连云港地区新生儿先天性肾上腺皮质增生症筛查的初步研究
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摘要
目的了解连云港地区新生儿先天性肾上腺皮质增生(CAH)的发病率以及患儿21羟化酶(CYP21A2)基因的突变特点,探讨建立适合本中心的早产儿(<37w)和足月儿(≥37w)CAH筛查中17羟基孕酮(17-OHP)的切值。方法对连云港地区2016年53 305例新生儿CAH筛查结果进行分析总结,用二代测序技术分析3例CAH患儿及其父母CYP21A2第1-10外显子及两侧内含子序列,去除确诊病例的17-OHP浓度数据,采用百分位数法确定切值。结果 53 305例接受CAH筛查的新生儿中,初筛阳性265例(0.497%);确诊CAH 3例均为失盐型,CAH发病率为0.056‰,患儿CYP21A2共检出4种共6个突变;早产儿(15.96±9.25nmol/L)和足月儿(8.30±3.86nmol/L)17-OHP浓度差异有统计学意义(P<0.05),早产儿17-OHP浓度的95%百分位数和99%百分位数分别为29.0nmol/L和48.03nmol/L。结论连云港地区新生儿CAH发病率为0.056‰,患儿CYP21A2突变均为常见类型;结合本中心实际情况,建议早产儿17-OHP切值采用45nmol/L,以减少假阳性率和需召回率。
Objective:To investigate the incidence of congenital adrenal hyperplasia(CAH)and the characteristics of 21-hydroxylase(CYP21A2)gene mutations of the child patients in Lianyungang,China. Methods:The CAH screening results of 53 305 neonates were analyzed and summarized. Three child patients with CAH and their parents were enrolled in this study.All of 10 exons and their flanking introns sequences of CYP21A2 in these subjects were directly sequenced by the next generation sequencing technique. The cut-off value of 17-OHP concentration was determined by the percentile method. Results:Among the 53 305 neonates who underwent CAH screening,265(0.497%)obtained a positive result and there were diagnosed with CAH. The type of CAH was salt wasting and the incidence rate of CAH was 0.056‰. A total of six mutations which were four classes were detected in CYP21A2 of three neonates with CAH. The distribution level of 17-OHP concentration was(15.96±9.25)nmol/L in premature neonates,and(8.30±3.86)nmol/L in term neonates. The difference of 17-OHP concentration between the two groups had statistical significance(P<0.05). Percentiles of 95% and 99% 17-OHP concentration in premature neonates were29.0and 48.03 nmol/L. Conclusion:The incidence of CAH of neonates in Lianyungang region was 0.056‰,and the types of CYP21A2 mutations were common. According to the actual situation of the screening center,it was suggested that the cut-off value of 17-OHP of concentration in premature neonates should be 45 nmol/L which would decrease the false positive and recall rate.
Objective:To investigate the incidence of congenital adrenal hyperplasia(CAH)and the characteristics of 21-hydroxylase(CYP21A2)gene mutations of the child patients in Lianyungang,China. Methods:The CAH screening results of 53 305 neonates were analyzed and summarized. Three child patients with CAH and their parents were enrolled in this study.All of 10 exons and their flanking introns sequences of CYP21A2 in these subjects were directly sequenced by the next generation sequencing technique. The cut-off value of 17-OHP concentration was determined by the percentile method. Results:Among the 53 305 neonates who underwent CAH screening,265(0.497%)obtained a positive result and there were diagnosed with CAH. The type of CAH was salt wasting and the incidence rate of CAH was 0.056‰. A total of six mutations which were four classes were detected in CYP21A2 of three neonates with CAH. The distribution level of 17-OHP concentration was(15.96±9.25)nmol/L in premature neonates,and(8.30±3.86)nmol/L in term neonates. The difference of 17-OHP concentration between the two groups had statistical significance(P<0.05). Percentiles of 95% and 99% 17-OHP concentration in premature neonates were29.0and 48.03 nmol/L. Conclusion:The incidence of CAH of neonates in Lianyungang region was 0.056‰,and the types of CYP21A2 mutations were common. According to the actual situation of the screening center,it was suggested that the cut-off value of 17-OHP of concentration in premature neonates should be 45 nmol/L which would decrease the false positive and recall rate.
引文
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[14]Yu Y,J Wang X.Huang,et al.Molecular characterization of 25Chinese pedigrees with 21-hydroxylase deficiency[J].Genetic Testing&Molecular Biomarkers,2011,15(3):137-42.
[15]谢波波,陈少科,范歆,等.33例先天性肾上腺皮质增生症患儿CYP21A2基因突变研究[C].第十四次全国医学遗传学学术会议论文汇编.2015.
[16]叶立新,陈锦国,钟玉杭,等.不同出生孕周新生儿先天性肾上腺皮质增生症筛查中17-羟孕酮切值初探[J].中国现代药物应用,2015(14):8-10.
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[18]LI Jing,LY-F,Mireguli MAIMAITI Genotypes and phenotypes in Uygur children with 21-hydroxylase deficiency in Xinjiang,China[J].CJCP,2016,18(2):141-146.
[2]李媛媛,王建华,王金锐.先天性肾上腺皮质增生症的诊治现状[J].中国现代医药杂志,2010,12(12):130-132.
[3]Hong G,HD Park,R Choi,et al.CYP21A2 Mutation Analysis in Korean Patients With Congenital Adrenal Hyperplasia Using Complementary Methods:Sequencing After Long-Range PCR and Restriction Fragment Length Polymorphism Analysis With Multiple Ligation-Dependent Probe Amplification Assay[J].Annals of Laboratory Medicine,2015,35(5):535-9.
[4]Williams,JS,GH Williams 50th anniversary of aldosterone[J].Journal of Clinical Endocrinology&Metabolism,2003,88(6):2364-72.
[5]Forouzanfar K,M Seifi F.Hashemigorji,et al.Mutation analysis of the CYP21A2 gene in congenital adrenal hyperplasia[J].Cellular and molecular biology(Noisy-le-Grand,France),2015,61(4).
[6]New,MI.Inborn errors of adrenal steroidogenesis[J].Molecular&Cellular Endocrinology,2003,211(1-2):75-83.
[7]Speiser,PW,PC White Congenital adrenal hyperplasia[J].New England Journal of Medicine,2003,349(8):776-88.
[8]Cutler GB,L Laue.Congenital adrenal hyperplasia due to21-hydroxylase deficiency[J].Journal for Specialists in Pediatric Nursing,2010,10(3):104-14.
[9]王本敬,陈亚平,陈瑛.2010年-2012年苏州地区新生儿先天性肾上腺皮质增生症筛查结果分析[J].中国优生与遗传杂志,2013(10):80-83.
[10]叶军.先天性肾上腺皮质增生症新生儿筛查[J].中国实用儿科杂志,2016(6).
[11]毛新梅,井淼,田海燕.宁夏地区160046名新生儿先天性肾上腺皮质增生症筛查与治疗随访分析[J].中国当代儿科杂志,2016,18(8):698-701.
[12]罗超,范歆,林彩娟,等.广西地区单胎和双胎新生儿先天性肾上腺皮质功能增生症筛查确诊结果分析[J].中国儿童保健杂志,2016,24(2):183-184.
[13]穆文娟,杨建平,等.山西省六地市新生儿先天性肾上腺皮质增生症的筛查结果分析[J].中国药物与临床,2016,16(10).
[14]Yu Y,J Wang X.Huang,et al.Molecular characterization of 25Chinese pedigrees with 21-hydroxylase deficiency[J].Genetic Testing&Molecular Biomarkers,2011,15(3):137-42.
[15]谢波波,陈少科,范歆,等.33例先天性肾上腺皮质增生症患儿CYP21A2基因突变研究[C].第十四次全国医学遗传学学术会议论文汇编.2015.
[16]叶立新,陈锦国,钟玉杭,等.不同出生孕周新生儿先天性肾上腺皮质增生症筛查中17-羟孕酮切值初探[J].中国现代药物应用,2015(14):8-10.
[17]New MI.Steroid 21-hydroxylase deficiency(congenital adrenal hyperplasia)[J].American Journal of Medicine,2016,98(1A):1281-1300.
[18]LI Jing,LY-F,Mireguli MAIMAITI Genotypes and phenotypes in Uygur children with 21-hydroxylase deficiency in Xinjiang,China[J].CJCP,2016,18(2):141-146.