol/L. The remaining 15 patients were non-TIO. Results of 99mTc-HYNIC-TOC SPECT showed 33 cases were positive, with a diagnostic sensitivity, specificity, and accuracy of 58.54%, 86.67%, and 66.07%, respectively. Results of 68Ga-DOTA-TATE PET/CT imaging showed 46 cases were positive, with a diagnostic sensitivity, specificity, and accuracy of 95.13%, 60.00%, 71.43%, respectively. The average tumor size with 68Ga-DOTA-TATE PET/CT imaging was 2.58±1.71 cm. The lesions of 41 patients involved bone and soft tissue, while 18 patients showed osteolytic bone destruction. Distribution was mainly under the skin, followed by intermuscular space, and cortex of bone. Compared with muscle density, the lesions showed uniformly or slightly lower density nodules. Using 99mTc-HYNIC-TOC SPECT, the planar imaging of 30 patients showed that radioactive uptake increased at the early stage, and it can be accurately positioned on the SPECT imaging., Conclusions: The 68Ga-DOTA-TATE PET/CT imaging demonstrated high accuracy in the diagnosis of TIO and detected small lesions, which could provide more comprehensive information for clinicians, and provide a reference value for the treatment and prognosis of patients.

A 50-year-man presented with debilitating lower-limb proximal muscle weakness and hip pain since 3 years. Investigations (serum calcium (8.9 mg/dL), serum phosphorus (1.5 mg/dL), serum albumin (40 g/L), parathyroid hormone (116 pg/mL (12.30 pmol/L)), 25(OH)D3 (25.2 ng/mL (63 nmol/L)) 1,25(OH) 2 D3 (19 pg/mL (45.60 pmol/L)), tubular reabsorption of phosphate of 0.22 and elevated serum fibroblast growth factor 23 (FGF23) (387.7 RU/mL)) were consistent with tumour-induced osteomalacia (TIO). Localisation studies ( 68 Ga DOTATATE positron emission tomography (PET)/CT and 18 FDG-PET/CT) did not reveal any lesion. Re-evaluation after 2 and 5 years with 68 Ga-DOTANOC PET/CT showed 2×1.4 cm progressively increasing rounded soft tissue enhancing mass close to splenic hilum (SUV max: 26.4). Tumour was resected by laparotomy. Both FGF23 (120 RU/mL on day 3) and serum phosphorus (2.5 mg/dL on day 10) normalised with significant clinical improvement after surgery. Histopathology revealed phosphaturic mesenchymal tumour. Here, we report the first case of intra-abdominal mesenchymal tumour causing TIO diagnosed by serial functional imaging., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: The mechanism behind hypophosphatemia in the setting of neurofibromatosis type 1 (NF1) is not known. We describe a possible role of fibroblast growth factor-23 (FGF23) in the pathophysiology of hypophosphatemia in a patient with NF1., Case Description: A 34-year woman with NF1 presented with severe hypophosphatemia, osteomalacia, and elevated plasma FGF23. The patient had considerable improvement on replacement of oral phosphate. Two Ga68 DOTANOC PET-CT scans over a period of 2 years failed to detect any localized uptake. Immuno-staining for FGF23 was absent in the neural-derived tumour cells of the neurofibromas in the proband., Conclusion: The patient with NF1 had elevated circulating FGF23. Tumour cells in the neurofibroma tissues did not stain for FGF23 on IHC. It is unlikely for neurofibromas to contribute to high circulating FGF23 levels in the proband., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Denosumab, a novel agent that inhibits osteoclasts, reduces the risk of fracture in patients with osteoporosis. However, worsening of hypophosphatemia and other symptoms may be induced by denosumab in patients with pre-existing hypophosphatemic osteomalacia. A 58-year-old man with hepatitis B presented with diffuse bone pain and muscle weakness. Denosumab was prescribed by the orthopedist according to documented low bone mass and spine compression fracture. After administering denosumab, the patient's bone pain worsened, and he later developed a right tibia stress fracture. His condition was diagnosed as adult-onset hypophosphatemic osteomalacia complicated by multiple bone fractures, which resulted from Fanconi syndrome with proximal tubulopathy due to tenofovir disoproxil fumarate (TDF) treatment for his hepatitis B. Denosumab use leads to aggressive hypophosphatemic osteomalacia and the complication of stress fractures, because of its effects on bone resorption. Physicians should be aware that in patients with chronic hepatitis B monoinfection who are administered TDF therapy, bone pain or fracture is possible but preventable by timely monitoring of serum phosphate levels. Denosumab should not be used in patients with untreated osteomalacia or vitamin D deficiency, as it may lead not only to hypocalcemia but also to hypophosphatemia in these patients.

Objective: To examine the CT and MR imaging features of phosphaturic mesenchymal tumors (PMTs)., Materials and Methods: With IRB approval, our institutional radiology/pathology database was reviewed for pathologically-proven PMTs. CT and MRI examinations were reviewed in consensus noting several imaging features, and if available, comparative molecular imaging tests were analyzed., Results: We identified 39 patients (21 male, 18 females) with 40 PMTs [mean age, 52.9 ± 14.9 years (range, 14-78)], including 20 bone and 20 soft tissue lesions. Mean maximal lesion diameter was 3.4 ± 2.0 cm (range, 1.1-9.8). 12/18 primary bone lesions (66.6%) were osteolytic and 15/20 (75.0%) had a narrow zone of transition. Internal matrix was present in 18/32 (56.3%) lesions. PMTs were most commonly T1 isointense (31/37, 83.8%), T2 hyperintense (14/36, 38.9%), and solidly enhancing (21/30, 70.0%). The majority (32/36, 88.9%) contained areas of dark T2 signal. 8/9 PMTs were positive by 99m Tc-sestamibi scintigraphy, 2/4 by 111 In-pentetreotide scintigraphy, 2/2 by 68 Ga-DOTATATE PET/CT and 11/13 by 18 F-FDG PET/CT. On FDG PET/CT, the mean SUVmax was 4.1 ± 2.5 (range, 1.5-10.8)., Conclusions: Osseous PMTs are commonly osteolytic with a narrow zone of transition. Both bone and soft tissue PMTs often contain matrix and areas of dark T2 signal on MRI, independent of the presence of matrix. However, PMTs may mimic other bone and soft tissue neoplasms, including fibrous dysplasia, tenosynovial giant cell tumor, and even atypical lipomatous tumor. As such, clinical presentation and laboratory correlation are critical to PMT recognition and accurate diagnosis.

Objective To analyze 68 Ga-DOTA-TATE positron emission tomography/computed tomography (PET/CT) imaging features of tumor-indud osteomalacia (TIO) patients with negative 99m Tc-HYNIC-TOC single photo emission computed tomography (SPECT) findings and to investigate the value of 68 Ga-DOTA-TATE PET/CT in accurate localization of culprit tumors.Methods We retrospectively analyzed 68 Ga-DOTA-TATE PET/CT imaging features including location,size,density,the maximum and mean standardized uptake value in 37 TIO patients with negative 99m Tc-HYNIC-TOC SPECT findings.Results Totally 37 solitary TIO tumors,including 35 phosphaturic mesenchymal tumors and 2 spindle cell tumors confirmed by pathological examinations,were detected via 68 Ga-DOTA-TATE PET/CT scans in the included 37 cases. These 37 TIO tumors showed obviously increased activities,with an maximum standardized uptake value of 7.2±4.3 and mean standardized uptake value of 4.3±2.4. The average maximum diameter was (1.9±0.7) cm. The majority of the tumors occurred in the lower extremities (19/37),followed by the trunk (11/37),maxillary/mandibular bone (5/37),and upper extremities (2/37). In addition,24 bone lesions were located in long bones of lower extremities (13/24),most of which demonstrated eccentric growth (8/13). Osteolytic changes (14/24) were observed mainly in the lesions via the corresponding CT imaging;meanwhile,sclerotic changes presented in nine cases. Of the 13 soft-tissue lesions,the majority (10/13) showed well-circumscribed isodense or hypodense nodules on the CT images,with spot calcification in one lesion located in the pleura.Conclusions 68 Ga-DOTA-TATE PET/CT scans can detect the TIO culprit tumors miss-diagnosed by 99m Tc-HYNIC-TOC SPECT. Somatostatin-receptors highly expressed lesions with focal osteolytic or osteosclerotic change in bone and isodense or hypodense nodules in soft tissue will favor the diagnosis of TIO tumors.

Pseudofractures, lucent bands that occur due to a build-up of osteoid, are a key feature of osteomalacia. In paleopathology, pseudofractures are often marked by small, linear cracks in the cortex of the bone surrounded by irregular, bony spicule formation. Radiography can be used to help diagnose pseudofractures, both clinically and in paleopathology. A detailed understanding of the radiographic appearance of pseudofractures and their development is, therefore, necessary to aid a diagnosis of vitamin D deficiency. The present study examined the clinical literature to determine current ideas on the appearance of pseudofractures with the aim of applying this knowledge to paleopathology. A radiographic study of the characteristics of pseudofractures was performed on five individuals with clear skeletal features of osteomalacia from archaeological sites in Canada and the United Kingdom dating to the medieval period (5th to 15th centuries) and the 18th to 19th century. Results show that the radiographic appearance of pseudofractures could potentially reveal information about the cause of the deficiency and the chronicity of pseudofractures. This type of information has the potential to further our understanding of the lived experiences of archaeological individuals with osteomalacia., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Rickets and residual rickets are often encountered in Dutch archeological skeletal samples. However, no archeological Dutch paleopathological case of adult osteomalacia has been described in literature to date. This paper describes the first four archeological Dutch paleopathological cases of osteomalacia and assesses the value of the various modalities (macroscopic assessment, radiology and histology) that may be used for diagnosis. The skeletal remains investigated originate from the Meerenberg psychiatric hospital cemetery in Bloemendaal, the Netherlands, and date from 1891 - 1936. The remains of 69 adult individuals were inspected for macroscopic lesions which may be associated with osteomalacia. In cases suspect for osteomalacia, complimentary radiological and histological investigations (BSE-SEM and light microscopy) were performed. Macroscopically, four individuals presented with lesions (highly) suggestive of osteomalacia. Histological examination (both BSE-SEM and light microscopy) provided valuable information to come to an eventual diagnosis of osteomalacia in all four cases. Light microscopy proved to be an feasible alternative for BSE-SEM. The added value of radiological analyses was limited. The individuals identified were most likely patients in the psychiatric hospital, and the reason for their institutionalization and/or the regime in the institution may have played a role in the development of the osteomalacia observed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hypophosphatemic rickets/osteomalacia is characterized by defective renal phosphate reabsorption and abnormal bone mineralization. Hypophosphatemic rickets/osteomalacia consists of inherited and acquired forms, many of which have unknown aetiology. In the present study, next‑generation sequencing‑based resequencing was used on samples from Chinese subjects with hypophosphatemic rickets/osteomalacia, aiming to detect the spectrum of pathogenic genes in these patients. A total of 86 hypophosphatemic rickets/osteomalacia patients (ranging from 3 to 70 years old) were recruited. Patients with tumour‑induced osteomalacia (TIO), renal tubular acidosis, renal osteodystrophy, and adefovir‑induced Fanconi syndrome were excluded. Targeted massively parallel resequencing of 196 candidate genes for hypophosphatemic rickets/osteomalacia was performed in the 86 affected unrelated individuals (cases) and in 100 unrelated healthy controls to identify new genes and mutations in known genes that cause hypophosphatemic rickets/osteomalacia. The results identified seven phosphate‑regulating gene with homologies to endopeptidases on the X chromosome (PHEX) mutations (of which two were novel) and one novel dentin matrix protein 1 (DMP1) mutation in eight patients. Following targeted exome sequencing data analysis, 14 candidate disease‑related gene loci were selected, two of which were of most concern regarding disease severity. Further validation of the present results is warranted, with additional sequencing projects and functional tests. To our knowledge, the present study is the largest cohort of cases with hypophosphatemic rickets/osteomalacia to undergo targeted resequencing. The diagnosis and understanding of the molecular aetiologies of these disorders will be improved by this fast and efficient approach.

Phosphaturic mesenchymal tumors are benign tumors causing majority of tumor-induced osteomalacia. These tumors are most commonly located in the lower extremities followed by craniofacial regions. However, intracranial lesion is very rare. Here we describe Ga-DOTATATE PET/CT findings of a recurrent intracranial phosphaturic mesenchymal tumor in a 68 year old woman.

Sjögren's syndrome (SS) is a chronic autoimmune inflammatory disease that typically affects the salivary and lacrimal glands. Renal involvement is relatively uncommon and may precede other complaints. Tubulointestitial nephritis (TIN) is the most common renal involvement in SS. Osteomalacia occurring as the first manifestation of renal tubular disorder due to SS is very rare. We report a 39-year-old male who presented with polydipsia, polyuria, and multiple bone pain. Bone density test showed severe osteoporosis, and laboratory findings suggested hypokalemia, hypophosphatemia, and vitamin D deficiency, which supported the diagnosis of hypophosphatemic osteomalacia. He had nephrogenic loss of phosphate and potassium, tubular acidification, and concentration dysfunction. And, the diagnosis of chronic TIN was subsequently confirmed by renal biopsy. The patient reported dry mouth and physical examination showed multiple dental caries. Xerophthalmia, abnormal morphology, and function of the salivary glands by sonography and scintigraphy, together with positive anti-SSA and anti-SSB, confirmed the diagnosis of SS. The TIN indicated SS as the underlying cause of osteomalacia. After taking supplements of potassium, phosphate, vitamin D, and sodium bicarbonate for 1 month, bone pain was alleviated and serological potassium and phosphorus were also back to normal. In conclusion, renal involvement in SS may be latent and precede the typical sicca symptoms. Osteomalacia can be the first manifestation of renal disorder due to SS. Therefore, autoantibody investigations as well as the lacrimal and salivary gland examinations for SS should be considered and performed for suspected patients.

Histomorphometry or quantitative histology is the analysis on histologic sections of bone resorption, formation and structure parameters. It is the only technique allowing a dynamic evaluation of osteoblast activity after labelling with tetracycline. In addition, the use of computed image analyzer allows the possibility to assess bone microarchitecture. Histomorphometric bone biopsy is a reliable and well-tolerated procedure. Bone samples are taken at iliac crest level under local anesthesia and sedation. Samples are put into methyl-metacrilate resin where the sections are prepared for the microscopic analysis of different histomorphometric parameters. Histomorphometry is used to exclude or confirm the diagnosis of osteomalacia and also to evaluate bone damage associated with particular treatments (for example, glucocorticoids, anticonvulsants) or in case of rare bone diseases (osteogenesis imperfecta). Recently, this approach has been repurposed for the evaluation of bone disease during Chronic Kidney Disease, particularly to differentiate high and low bone turnover osteodystrophy. Kidney Disease Improving Global Outcomes (KDIGO) guidelines have pointed out the situations requiring bone biopsy for histomorphometric analysis. New techniques using molecular biology will improve the accuracy and predictive value of this approach., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Background: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by severe hypophosphatemia and osteomalacia. Nonspecific symptoms make the diagnosis elusive. In addition, locating the responsible tumor(s) is challenging. The aim of this study was to investigate the clinical management and outcomes of TIO., Methods: The clinical features, diagnostic procedures, treatment, and outcomes of 12 patients were reviewed retrospectively., Results: The cohort comprised six men and six women (mean age 45.5 ± 9.9 years, range 23-61 years). The mean duration of disease was 3.7 ± 2.6 years. All patients manifested progressive bone pain, muscle weakness, and/or difficulty walking. Serum phosphorus concentrations were low in all patients (mean 0.42 ± 0.12 mmol/L). Technetium-99m octreotide scintigraphy was performed in 11 patients and showed lesions in the right distal femur, left femoral head, and right tibial plateau, respectively, in three patients. Magnetic resonance imaging (MRI) was negative for lesions in one patient. Two patients underwent biopsies that showed negative histopathology. Two patients, at 2 years and 8 months, respectively, after having negative technetium-99m octreotide studies, underwent 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (CT), which revealed lesions in the sacrum and soft tissue of the left palm, respectively. One tumor was detected by CT and MRI. Overall, lesion sites were the head (two patients, 16.7%), thoracic and lumbar region (two, 16.7%), pelvis (three, 25%), lower limbs (four, 33.3%), and upper limbs (one, 8.3%). All patients underwent surgery, and histopathology showed phosphaturic mesenchymal tumors in each. Postoperatively, serum phosphorus concentrations normalized within 2-7 days in 11 patients. With follow-ups of 1-41 months, surgery was effective in 10 patients. One patient developed local recurrence and another had metastases., Conclusions: Locating tumors responsible for tumor-induced osteomalacia is often challenging. Although complete tumor resection confers a good prognosis in most patients, surveillance for recurrence and metastasis is necessary. Before surgery or when surgery is not indicated, oral phosphate can alleviate symptoms and metabolic imbalance.

Background: An increasing number of case reports suggest that acquired renal Fanconi syndrome may be associated with prolonged use of adefovir against hepatitis B virus. Renal Fanconi syndrome is an uncommon disease, and its complication with nephrolithiasis is quite rare. Herein, we report a rare coexistence of nephrolithiasis and acquired renal Fanconi syndrome in a chronic hepatitis B-positive patient with prolonged adefovir therapy., Case Presentation: The patient presented with osteomalacia and nephrolithiasis. Consequently, extracorporeal shock-wave lithotripsy and left double-J ureteral stent insertion were considered for obstructive nephropathy, which was caused by nephrolithiasis. However, osteomalacia had been misdiagnosed as osteoporosis before admission to our hospital. On admission, a complexity of multiple fractures, hypophosphataemia, glycosuria without hyperglycaemia and non-anion-gap metabolic acidosis indicated a diagnosis of acquired renal Fanconi syndrome induced by adefovir. After switching from adefovir to entecavir, the patient's symptoms and laboratory findings improved significantly., Conclusions: The mechanism responsible for nephrolithiasis in renal Fanconi syndrome is still unclear. We recommend regularly monitoring renal function and serum calcium and serum phosphate to prevent renal Fanconi syndrome during the prolonged use of adefovir for hepatitis B virus.

Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians' awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians' poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.

In 1985, we briefly reported infant sisters with a unique, lethal, autosomal recessive disorder designated congenital sclerosing osteomalacia with cerebral calcification. In 1986, this condition was entered into Mendelian Inheritance In Man (MIM) as osteomalacia, sclerosing, with cerebral calcification (MIM 259660). However, no attestations followed. Instead, in 1989 Raine and colleagues published an affected neonate considering unprecedented the striking clinical and radiographic features. In 1992, "Raine syndrome" entered MIM formally as osteosclerotic bone dysplasia, lethal (MIM #259775). In 2007, the etiology emerged as loss-of-function mutation of FAM20C that encodes family with sequence similarity 20, member C. FAM20C is highly expressed in embryonic calcified tissues and encodes a kinase (dentin matrix protein 4) for most of the secreted phosphoproteome including FGF23, osteopontin, and other regulators of skeletal mineralization. Herein, we detail the clinical, radiological, biochemical, histopathological, and FAM20C findings of our patients. Following premortem tetracycline labeling, the proposita's non-decalcified skeletal histopathology after autopsy indicated no rickets but documented severe osteomalacia. Archival DNA revealed the sisters were compound heterozygotes for a unique missense mutation and a novel deletion in FAM20C. Individuals heterozygous for the missense mutation seemed to prematurely fuse their metopic suture and develop a metopic ridge sometimes including trigonocephaly. Our findings clarify FAM20C's role in hard tissue formation and mineralization, and show that Raine syndrome is congenital sclerosing osteomalacia with cerebral calcification. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Rationale: Hypophosphatemic osteomalacia (HO) is a metabolic bone disease, exhibiting different etiologies such as genetic mutation, tumor induction, dysimmunity, or renal disease. Sjogren's syndrome (SS) is a connective tissue disorder commonly involving exocrine glands; however kidney involvement is also encountered, leading to abnormal phosphorus metabolism, even HO., Patient Concerns: A 47-year-old female patient presented progressively worsening pain in the chest wall, back and bilateral lower extremities as well as muscle weakness was referred to our department., Diagnoses, Interventions and Outcomes: Due to the laboratory test results, radiographic findings and pathologic results, she was diagnosed with adult-onset HO associated with SS. She was then treated with alkalinization, steroids, neutral phosphate, calcium supplements together with activated vitamin D. So far, she recovered uneventfully with relieved pain and increased serum phosphorus level., Lessons: HO may be secondary to renal tubular acidosis of SS patients, and it might be a diagnostic challenge when the kidney involvement in SS is latent and precede the typical sicca symptoms.

Context: Adefovir dipivoxil (ADV) was an important cause of adult-onset hypophosphatemic osteomalacia. However, its clinical characteristics and mechanisms have not been well defined., Objective: The objective of the study was to summarize the clinical characteristics of ADV-induced osteomalacia and to explore the association between ADV-associated tubulopathy and polymorphisms in genes encoding drug transporters., Design, Setting, Patients, and Main Outcome Measure: Seventy-six affected patients were clinically studied. The SLC22A6 and ABCC2 genes were screened and compared with healthy people from the HapMap., Results: Hypophosphatemia, high serum alkaline phosphatase (ALP) levels, hypouricemia, nondiabetic glycosuria, proteinuria, metabolic acidosis and high bone turnover markers were the main metabolic characteristics. Fractures and pseudofractures occurred in 39 patients. Stopping ADV administration, supplementing calcitriol and calcium was effective during the follow-up period. Single SNP analysis revealed a higher percentage of the G/A genotype at c.2934 in exon 22 of the ABCC2 gene (rs3740070) in patients than in healthy people (12% [7 of 58 patients] vs. 0% [0 of 45 patients]; P=0.017), while there was no subject with homozygosity for the A allele at c.2934., Conclusions: ADV can be nephrotoxic at a conventional dosage. The G/A genotype at c.2934 of the ABCC2 gene may be a predictor of patients at greater risk for developing ADV-associated tubulopathy. Larger case-control studies are needed to further verify this finding., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The development of hypophosphataemic osteomalacia has been linked with several treatments, mainly antiretroviral and intravenous iron administration. The frequency of the hypophosphataemia requires monitoring the phosphate after the administration of iron carboxymaltose. We describe a case of a woman with no calcium-phosphorous metabolism disorder, to whom this treatment was prescribed for anaemia due to menorrhagia and intolerance to oral iron. She started with oligoarticular pain, which was spreading with a significant functional loss. The relationship with the administration of intravenous iron was discovered when scintigraphic findings together with laboratory results led to a diagnosis of hypophosphataemic osteomalacia. The patient responded satisfactorily to treatment with phosphate both clinically and in the follow-up bone scintigraphy., (Copyright © 2016 Elsevier España, S.L.U. y SEMNIM. All rights reserved.)