Adult-onset hypophosphatemic osteomalacia as a cause of widespread musculoskeletal pain:A retrospective case series of single center experience

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.

Development of osteomalacia in a post-liver transplant patient receiving adefovir dipivoxil

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.

The hypoxia-inducible factor-1α activates ectopic production of fibroblast growth factor 23 in tumor-induced osteomalacia

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.

Tumour induced osteomalacia due to a sinonasal hemangiopericytoma:A case report

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.

Oncogenic osteomalacia caused by a phosphaturic mesenchymal tumor of the femur: A case report

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.

Oncogenic Osteomalacia Associated with Phosphaturic Mesenchymal Tumor of the Knee: Case Presentation and Review of the Literature

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.

Tumor-induced osteomalacia with elevated fibroblast growth factor 23: a case of phosphaturic mesenchymal tumor mixed with connective tissue variants and review of the literature

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.

生长抑素受体显像术前定位诊断导致肿瘤诱发低磷骨软化症的原发肿瘤病灶

肿瘤诱发低磷骨软化症(tumor induced osteomalacia, TIO)为间叶源性肿瘤所致低磷骨软化症,多表现为进行性骨痛、骨质疏松、行走困难及活动受限甚至多发骨折,严重影响患者生活质量。手术切除原发灶为治疗TIO的有效方法,但间叶源性肿瘤往往位置隐匿、定位困难。本研究报道5例以生长抑素受体显像术前定位诱发TIO的磷酸盐尿性间叶肿瘤(phosphaturic mesenchymal tumor, PMT)原发病灶的结果。

磷酸盐尿性间叶性肿瘤影像学表现

目的分析磷酸盐尿性间叶性肿瘤的多模态影像学表现。资料与方法回顾性收集2012年11月—2022年6月华中科技大学同济医学院附属同济医院经病理及分子影像证实的磷酸盐尿性间叶性肿瘤10例,分析4例CT、7例MRI及10例核医学影像特征和临床特点。结果10例患者主要临床症状:疼痛8例,无力4例,伴多发骨折9例。实验室检查:10例血磷降低,6例血25-羟维生素D降低,10例血碱性磷酸酶升高。CT平扫混杂密度4例,MRI平扫混杂信号6例,钙化多见,部分伴囊变及脂肪成分;增强后7例呈中度到明显不均匀强化。8例99Tcm-MDP SPECT全身骨显像示多发骨及关节摄取增高,8例18FFDG PET/CT示病灶代谢无增高或轻度增高,10例68Ga-DOTATATE PET/CT均表现为病灶部位明显高摄取。结论磷酸盐尿性间叶性肿瘤患者以疼痛、骨折及低磷血症为典型临床表现,影像学特征为病灶小且隐匿、成分复杂,68Ga-DOTATATE PET/CT显像对检出肿瘤高度敏感。

Levels and dynamic changes of serum fibroblast growth factor 23 in hypophosphatemic rickets/osteomalacia

Background Hypophosphatemic rickets/osteomalacia is a group of diseases characterised by defective mineralization of bone due to hypophosphatemia and low 1,25-dihydroxy vitamin D. To explore the role of fibroblast growth factor 23 （FGF-23） in the regulation of phosphate homeostasis, we measured the circulating concentrations of this growth factor in healthy individuals and in patients with hypophosphatemic rickets/osteomalacia. Methods Nineteen patients with hypophosphatemic rickets/osteomalacia were included in hypophosphatemic group （HP, 12 female and 7 male, mean age was 30 years）, and 19 healthy age-matched individuals served as the control group. Full length FGF-23 fragments were measured by two-site enzyme-linked immunosorbent assay.Results Mean FGF-23 concentrations were significantly higher in the HP group （（87.4±43.6） pg/ml） compared with the control group （（19.2±6.16） pg/ml; P 〈0.001）. In 1 patient with tumour-induced osteomalacia, serum FGF-23 concentrations were 84.1 pg/ml; these concentrations were normalized 2 hours after a hemangiopericytoma resection （7.8 pg/ml）. Subsequently, serum 1,25（OH）2 vitamin D3 concentrations significantly increased from 21.3 pg/ml to 89.3 pg/ml, and serum phosphorus levels were normalized. Conclusions Serum FGF-23 concentrations were markedly elevated in patients with hypophosphatemic rickets. FGF-23 plays an important role in the pathogenesis of hypophosphatemic rickets/osteomalacia.

中年女性-全身骨痛-低磷血症

肿瘤性骨软化症(tumor-induced osteomalacia,TIO)为一种罕见的获得性代谢性骨病,TIO肿瘤常起病隐匿,瘤体较小,分布广泛,发生在颅内更为罕见。本文报告一位44岁女性患者,3年前出现双下肢疼痛、乏力,并逐渐全身骨痛、活动障碍、多处骨折,实验室检查提示低磷血症、碱性磷酸酶(alkaline phosphatase,ALP)高、成纤维细胞生长因子23(fibroblast growth factor-23,FGF-23)水平明显增高,考虑TIO。通过^(68)Ga-DOTATATE PET/CT全身成像发现大脑左侧额叶镰旁占位,并行头部MR进一步确认后,通过手术全切肿瘤,术后患者血磷逐渐恢复正常水平,FGF-23水平下降,全身骨痛消失,病理学检查证实肿瘤为磷酸盐尿性间叶性肿瘤(phosphaturic mesenchymal tumor,PMT)。

Osteomalacia and osteoporosis associated with primary intestinal lymphangiectasis

Primary Intestinal lymphangiectasia （PIL） is a common cause of protein losing enteropathy （PLE）. It will affect enter-hepatic circulation of lipid-soluble vitamin, and absorption of electrolytes, cause malnutrition related osteomalacia or osteoporosis. While seldom health care workers noted to assess and treat osteomalacia or osteoporosis in PIL. Here we report a related case. We found increased parathyroid hormone, decreased 25（OH）D3, low bone mineral density, which indicated that the PIL patient had osteomalacia and/or osteoporosis. Adequate calcium and vitamin D supply can relieve the condition efficaciously. We should pay attention to osteomalacia and osteoporosis in PIL patients.

FGF23基因突变致低血磷性佝偻病一例报告

低血磷性佝偻病/骨软化症是一组由于遗传性或获得性原因导致以低磷血症为主要特征的骨骼矿化障碍性疾病,儿童起病称为佝偻病,成人起病称为骨软化症。儿童患者的主要临床表现为骨骼异常,包括佝偻病和生长障碍。成人患者主要临床表现为骨痛、关节炎、活动受限等。本文报道1例FGF23基因突变致常染色体显性遗传性低血磷性佝偻病(autosomal dominant hypophosphatemic rickets,ADHR)年轻患者及其母亲,经口服补磷和骨化三醇治疗2个月后血磷上升不明显,骨痛改善欠佳。加用琥珀酸亚铁口服治疗2个月后,血磷恢复正常。停止补磷,仅口服琥珀酸亚铁后监测血磷正常,骨痛明显改善。

X连锁显性低血磷性佝偻病/骨软化的治疗

X连锁显性低血磷性佝偻病/骨软化(X-linked hypophosphatemic rickets/osteomalacia,XLH)是由X染色体上内肽酶同源磷调节基因(phosphate regulating endopeptidase homolog X-linked,PHEX)突变导致的最为常见的遗传性低磷血症。XLH的传统治疗方法是补充活性维生素D和中性磷制剂。2018年,成纤维细胞生长因子23(fibroblast growth factors 23,FGF23)单克隆抗体布罗索尤单抗被批准用于治疗1岁以上儿童和成人XLH患者,疗效显著优于传统治疗。其他以FGF23信号通路为治疗靶向的药物,如FGF23/FGFR/αKlotho抑制剂、FGF23 c端片段、FGF23下游通路MAPK的抑制剂等尚在动物实验阶段,在PHEX基因失活性突变的小鼠模型(Hyp小鼠)中被证明可以纠正低磷血症并改善骨骼矿化,有望进一步成为XLH的新治疗手段。

Tumor-induced osteomalacia with IgG4-related lymph node disease

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].

磷酸盐尿性间叶肿瘤误诊分析(附7例)

目的:分析磷酸盐尿性间叶肿瘤(PMT)误诊原因,明确影像学检查路径。方法:回顾性分析我院2017年7月至2022年3月经病理证实PMT患者临床、影像、病理资料。结合文献复习,总结误诊原因,提出影像学检查路径。结果:7例患者3例男性,4例女性,平均年龄为(50.29±15.66)岁(范围17~69岁)。患者表现为不同程度乏力、骨痛等,均伴随骨折,病程平均(5.00±3.25)年(范围1~12年)。患者术前血磷均减低,术后血磷均升高,6例患者血磷在术后7~15天恢复正常,1例失访。6例患者术前碱性磷酸酶升高,1例正常。肿瘤最大径(2.01±1.32)cm(范围0.8~2.5 cm),2例位于软组织,5例位于骨组织。6例行X线检查,显示全身或局部骨质不同程度骨软化和伴随骨折,3例病灶无法显示。6例CT检查中5例骨组织病灶显示为高密度,1例为软组织密度结节。6例MRI平扫T1WI为低、等信号为主,偶尔见高信号,T2WI混杂高信号,内部或边缘可见低信号区。4例MRI增强检查显示病灶中度至明显强化,强化不均匀。结论:PMT影像表现缺乏特异性,容易被误诊。骨质软化、骨痛、骨折以及低血磷、高碱性磷酸酶患者,需考虑此病。可先行OCT检查发现可疑病灶,再行解剖学检查(X线、CT,MRI)对可疑致病肿瘤进一步诊断和术前定位、评估切缘和治疗随访。

肿瘤性骨软化症继发甲状旁腺功能亢进症1例

肿瘤性骨软化症(tumor-induced osteomalacia,TIO)是一种因肿瘤组织分泌过量成纤维细胞生长因子23(fibroblast growth factor 23,FGF23)而引起肾脏排磷增多的代谢性骨病,是一种罕见的副肿瘤综合征。中南大学湘雅三医院2021年9月收治1例罕见的TIO患者,该患者的肿瘤位于舌骨体,并且继发了三发性甲状旁腺功能亢进症。在舌骨体肿瘤切除后,患者的症状并未好转,随后对其进行左侧甲状旁腺切除,患者的低磷血症才逐渐改善。发源于舌部肿瘤的TIO十分少见,同时继发三发性甲状旁腺亢进的病例更是罕见,本报告有助于加深对TIO的了解,并为TIO的诊断和治疗提供参考。

Pathological Fractures in Chronic Hemodialysis Patients in a Teaching Hospital in Senegal: Prevalence and Associated Risk Factors

Introduction: The lack of follow-up and adequate management of chronic kidney disease-mineral and bone disorder (CKD-MBD) in chronic hemodialysis patients is associated with pathological fractures. Few studies are available on the subject in sub-Saharan Africa. The objective of this work was to evaluate the prevalence of pathological fractures in our chronic hemodialysis patients, to analyze their clinical aspects and to determine the factors associated with their occurrence. Patients and Methods: We conducted a retrospective, descriptive and analytical study over 9 years (January 1, 2011, to December 31, 2020) based on the medical records of chronic hemodialysis patients at the CHU Aristide Le Dantec. The diagnosis of pathological fracture was retained in front of any fracture occurring spontaneously or following minimal trauma and confirmed by X-ray. Results: Nineteen cases of pathological fractures were collected with a hospital prevalence of 19.39%. The mean age was 53.32 ± 13.94 years with a sex ratio of 0.36. The average seniority in dialysis was 84.16 ± 29.88 months. Among these patients, one had had 3 episodes of fractures and another 6 episodes. The circumstances of occurrence of the fractures were the fall in 63% of the cases, spontaneously in 37% of the cases. The predominant site of fractures was the femoral neck (47.38% cases). Female gender (p 5 years (p = 0.049), gait disturbances prior to the fracture (p = 0.001), positive CRP (p = 0.028) and the presence of vascular calcifications (p = 0.002) were significantly associated with the occurrence of pathological fractures. Conclusion: This study has identified the factors associated with the occurrence of pathological invoices in hemodialysis patients in our context. These fractures are often associated with the lack of regular biological follow-up due to the low socioeconomic level of our patients.

From Lysis to Hemolysis

Introduction: Sickle cell disease (SCD) is the most common genetic disease in the world. Vitamin D deficiency has been described in several patients with this disease. We report the case of a patient in whom osteomalacia revealed the disease. Observation: The patient was 35 years old, not an alcoholic, not exposed to toxic products, with a family history of sickle cell disease in her 4 brothers and sisters. She reports the appearance of diffuse bone pain but which predominates in the axial skeleton, the ribs and the rhizomelic zones having motivated several hospitalizations. These pains are recurrent with new attacks on the lumbar spine, and sacroiliac joints with intense pain. Paraclinical examinations revealed: normal long bone radiographs without bone lysis, a CT scan of the sacroiliac joints without any aspect of sacroiliitis, but revealing multiple vertebral condensing bone lesions in streaks, diffuse at the level of the iliac wings with osteolysis surrounded by non aggressive osteocondensation. Densitometry was normal, vitamin D deficiency was noted at 29 ng/mL with elevated alkaline phosphatase, normal concentrations of Calcemia and Phosphoremia respectively at 96 mg/L and 36 mg/L, contrasting with hyperparathyroidism with a blood level of parathyroid hormone elevated to twice the normal level at 104.4 pg/mL It should be noted that the patient had received per os vitamin D supplementation before coming to us. The diagnosis of osteomalacia secondary to vitamin D deficiency complicated by secondary hyperparathyroidism was retained. Given the family history, we looked for the existence of sickle cell disease which was finally confirmed on hemoglobin electrophoresis with an AS profile. Conclusion: The association between vitamin D deficiency and sickle cell disease is not uncommon, and is explained by the ethnic origin, race, skin color, genetics and physiological features of patients with this disease rather than the disease itself.

多灶性肿瘤性骨软化症一例报告

肿瘤性骨软化症是一种副肿瘤综合征,以低血磷、高尿磷、血钙及甲状旁腺素正常、1,25-二羟维生素D 3[1,25-dihydroxyvitamin D 3,1,25(OH)2D 3]正常或偏低、成纤维细胞生长因子23(fibroblast growth factor 23,FGF-23)升高为主要特征,经过手术治疗可获得根治。其多灶病例非常罕见。现报道多灶性肿瘤骨软化1例并文献复习,探讨该特殊情况下的处理策略。