Clinical Investigations Of Tumor-induced Osteomalacia,Paget’s Disease Of Bone And Progressive Diaphyseal Dysplasia

Introduction:The clinical data of 31 patients with tumor-induced osteomalacia（TIO）were analyzed to explore the clinical features,diagnosis and treatment methods.We characterized the clinical manifestations,pathogenic gene detection of SQSTM1 and treatment of bisphosphonates in 12 patients with Paget’s disease of bone（PDB）,with the purpose of improving the diagnosis and treatment of PDB.We investigated clinical features and pathogenesis of a family with progressive diaphyseal dysplasia（PDD）by summarizing the clinical characteristics and identifying the mutation of TGFβ1 gene.Methods:31 TIO patients were selected for medical history and physical examination,including sex,age and course of disease.The tumors were located by 18F-FDG PET/CT,^99mTc SPECT/CT,⁶⁸Ga DOTA-TATE PET.Biochemical indicators and FGF-23 levels before and after tumor resection were detected.12 patients with sporadic PDB were enrolled to collect their clinical data and peripheral blood DNA of the patients and their relatives was extracted to identify the SQSTM1 gene mutations.The biochemical markers of patients before and after bisphosphonate treatment,the clinical phenotypic characteristics and therapeutic effects of bisphosphonates were analyzed.Clinical data of two patients in a family clinically diagnosed with progressive diaphyseal dysplasia were collected,and mutations of TGFβ1 were identified by Sanger sequencing in order to summarize the clinical features,disease progression and relevant treatment measures of this family.Results:The main clinical manifestations of TIO patients were decreased blood phosphorus and abnormally elevated ALP level[259（198-391）U/L].They also possessed increased FGF-23[356.14（124.09-661.41）pg/m L]in 24 patients.After the operation,the blood phosphorus levels in 27 patients（87.1%）returned to normal within 30 days and 3 patients（9.7%）within 3 months.The average level of FGF-23decreased significantly to 10.93（5.53-54.85）pg/m L and FGF-23 of 14 patients（45.2%）returned to normal within 30 days after the resection of tumors.The clinical manifestations of 12 patients with PDB were mainly bone pain,bone deformity,abnormally elevated level of ALP[171（132-294）U/L],β-CTX[639（467-878）ng/L]and OC[26（21-49）μg/L].The most common areas affected are the pelvis,spine and skull.No mutation of SQSTM1 gene was detected in this group of cases and the detection rate of pathogenic gene of sporadic PDB patients in China is low,compared with western countries.After 6 months of bisphosphonate treatments,the symptoms of bone pain were significantly improved.The ALP level was 72（53-121）U/L with the downtrend of 50（34-65）%.After 12 months of bisphosphonate treatments,the ALP level was 54（47-63）U/L with the downtrend of 67（52-82）%.Both the father and son developed the disease in childhood of 3 years old and walked with duck steps in a family with PDD.The main symptoms of the disease consisted of body bone pain,fatigue and humble muscle.The laboratory examination mainly showed that ALP increased and bone conversion index increased significantly.X-ray film showed increased bone density and bone sclerosis of the skull,thickened cortex and narrowed medullary cavity in the long bone diaphysis.In addition,the father and his son possessed a missense mutation in the TGFβ1 at the same locus（a missense mutation in exon 4（c.652C>T）that resulted in the transformation of amino acid no.218 from arginine to cysteine）.Clinical symptoms and biochemical indicators were alleviated after bisphosphonate treatment.Conclusion:TIO is not uncommon disease.FGF-23 should be detected for patients with decreased blood phosphorus after the exclusion of genetic and other factors.The disease can be cured with the measures of active location and successful resection of the tumor.The clinical phenotype of Chinese patients with sporadic PDD is different from that of foreign patients,and bisphosphonates are effective in the treatment of this disease.PDD could be caused by a missense mutation of TGFβ1.Bisphosphonates can effectively relieve symptoms and improve abnormal bone metabolism in patients.