Clinical Study And Laboratory Analysis Of Osteopetrosis And Hypophophatemic Oestemalacia

Aims:We conducted a clinical study and laboratory analysis of bone metabolism of rare diseases,such as CLCN7 related osteopetrosis,X-linked dominant hypophosphatemia?XLH?and tumor-induced osteomalacia?TIO?.The objectives of the study were:1)to investigate the clinical manifestations and biochemical characteristics of CLCN7 related osteopetrosis and also identify and analyze the pathogenic genes of patients with osteopetrosis.2)to characterize the genetic,clinical and biochemical features of XLH and study the correlation between the mechanism of XLH and the levels of serum-intact fibroblast growth factor 23?FGF23?.3)to characterize the clinical and biochemical features of TIO and study the correlation between the mechanism of TIO and the levels of serum-intact FGF23.Methods:In the study of CLCN7 related osteopetrosis,we recruited 7 families that have been diagnosed or suspected osteopetrosis clinically but had not been reported before.We analyzed the inheritance patterns,clinical manifestations,biochemical features and radiographic findings of the probands,and extracted their genomic DNA for identification of disease-causing gene?CLCN7?.In the study of XLH,we recruited 21 families that have been diagnosed or suspected XLH clinically but had not been reported.We analyzed the clinical manifestations,inheritance patterns,biochemical features and radiographic findings of the probands,and extracted their genomic DNA for identification of disease-causing gene?PHEX?.We study the correlation between the mechanism of XLH and the levels of serum-intact FGF23.In the study of TIO,we recruited 27 patients that have been diagnosed TIO clinically but had not been reported.We analyzed the clinical manifestations,biochemical features and radiographic findings and treatment of TIO.Results:We identified five CLCN7 related autosomal dominant osteopetrosis type II?ADO-II?families and two CLCN7 related intermediate autosomal recessive osteopetrosis?IARO?families.Seven mutations in CLCN7 gene were identified.Among these mutations,two heterozygous mutations?c.2236T>G and c.2232-2A>G?,the homozygous mutation?c.2377G>C?and the compound heterozygous mutation?c.1409C>T and c.647₆48dupTG?were novel.Five were male and four were female among the patients of ADO-II and the patients with ADO-II were diagnosed at 5-47 years old.One patient exhibited a lower than normal height.There were 1 pigeon breast,1 dental abnormalities,1 thrombocytopenia,1visual impairment,1 splenomegaly,3 fractures,and 3 anaemia.We identified 19different PHEX mutations from 21 unrelated Chinese families.In the 21 families,12are familial mutations and nine are sporadic.11 were novel mutations and four are sporadic.The number of males is 11 and females is 24.Adults and children with XLH were diagnosed at a range age of 23-63 years old and 2-16 years old,respectively.The height of 9 juvenile patients was less than two standard deviations from the same age group,and the heights of adult females and males were[140.0?134.6-145.0?]cm and[130.0?127.3-145.0?]cm,respectively.There were 30 lower extremity deformities,22 dental abnormalities,and 8 instances of bone pain.Significant differences were found when those FGF23 levels[54.9?42.2-86.4?]pg/mLwere compared to measurements from the normal controls[40.6?33.9-51.8?]pg/mL?P=0.004?,and the patient group had higher levels than the healthy group.In the study of TIO,27 patients were diagnosed.Nonspecific progressive bone pain,muscle weakness,decreased serum phosphorus,elevated alkaline phosphatase?ALP?levels,normal serum calcium levels and elevated FGF23 levels[285.9?109.5-596.5?pg/mL]were found in these patients before surgery.Complete surgical resection is the effective treatment of TIO.The serum phosphorus[0.82?0.73-0.88?mmol/L after 3days of surgery],FGF23 levels[3.0?3.0-3.1?mmol/L after 1 day of surgery]returned to normal,postoperatively.Conclusion:Our study identified the mutations of CLCN7 in six patients with familial osteopetrosis and one patient with sporadic osteopetrosis.It confirmed the heterogeneity of osteopetrosis.Moreover,we enriched the phenotypes of patients with ADO-II and IARO.The findings broaden the spectrum of CLCN7 gene mutations.What's more,this study compared the X-ray findings of ADO-II and IARO and improved the understanding of CLCN7 related osteopetrosis via different inheritance patterns.Our study also confirmed that XLH was the most prevalent form of inherited ricket in Chinese,which enriched the spectrum of PHEX gene mutations.We emphasized the high incidence of sporadic cases for fear of misdiagnosis of sporadic patients.We also emphasized prenatal diagnosis and genetic identification for the prevention,diagnosis and treatment of XLH.This study compared the X-ray findings of children and adults as well as improved the understanding of XLH.In this study,27 patients with TIO were diagnosed,and the significance of FGF23 in the qualitative diagnosis and ^99mTc-octreotide scintigraphy(^99mTc-OCT)in the localized diagnosis of TIO were emphasized.It was confirmed that surgical treatment was the only effective way to cure the disease.The patient's symptoms were relieved after surgery.The serum phosphorus and FGF23 levels returned to normal,postoperatively.