成纤维细胞生长因子-23与肿瘤源性骨软化症

肿瘤源性骨软化症是一种少见的副肿瘤综合征,其病理机制尚不清楚.近年研究发现,肿瘤源性骨软化症患者血磷水平降低而成纤维细胞生长因子(FGF)-23水平显著增高,两者呈负相关性.FGF-23既可抑制肾脏对磷的重吸收及维生素D3活化,又可负性调节成骨细胞分化和基质矿物化.肿瘤源性骨软化症患者肿瘤切除后血FGF-23水平可恢复正常,低磷血症即获纠正,表明FGF-23与肿瘤源性骨软化症的病理生成密切相关.该文就FGF-23表达特点及其在肿瘤源性骨软化症发病机制中的作用等方面的研究进展作一综述.     

肿瘤源性骨软化症1例报道

目的熟悉肿瘤源性骨软化症(tumor induced osteomalacia,TIO)的特征。方法介绍1例低磷性骨软化症的临床表现、实验室检查、影像学和病理检查。结果患者,男,41岁,全身多关节疼痛伴跛行2年余。脊椎后突,肋外翻。血磷0.31mmol/L,血碱性磷酸酶255U/L;全身PET/CT:双侧多根肋骨、骶骨、双侧髋骨骨折;左侧股骨头低密度病灶,放射性摄取增高,肿瘤性病变可能。髋关节MRI:左侧股骨颈局限性骨质缺损,大小约1.0×1.5cm,为良性骨病,肿瘤样病变不除外。区域组织麻醉下行左股骨颈肿瘤切除术,病理报告:间叶源性肿瘤,联系临床考虑考虑为尿磷性间叶肿瘤(Phosphaturic mesenchymal tumor)。术后第7天复查血磷升至0.76mmol/L,碱性磷酸酶降至215U/L,24h尿磷降至8.4mmol/24h。术后一月随访骨痛症状及近端肌肉无力症状均有好转。本例最后诊断肿瘤源性骨软化(TIO)。结论成年发生的无家族史低磷性骨软化症应排除TIO,全身PET/CT功能显像和局部MRI解剖显像可确定肿瘤部位,手术切除肿瘤是治疗的关键。     

低磷抗维生素D骨软化症2例报道

通过低磷抗维生素D骨软化症2例分析,了解其相关发病机理和临床表现,以及实验室相关异常指标和治疗体会。     

家族性低血磷性骨软化症一例

低血磷性骨软化症有X性连锁显性遗传性低血磷性骨软化症(X-link,hypophosphatemia,XLH)、常染色体显性遗传低血磷性骨软化症(autosomal dominant hypophosphatemia osteomalacia,ADHO)、肿瘤相关性低血磷性骨软化症(tumor induced osteomalacia,TIO)3种病因[1].笔者在重庆医科大学附属第一医院进修期间收治1例XLH,报道如下.     

散发性低磷性骨软化症5例误诊临床分析

目的 通过对少见疾病散发性低磷性骨软化症(sporadic hypophosphatemic rickets)误诊原因分析,旨在提高临床对其诊治水平.方法 回顾性分析本院收治的5例散发性低磷性骨软化症的临床资料,包括临床表现、误诊情况、实验室检查以及诊治转归等情况.结果 5例患者中男4例、女1例,初诊分别误诊为原发性骨质疏松症、腰椎间盘突出症、强直性脊柱炎、无菌性股骨头坏死和肿瘤骨转移.临床表现主要为骨痛、骨折、行动困难等.5例患者显示低磷血症和高碱性磷酸酶水平.确诊散发性低磷性骨软化症前,治疗效果不佳,确诊后,经药物治疗病情显著改善.结论 临床上对散发性低磷性骨软化症容易误诊为原发性骨质疏松症等以骨痛、骨折为临床表现的疾病,结合其实验室生化检查及影像学特点,可与常见病相鉴别.     

肿瘤相关性成人低血磷骨软化症1例报道

目的报道一例肿瘤相关性低磷骨软化症(tumor-induced hypophosphorus osteomalacia,TIO),提高临床医师对本病的认识。方法对该TIO患者的临床表现、实验室检查、影像学、病理检查和治疗随访结果进行分析和总结。结果该病例支持成人低血磷骨软化症诊断,手术切除右下腹包块,病理符合良性磷酸盐尿性间叶肿瘤(PMT),进一步行FGF-23组化染色,显示FGF-23(+)。术后患者血磷快速恢复正常,尿磷降低;给予适当钙剂和维生素D制剂治疗,随访12周,患者全身疼痛完全缓解,步态恢复正常;随访至24周,患者的骨转换指标、血钙磷基本维持正常;随访36周时骨密度恢复正常,获得临床治愈。结论对于无家族史成人发病的低血磷骨软化症应考虑肿瘤相关性骨软化症的可能,手术切除肿瘤是治疗的关键,FGF-23染色阳性证实了对TIO的诊断。     

海绵状血管瘤诱发低磷性骨软化症1例并文献复习

<正>低磷性骨软化症是以低磷血症和活性维生素D合成不足造成的以骨骼矿化不良为特征的一种疾病,主要包括X连锁低磷性佝偻病、常染色体显性低磷性佝偻病、肿瘤相关性低磷性骨软化症(tumor induced osteomalacia,TIO)3型。肿瘤源性低磷骨软化症临床少见,2014年6月5日本院收治1例海绵状血管瘤所致TIO,经手术治疗症状明显好转,经文献检索,在     

阿德福韦酯致低血磷性骨软化症2例分析

目的探讨长期服用小剂量阿德福韦酯导致低血磷性骨软化症的临床特点。方法对大连大学附属中山医院2015年2月至6月收治的2例长期口服阿德福韦酯(10 mg/d)导致低血磷性骨软化症患者的临床资料进行回顾性病例分析。结果2例患者分别为75岁男性和79岁女性,均因全身骨痛、肌肉无力和行走困难2年就诊,既往均有慢性乙型肝炎病史,分别口服阿德福韦酯(10 mg/d)8年和4年;化验提示低磷血症(男患为0.44 mmol/L,女患为0.47 mmol/L),低钾血症(男患为3.0mmol/L,女患为3.1 mmol/L),血碱性磷酸酶升高(男患为227 IU/L,女患为566 IU/L),25(OH)D降低(男患为18.16 ng/ml,女患为3 ng/ml),尿常规检测提示尿蛋白及尿糖为阳性,骨密度均提示骨质疏松,影像学显示多发性骨折。停服阿德福韦酯,补充钙剂、骨化三醇、氯化钾和中性磷溶液等治疗,患者生化指标逐渐恢复正常,骨痛及肌肉无力减轻,行走较正常。结论长期服用小剂量阿德福韦酯可以导致低血磷性骨软化症,应定期监测血电解质、肾脏功能、尿常规及骨密度,一旦出现阿德福韦酯相关的肾损伤,应停用阿德福韦酯,并纠正电解质紊乱,以避免引起低血磷性骨软化症。     

血磷对血液透析患者成纤维细胞生长因子23的影响

目的：检测维持性血液透析（MHD）患者血中成纤维细胞生长因子23（FGF－23）水平,探讨血磷等因素对MHD患者FGF－23的影响。方法：MHD患者67例,对照组肾小球过滤率正常共28例,MHD患者根据血磷水平分为低磷组、血磷达标组和高磷组,酶联免疫吸附法测定血中FGF－23的水平,测定对照组及MHD患者血中碱性磷酸酶、钙、磷水平。结果：MHD组血清FGF－23高于对照组（P〈0．01）;低磷组、血磷达标组和高磷组FGF－23水平差异无统计学意义（P〉0．05）,高磷组甲状旁腺激素明显高于低磷组及血磷达标组（P〈0．01）;单因素直线相关分析未见到血磷与FGF－23的相关性（r＝0．018,P〉0．05）;多元回归分析显示1,25（OH）2D3是MHD患者FGF－23的影响因素（β＝0．521,P〈0．01）。结论：MHD患者血中FGF－23水平明显升高,血磷不是维持性血液透析患者FGF－23升高的影响因素。     

距骨肿瘤相关性低磷抗D骨软化症1例报道

肿瘤相关性低磷抗D骨软化症是由于新形成的骨基质不能正常矿化的一种代谢性骨病。该病病因之一是由肿瘤引起肾脏排磷增加而导致的获得性低血磷性骨软化症,由McCance于1947年首次描述。目前国内外文献对该病报道不足200例,发病部位主要集中在股骨和胫骨等负重部位,而未有距骨发生此病的文献报道,现有1例报道如下。     

Burosumab in tumor-induced osteomalacia: A case report

Tumor-induced osteomalacia is a rare cause of acquired hypophosphatemia due to the paraneoplastic overproduction of fibroblast growth factor-23. Unlike many causes of osteomalacia, tumor-induced osteomalacia is curable by resection of the offending tumor. If a patient has a tumor that is unidentifiable, unresectable, or makes the decision to forgo surgery, medical treatment is recommended. Burosumab (KRN23) is a fully human monoclonal antibody against fibroblast growth factor-23 that was recently approved for the treatment of X-linked hypophosphatemia. We present a case of tumor-induced osteomalacia due to two somatostatin receptor avid meningiomas. The patient initially was wheelchair bound due to symptoms of diffuse bone and muscle pain with recurrent traumatic and nontraumatic fractures. Serum phosphate was 1.8 mg/dL (reference range: 2.4–5.0 mg/dL) with no other laboratory or historical cause. Workup revealed two widely separated intracranial meningiomas with typical magnetic resonance imaging characteristics. The duplicity of tumors precluded safe surgery and the potential delay in, or lack of, efficacy using radiosurgery prompted the treatment team to opt for medical treatment. Burosumab was initiated resulting in improvement in pain symptoms and mobility. Serum phosphate normalized. Trials are ongoing to assess the utility of burosumab in the treatment of tumor-induced osteomalacia.     

Oncogenic osteomalacia: two case reports with surprisingly different outcomes

Oncogenic osteomalacia is a rare paraneoplastic syndrome of acquired hypophosphatemic osteomalacia, resulting from a deficit in renal tubular phosphate reabsorption, in which fibroblast growth factor 23 (FGF23) seems to be implicated. This condition is usually associated with a phosphaturic mesenchymal tumor of mixed connective tissue located in the bone or soft tissue. The clinical and the radiologic findings are the same as those seen in osteomalacia, and the biochemical features include renal phosphate loss, low serum phosphate and 1,25-(OH)₂ vitD₃ levels, increased alkaline phosphatase, and normal calcium, PTH, calcitonin, 25-OH-vitD₃ and 25,25-(OH)₂ vitD₃. We present two cases of oncogenic osteomalacia associated with phosphaturic mesenchymal tumors, which were histologically similar, but presented a completely different evolution. In the first patient, the tumor developed on the sole of the foot. Following removal of the mass, the symptoms resolved and biochemical and radiological parameters returned to normal. However, in the second patient, a liver tumor developed and resection did not resolve the disease. Multiple lesions appeared in several locations during follow-up. This disease usually remits with complete tumor resection. Nevertheless, if this is not possible, oral treatment with phosphate, calcium and calcitriol can improve the symptoms. If scintigraphy of the tumor shows octreotide receptors, patients may respond partially to therapy with somatostatin analogs, with stabilization of the lesion.     

肿瘤相关性低磷抗D骨软化症的外科干预治疗

目的观察分析采用外科手术方法治疗肿瘤相关性低磷抗D骨软化症的早期疗效及此类肿瘤的外科学特点.方法从2004年2月至2005年3月,对7例诊断为肿瘤相关性低磷抗D骨软化症的患者进行手术治疗,完整切除软组织肿瘤5例,骨肿瘤2例.术后平均随访4个月（2周～12月）.结果6例患者术后临床症状明显改善,血磷恢复正常,1例未见明显改善.结论肿瘤低磷抗D骨软化症是一种罕见病例,5例软组织肿瘤临床症状少,常规体检不易发现;2例骨肿瘤在X线片上仅表现为骨密度增高区,无明显溶骨及破坏,易被误诊.一经确诊,手术治疗效果良好.     

Effects of Tumor-Induced Osteomalacia on the Bone Mineralization Process

Fibroblast growth factor 23 (FGF23) overexpression has been identified as a causative factor for tumor-induced osteomalacia (TIO) characterized by hypophosphatemia due to increased renal phosphate wasting, low 1,25(OH)₂D₃ serum levels, and low bone density. The effects of long-lasting disturbed phosphate homeostasis on bone mineralization are still not well understood. We report on a patient with a 12-year history of TIO, treated with 1,25(OH)₂D₃ and phosphate, who finally developed hyperparathyroidism with gland hyperplasia before the tumor could be localized in the scapula and removed. During surgery a transiliac bone biopsy was obtained. FGF23 expression in the tumor cells was confirmed by in situ hybridization. Serum FGF23 levels as measured by ELISA were found to be extremely elevated before and decreased after removal of the tumor. Bone histology/histomorphometry and measurement of bone mineralization density distribution using quantitative backscattered electron imaging were performed on the bone biopsy. The data showed important surface osteoidosis and a slightly increased osteoblast but markedly decreased osteoclast number. The mineralized bone volume (−11%) and mineralized trabecular thickness (−18%) were low. The mean degree of mineralization of the bone matrix (−7%), the most frequent calcium concentration (−4.1%), and the amounts of fully mineralized bone (−40.3%) were distinctly decreased, while the heterogeneity of mineralization (+44.5%) and the areas of primary mineralization (+131.6%) were dramatically increased. We suggest that the elevated levels of FGF23 and/or low phosphate concentrations disturb the mineralization kinetics in vivo without affecting matrix mineralization of pre-existing bone packets. K. Nawrot-Wawrzyniak and F. Varga contributed equally to this work.     

Evaluation of hypophosphatemia: lessons from patients with genetic disorders

Phosphate is a key component of several physiologic pathways, such as skeletal development, bone mineralization, membrane composition, nucleotide structure, maintenance of plasma pH, and cellular signaling. The kidneys have a key role in phosphate homeostasis, with 3 hormones having important roles in renal phosphate handling: parathyroid hormone, fibroblast growth factor 23 (FGF-23), and 1,25-dihydroxyvitamin D. Independent of the genetic diseases affecting the FGF-23 pathway (such as hypophosphatemic rickets), hypophosphatemia is a frequent condition encountered in daily practice, and untreated critical hypophosphatemia can induce hemolysis, rhabdomyolysis, respiratory failure, cardiac dysfunction, and neurologic impairment. Rapid correction thus is necessary to avoid severe complications. The aims of this teaching case are to summarize the causes and biological evaluation of hypophosphatemia and provide an overview of our current understanding of phosphate metabolism.     

锁颅骨发育不全症1例

正患者,男,8岁,以左下肢无痛性跛行2年、加重1个月来诊。家长于2年前发现患儿行走稍微跛行,跑步时明显,因无任何不适及疼痛,而未予重视,未曾就诊。近1个月跛行情况加重,无明显诱因,无外伤及疼痛,无家族遗传病史。查体发现左下肢较对侧短缩2 cm,双侧臀纹不对称,表面肤色正常,无压痛及纵向扣击痛,左髋外展内旋轻度受限,膝踝诸关节活动良好,下肢肌力、感觉及足趾循环良好,Trende-     

甲状腺功能亢进症合并骨软化1例并文献复习

甲状腺功能亢进(简称甲亢)是导致碱性磷酸酶升高的原因之一,在甲亢的治疗过程中,如碱性磷酸酶进行性升高,伴骨痛,不能排除骨软化的可能性,值得引起注意。随着对代谢病骨病研究的深入,骨软化患者逐渐增多,病因包括维生素D摄入不足、维生素D吸收和代谢障碍、肾脏疾病(肾病综合征、慢性肾衰、肾小管酸中毒、范可尼综合征等),以及遗传性和肿瘤性低磷性骨软化,其他如重金属中毒、高氟摄入、某些药物等。然而,甲状腺功能亢进症患者出现骨质疏松多见,出现骨软化者较少见,罕有报道,容易漏诊和误诊。本文报道l例甲状腺功能亢进患者口服赛治(甲巯咪唑)后碱性磷酸酶进行性升高,伴全身骨痛,应用骨化三醇后碱性磷酸酶逐渐下降和骨痛消失。为此,甲亢治疗期间,结合国外文献报告,考虑骨软化可能性较大,密切观察患者碱性磷酸酶变化,给予积极对症治疗后,骨软化症状明显缓解。因此,应重视碱性磷酸酶的变化及临床特点,以明确是否合并骨软化并予尽早处理。     

双侧锁骨外端骨折1例报告

2010年1月4日收治1例双侧锁骨外端骨折患者,男,34岁,主因外伤后双肩及头部疼痛1h入院。入院查体：神智清晰,血压110/80mmHg,头于右侧顶部有一5cm的头皮裂伤,边缘不齐,深达皮下层,出血。双侧瞳孔等大等圆,