Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures...Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.展开更多
Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpresse...Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "glomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.展开更多
To the Editor:A 60-year-old man presented with progressively worsened limb weakness of 4 years duration,which had rendered him wheelchair-bound since May 2018.The patient also had muscle and joint pain and numbness.He...To the Editor:A 60-year-old man presented with progressively worsened limb weakness of 4 years duration,which had rendered him wheelchair-bound since May 2018.The patient also had muscle and joint pain and numbness.He had a history of type 2 diabetes,hypertension,and gout,no family history of bone disease.He took diabetic peripheral neuropathy treatment but the symptoms kept progressing.On admission,the patient was well developed and in normal body shape.Physical examination was unremarkable except for all-sided weakness.Laboratory evaluation showed hypophosphatemia with notable elevated urinary phosphorus loss.Other laboratory abnormalities were elevated alkaline phosphatase levels,mild insufficient vitamin D status,and mild elevated parathyroid hormone.After bone scintigraphy failed to localize an osseous tumor,whole-body positron emission tomography(PET)/computed tomography(CT)using 18F-fluorodeoxyglucose(18F-FDG)and the radiolabeled somatostatin analog 68Ga-DOTATATE were performed to make clear diagnosis of oncogenic hypophosphatemic osteomalacia.Both of the examinations revealed a suspicious mass in subcutaneous tissue around the umbilicus and enlarged right axillary lymph nodes[Figure 1A and 1B].展开更多
To investigate tumor-induced angiogenesis under the influence of the mechanical environments inside and outside the tumor, mathematical model of tumor angiogenesis was developed. In the model, extra-cellular matrix （...To investigate tumor-induced angiogenesis under the influence of the mechanical environments inside and outside the tumor, mathematical model of tumor angiogenesis was developed. In the model, extra-cellular matrix （ECM） was treated as a thin plane. The displacement of ECM is obtained from the force balance equation consisted of the ECs traction, the ECM visco-elastic forces and the exter- nal forces. Simulation results show that a layered capillary network is obtained with a well vascularized region at the periphery of the tumor. The present model can be used as a valid theoretical method in the basic researches in tumorinduced angiogenesis.展开更多
BACKGROUND Osteomalacia(OM)is frequently confused with various musculoskeletal or other rheumatic diseases,especially in patients with adult-onset widespread musculoskeletal pain because of its low prevalence and non-...BACKGROUND Osteomalacia(OM)is frequently confused with various musculoskeletal or other rheumatic diseases,especially in patients with adult-onset widespread musculoskeletal pain because of its low prevalence and non-specific manifestations.AIM To facilitate the early diagnosis and etiology-specific treatment of adult-onset hypophosphatemic OM.METHODS A retrospective review of medical records was performed to screen adult patients who visited a physiatry locomotive medicine clinic(spine and musculoskeletal pain clinic)primarily presenting with widespread musculoskeletal pain at a single tertiary hospital between January 2011 and December 2019.We enrolled patients with hypophosphatemia,high serum bone-specific alkaline phosphatase levels,and at least one imaging finding suggestive of OM.RESULTS Eight patients with adult-onset hypophosphatemic OM were included.The back was the most common site of pain.Proximal dominant symmetric muscle weakness was observed in more than half of the patients.Bone scintigraphy was the most useful imaging modality for diagnosing OM because radiotracer uptake in OM showed characteristic patterns.Six patients were diagnosed with adefovir(ADV)-induced Fanconi syndrome,and the other two patients were diagnosed with tumor-induced OM and light-chain nephropathy,respectively.After phosphorus and vitamin D supplementation and treatment for the underlying etiologies,improvements in pain,muscle strength,and gait were observed in all patients.CONCLUSION Mechanical pain characteristics,hypophosphatemia,and distinctive bone scintigraphy patterns are the initial diagnostic indicators of adult-onset hypophosphatemic OM.ADV-induced Fanconi syndrome is the most common etiology of hypophosphatemic OM in hepatitis B virus-endemic countries.展开更多
We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B ...We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B virus infection. The patient had generalized bone pain,with severe hypophosphatemia after 20 mo of ADV therapy. Radiographic studies demonstrated the presence of osteomalacia. The peak plasma ADV level was 38 ng/mL after administration of ADV at 10mg/day. It was also found that ADV affected the metabolism of tacrolimus,a calcineurin-inhibitor,and caused an increase in the plasma levels of tacrolimus. The disability was reversed with the withdrawal of ADV and with mineral supplementation. ADV can cause an elevation of plasma tacrolimus levels,which may be associated with renal dysfunction. High levels of ADV and tacrolimus can cause nephrotoxicity and osteomalacia. This case highlights the importance of considering a diagnosis of osteomalacia in liver transplantation recipients treated with both ADV and tacrolimus.展开更多
Tumour induced osteomalacia(TIO) is a rare and often unrecognized cause of hypophosphatemia. We report on a case of TIO due to a hemangiopericytoma originating from the left nasal sinus. The patient was a 55-year-old ...Tumour induced osteomalacia(TIO) is a rare and often unrecognized cause of hypophosphatemia. We report on a case of TIO due to a hemangiopericytoma originating from the left nasal sinus. The patient was a 55-year-old male with a 3-year history of left hip pain and an undisplaced left hip fracture. Biochemical testing demonstrated low levels of serum phosphate and serum 1,25-dihydroxyvitamin D, and an elevated level of fibroblast growth factor 23. Octreotide scanning demonstrated uptake in the left nasal sinus area and a computed tomography scan revealed a left nasal sinus mass. The patient underwent surgical resection of the mass and histology was consistent with a sinonasal hemangiopericytoma. His serum phosphate levels normalized almost immediately after surgery and he had complete resolution of hip pain. Our case highlights the importance of considering TIO when assessing patients with low serum phosphate.展开更多
BACKGROUND Oncogenic osteomalacia caused by phosphaturic mesenchymal tumors is very difficult to detect.We report a case of tumor-induced osteomalacia caused by a phosphaturic mesenchymal tumor of the left femur in a ...BACKGROUND Oncogenic osteomalacia caused by phosphaturic mesenchymal tumors is very difficult to detect.We report a case of tumor-induced osteomalacia caused by a phosphaturic mesenchymal tumor of the left femur in a middle-aged woman after medical imaging and biopsy.CASE SUMMARY A 57-year-old woman presented with progressive bone pain for five years.She was diagnosed with hypophosphatemic osteomalacia,as her laboratory data showed low serum phosphorus and low serum calcium.Her knee joint radiography revealed an osteolytic lesion of the left femur.A computed tomography scan showed mixed density shadows in the left femur.Magnetic resonance imaging of the left femur showed the presence of an oval area with a hypointense signal in T1-weighted magnetic resonance imaging(MRI)and highlow mixed signal in T2-weighted MRI.Biopsy samples revealed the presence of short spindle cells,vascularization,and characteristics of phosphaturic mesenchymal tumors.Tumor resection was performed,and the clinical presentations and laboratory abnormalities were reversed.CONCLUSION Diagnosis of oncogenic osteomalacia is difficult due to the varieties and localization of source tumors and absence of pathognomonic biomedical signs.Our case highlights the importance of a combination of medical imaging and biopsy in the diagnosis of oncogenic osteomalacia caused by a phosphaturic mesenchymal tumor.展开更多
Oncogenic osteomalacia (OOM) is an uncommon metabolic and bone disease caused by fibroblast growth factor 23 (FGF23), a phosphaturic factor produced by phosphaturic mesenchymal tumors (mixed connective tissue variant,...Oncogenic osteomalacia (OOM) is an uncommon metabolic and bone disease caused by fibroblast growth factor 23 (FGF23), a phosphaturic factor produced by phosphaturic mesenchymal tumors (mixed connective tissue variant, PMTMCTV) characterized by phosphate leakage from kidneys and subsequent hypophosphatemia. In this paper, we present the case of a patient, 42-year-old woman affected by left side limp and pain involving lumbar spine, pelvis and hip joints, referred to the Rheumatology Department of our Hospital for the treatment of a suspected sero-negative spondilo-arthritis. During hospitalization patient began an immuno-suppressive therapy with TNF-alpha inhibitors associated with Pamidornate, Indometacin, Esomeprazole and vitamin D3. Nevertheless pain did not decrease and a new examination found a worst hypophosphatemia (1 mg/dl) with normal Ca and PTH’s plasma values. During the same check-up a painful bulge on the anterior part of the right knee was observed and the Magnetic Resonance Imaging scan revealed an ovular solid lesion in the soft tissue closed to the upper part of the patella. Histological analysis identified the lesion as a PMTMCTV. After surgical removal patient got complete recovery. We will discuss about diagnostic evaluation, differential diagnosis and treatment.展开更多
基金supported by NIH grants AR049510 (TLC) and AR045955 (LDQ)
文摘Tumor-induced osteomalacia （TIO） is a rare paraneoplastic syndrome in which ectopic production of fibroblast growth factor 23 （FGF23） by non-malignant mesenchymal tumors causes phosphate wasting and bone fractures. Recent studies have implicated the hypoxia-inducible factor-la （HIF-la） in other phosphate wasting disorders caused by elevated FGF23, including X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemia. Here we provide evidence that HIF-la mediates aberrant FGF23 in TIO by transcriptionally activating its promoter. Immunohistochemical studies in phosphaturic mesenchymal tumors resected from patients with documented TIO showed that HIF-la and FGF23 were co-localized in spindle- shaped cells adjacent to blood vessels. Cultured tumor tissue produced high levels of intact FGF23 and demonstrated increased expression of HIF-la protein. Transfection of MC3T3-E1 and Saos-2 cells with a HIF-la expression construct induced the activity of a FGF23 reporter construct. Prior treatment of tumor organ cultures with HIF-la inhibitors decreased HIF-la and FGF23 protein accumulation and inhibited HIF-la-induced luciferase reporter activity in transfected cells. Chromatin immunoprecipitation assays confirmed binding to a HIF-la consensus sequence within the proximal FGF23 promoter, which was eliminated by treatment with a HIF-la inhibitor. These results show for the first time that HIF-la is a direct transcriptional activator of FGF23 and suggest that upregulation of HIF-la activity in TIO contributes to the aberrant FGF23 production in these patients.
文摘Tumor-induced osteomalacia (TIO), or oncogenic osteomalacia (OOM), is a rare acquired paraneoplastic disease characterized by renal phosphate wasting and hypophosphatemia. Recent evidence shows that tumor-overexpressed fibroblast growth factor 23 (FGF23) is responsible for the hypophosphatemia and osteomalacia. The tumors associated with TIO are usually phosphaturic mesenchymal tumor mixed connective tissue variants (PMTMCT). Surgical removal of the responsible tumors is clinically essential for the treatment of TIO. However, identifying the responsible tumors is often difficult. Here, we report a case of a TIO patient with elevated serum FGF23 levels suffering from bone pain and hypophosphatemia for more than three years. A tumor was finally located in first metacarpal bone by octreotide scintigraphy and she was cured by surgery. After complete excision of the tumor, serum FGF23 levels rapidly decreased, dropping to 54.7% of the preoperative level one hour after surgery and eventually to a little below normal. The patient's serum phosphate level rapidly improved and returned to normal level in four days. Accordingly, her clinical symptoms were greatly improved within one month after surgery. There was no sign of tumor recurrence during an 18-month period of follow-up. According to pathology, the tumor was originally diagnosed as "glomangioma" based upon a biopsy sample, "proliferative giant cell tumor of tendon sheath" based upon sections of tumor, and finally diagnosed as PMTMCT by consultation one year after surgery. In conclusion, although an extremely rare disease, clinicians and pathologists should be aware of the existence of TIO and PMTMCT, respectively.
基金the National Natural Science Foundation of China(No.81670754).
文摘To the Editor:A 60-year-old man presented with progressively worsened limb weakness of 4 years duration,which had rendered him wheelchair-bound since May 2018.The patient also had muscle and joint pain and numbness.He had a history of type 2 diabetes,hypertension,and gout,no family history of bone disease.He took diabetic peripheral neuropathy treatment but the symptoms kept progressing.On admission,the patient was well developed and in normal body shape.Physical examination was unremarkable except for all-sided weakness.Laboratory evaluation showed hypophosphatemia with notable elevated urinary phosphorus loss.Other laboratory abnormalities were elevated alkaline phosphatase levels,mild insufficient vitamin D status,and mild elevated parathyroid hormone.After bone scintigraphy failed to localize an osseous tumor,whole-body positron emission tomography(PET)/computed tomography(CT)using 18F-fluorodeoxyglucose(18F-FDG)and the radiolabeled somatostatin analog 68Ga-DOTATATE were performed to make clear diagnosis of oncogenic hypophosphatemic osteomalacia.Both of the examinations revealed a suspicious mass in subcutaneous tissue around the umbilicus and enlarged right axillary lymph nodes[Figure 1A and 1B].
基金supported by the National Natural Science Foundation of China (10372026 and 10772751)Shanghai Leading Academic Discipline Project (B 112).
文摘To investigate tumor-induced angiogenesis under the influence of the mechanical environments inside and outside the tumor, mathematical model of tumor angiogenesis was developed. In the model, extra-cellular matrix （ECM） was treated as a thin plane. The displacement of ECM is obtained from the force balance equation consisted of the ECs traction, the ECM visco-elastic forces and the exter- nal forces. Simulation results show that a layered capillary network is obtained with a well vascularized region at the periphery of the tumor. The present model can be used as a valid theoretical method in the basic researches in tumorinduced angiogenesis.
基金This study was approved by the Institutional Review Board of Samsung Medical Center(approval number:2020-09-027-001).
文摘BACKGROUND Osteomalacia(OM)is frequently confused with various musculoskeletal or other rheumatic diseases,especially in patients with adult-onset widespread musculoskeletal pain because of its low prevalence and non-specific manifestations.AIM To facilitate the early diagnosis and etiology-specific treatment of adult-onset hypophosphatemic OM.METHODS A retrospective review of medical records was performed to screen adult patients who visited a physiatry locomotive medicine clinic(spine and musculoskeletal pain clinic)primarily presenting with widespread musculoskeletal pain at a single tertiary hospital between January 2011 and December 2019.We enrolled patients with hypophosphatemia,high serum bone-specific alkaline phosphatase levels,and at least one imaging finding suggestive of OM.RESULTS Eight patients with adult-onset hypophosphatemic OM were included.The back was the most common site of pain.Proximal dominant symmetric muscle weakness was observed in more than half of the patients.Bone scintigraphy was the most useful imaging modality for diagnosing OM because radiotracer uptake in OM showed characteristic patterns.Six patients were diagnosed with adefovir(ADV)-induced Fanconi syndrome,and the other two patients were diagnosed with tumor-induced OM and light-chain nephropathy,respectively.After phosphorus and vitamin D supplementation and treatment for the underlying etiologies,improvements in pain,muscle strength,and gait were observed in all patients.CONCLUSION Mechanical pain characteristics,hypophosphatemia,and distinctive bone scintigraphy patterns are the initial diagnostic indicators of adult-onset hypophosphatemic OM.ADV-induced Fanconi syndrome is the most common etiology of hypophosphatemic OM in hepatitis B virus-endemic countries.
文摘We report the case of a patient treated with living donor-related liver transplantation who suffered from osteomalacia during adefovir dipivoxil (ADV)-containing antiviral therapy for lamivudine-resistant hepatitis B virus infection. The patient had generalized bone pain,with severe hypophosphatemia after 20 mo of ADV therapy. Radiographic studies demonstrated the presence of osteomalacia. The peak plasma ADV level was 38 ng/mL after administration of ADV at 10mg/day. It was also found that ADV affected the metabolism of tacrolimus,a calcineurin-inhibitor,and caused an increase in the plasma levels of tacrolimus. The disability was reversed with the withdrawal of ADV and with mineral supplementation. ADV can cause an elevation of plasma tacrolimus levels,which may be associated with renal dysfunction. High levels of ADV and tacrolimus can cause nephrotoxicity and osteomalacia. This case highlights the importance of considering a diagnosis of osteomalacia in liver transplantation recipients treated with both ADV and tacrolimus.
文摘Tumour induced osteomalacia(TIO) is a rare and often unrecognized cause of hypophosphatemia. We report on a case of TIO due to a hemangiopericytoma originating from the left nasal sinus. The patient was a 55-year-old male with a 3-year history of left hip pain and an undisplaced left hip fracture. Biochemical testing demonstrated low levels of serum phosphate and serum 1,25-dihydroxyvitamin D, and an elevated level of fibroblast growth factor 23. Octreotide scanning demonstrated uptake in the left nasal sinus area and a computed tomography scan revealed a left nasal sinus mass. The patient underwent surgical resection of the mass and histology was consistent with a sinonasal hemangiopericytoma. His serum phosphate levels normalized almost immediately after surgery and he had complete resolution of hip pain. Our case highlights the importance of considering TIO when assessing patients with low serum phosphate.
基金Supported by Research Fund of Hangzhou Normal University Affiliated Hospital
文摘BACKGROUND Oncogenic osteomalacia caused by phosphaturic mesenchymal tumors is very difficult to detect.We report a case of tumor-induced osteomalacia caused by a phosphaturic mesenchymal tumor of the left femur in a middle-aged woman after medical imaging and biopsy.CASE SUMMARY A 57-year-old woman presented with progressive bone pain for five years.She was diagnosed with hypophosphatemic osteomalacia,as her laboratory data showed low serum phosphorus and low serum calcium.Her knee joint radiography revealed an osteolytic lesion of the left femur.A computed tomography scan showed mixed density shadows in the left femur.Magnetic resonance imaging of the left femur showed the presence of an oval area with a hypointense signal in T1-weighted magnetic resonance imaging(MRI)and highlow mixed signal in T2-weighted MRI.Biopsy samples revealed the presence of short spindle cells,vascularization,and characteristics of phosphaturic mesenchymal tumors.Tumor resection was performed,and the clinical presentations and laboratory abnormalities were reversed.CONCLUSION Diagnosis of oncogenic osteomalacia is difficult due to the varieties and localization of source tumors and absence of pathognomonic biomedical signs.Our case highlights the importance of a combination of medical imaging and biopsy in the diagnosis of oncogenic osteomalacia caused by a phosphaturic mesenchymal tumor.
文摘Oncogenic osteomalacia (OOM) is an uncommon metabolic and bone disease caused by fibroblast growth factor 23 (FGF23), a phosphaturic factor produced by phosphaturic mesenchymal tumors (mixed connective tissue variant, PMTMCTV) characterized by phosphate leakage from kidneys and subsequent hypophosphatemia. In this paper, we present the case of a patient, 42-year-old woman affected by left side limp and pain involving lumbar spine, pelvis and hip joints, referred to the Rheumatology Department of our Hospital for the treatment of a suspected sero-negative spondilo-arthritis. During hospitalization patient began an immuno-suppressive therapy with TNF-alpha inhibitors associated with Pamidornate, Indometacin, Esomeprazole and vitamin D3. Nevertheless pain did not decrease and a new examination found a worst hypophosphatemia (1 mg/dl) with normal Ca and PTH’s plasma values. During the same check-up a painful bulge on the anterior part of the right knee was observed and the Magnetic Resonance Imaging scan revealed an ovular solid lesion in the soft tissue closed to the upper part of the patella. Histological analysis identified the lesion as a PMTMCTV. After surgical removal patient got complete recovery. We will discuss about diagnostic evaluation, differential diagnosis and treatment.
