CYP27B1基因突变所致维生素D依赖性佝偻病ⅠA型患儿临床特征与基因分析  

Clinical characteristics and genetic analysis of vitamin D-dependent ricketsⅠA caused by CYP27B1 gene mutation

作　　者：杜牧[1] 陈晓波[1] 宋福英[1] 刘子勤[1] 钱坤 Du Mu;Chen Xiaobo;Song Fuying;Liu Ziqin;Qian Kun(Department of Endocrinology,Children′s Hospital,Capital Institute of Pediatrics,Beijing 100020,China)

机构地区：[1]首都儿科研究所附属儿童医院内分泌科,北京100020

出　　处：《中华妇幼临床医学杂志（电子版）》2022年第2期175-184,共10页Chinese Journal of Obstetrics & Gynecology and Pediatrics(Electronic Edition)

基　　金：北京市卫生计生委首都卫生发展科研专项项目(首发2018-2-2101);北京市属医院科研培育计划项目(PX2020054)。

摘　　要：目的探讨维生素D依赖性佝偻病(VDDR)ⅠA型患儿的临床特征,以及CYP27B1基因突变情况。方法选择2019年3月至12月,于首都儿科研究所附属儿童医院内分泌科确诊为VDDRⅠA型的2例患儿(患儿1、2)为研究对象。采用回顾性研究方法,①分析其临床表现,基因检测、治疗、转归及随访结果等。②对2例患儿检出的新突变,采用MutationTaster、SIFT、PROVEAN、Polyphen-2等蛋白质功能预测软件,预测该基因新突变的致病性。按照2015年美国医学遗传学与基因组学学会(ACMG)制定的《ACMG遗传变异分类标准与指南》,对该基因新突变致病性进行分级。③通过比对8种灵长类及100种脊椎动物CYP27B1基因编码蛋白质序列,判断新突变位点在不同物种中的保守性。④利用Rosetta软件,对CYP27B1基因新突变后编码蛋白质建立同源3D模型,分析突变前、后蛋白质结构。本研究经首都儿科研究所伦理委员会批准(审批文号:首都儿科研究所SHERLL2020003)。结果①一般临床资料:患儿1、2均为男性患儿,年龄分别为5岁7个月和1岁8个月,分别因为"双下肢畸形3年"及"走路始步态不稳8个月",于病例收集医院住院治疗。②入院查体:身高均低于同性别、年龄健康儿童,均存在肋下缘、双膝关节外翻,双下肢呈"X"型。患儿1存在方颅畸形、"鸡胸"、肋骨"串珠"样改变。③入院时实验室及影像学检查:血钙、磷均降低,25-羟维生素D3[25(OH)-D3]稍低(患儿1)或正常(患儿2),碱性磷酸酶(ALP)、甲状旁腺素(PTH)均明显升高。腕、膝关节X射线摄片检查均可见尺、桡骨干骺端先期钙化带不规则,放射冠征、杯口征等佝偻病特征性改变。④基因检测:患儿1存在CYP27B1基因c.1358G>A与c.184C>T复合杂合突变;患儿2存在c.1325_1326insCCCACCC纯合突变,均遗传自其父母,被确诊为VDDRⅠA型。⑤治疗及随访:对2例患儿采取骨化三醇及钙剂口服治疗后分别随访15个月和22个月,�Objective To explore clinical characteristics and CYP27B1 gene mutation of children with vitamin D-dependent rickets(VDDR)IA.Methods Two boys(case 1 and 2)with VDDR IA diagnosed in Department of Endocrinology,Children′s Hospital,Capital Institute of Pediatrics from March to December 2019 were selected as research subjects.Their clinical data of were analyzed by retrospective research methods.①The clinical manifestations,gene detection,treatment,and follow-up results were analyzed.②Protein function prediction softwares,such as MutationTaster,SIFT,PROVEAN,and Polyphen-2 were used to predict their pathogenicity of unreported novel mutation.Their pathogenicity of novel mutation was graded according to the ACMG Standards and Guidelines for the Interpretation of Sequence Variants developed by American College of Medical Genetics and Genomics(ACMG)in 2015.③The conservation of novel mutation was judged by comparing protein sequences encoded by CYP27B1 gene in 8 species of primates and 100 species of vertebrates.④Coding protein of novel mutation of CYP27B1 gene was built homologous 3D model by Rosetta software,and changes of protein structure before and after variant were analyzed.This study was approved by the Ethics Committee of Capital Institute of Pediatrics(No.SHERLL2020003).Results①Age of case 1 and 2 were 5-year-7-month,and 1-year-8 month.They admitted because of"lower limb deformity for more than 3 years"and"unsteady gait since walking for 8 months"in cases collection hospital.②They were all shorter than children of the same gender and age,and both had valgus of lower costal margin,valgus of both knees,and an"X"shape of both lower extremities.Case 1 also had caput quadratum deformity,"chicken breast"and"beaded"rib changes.③Their serum calcium and phosphorus decreased,25-hydroxyvitamin D3[25(OH)-D3]slightly decreased(case 1)or normal(case 2),alkaline phosphatase(ALP)and parathyroid hormone(PTH)were significantly increased.X-ray examination of wrist and knee joints showed that there were irregular ca

关 键 词：佝偻病 维生素D依赖性佝偻病ⅠA型 25-羟化维生素D3 1-α-羟化酶 维生素D 骨化三醇 CYP27B1基因 基因突变 碱性磷酸酶 甲状旁腺素 患儿 

分 类 号：R72[医药卫生—儿科]