The Investigation Of Prenatal Genetic Diagnosis And Intrauterine Therapy Of The Fetuses With Congenital Cystic Adenomatoid Malformation

Objective:1.To understand the prevalence,pregnancy outcome and postpartum visit of fetal congenital cystic adenomatoid malformation(CCAM),explore the related influencing factors of pregnancy outcome in Guangzhou and Foshan.2.To evaluate the pooled prevalence and characteristics of fetuses with CCAM in China.3.To explore the application value of chromosome microarray analysis(CMA)in CCAM.4.To evaluate the effect of maternal steroids administration and explore its determinants to CCAM.5.To evaluate the effect of open fetal surgery and ex-utero intrapartum therapy(EXIT)for CCAM.Methods:1.The CCAM cases were selected from six hospitals in Guangzhou and Foshan from 2009.7 to 2017.3,The clinical data were obtained through the internal clinical information registration systerm in each hospital,and the pregnancy outcome was followed up by telephone.Chi-square test for trend was used to analyze the changetrends of morbidity and pregnancy outcome of CCAM cases,multivariate logistic regression analysis was used to analyze the related influencing factors of pregnancy outcome of CCAM cases.2.Then meta-analysis was intended to evaluate the pooled prevalence of fetuses in China.Five studies with 393496 fetuses were chosen for this meta-analysis.3.A total of 57 women with fetal congenital cystic lesions of the lung(CC AM)at Guangzhou Women and Children's Medical Center were examined via invasive prenatal diagnosis From July 2009 to March 2017.QF-PCR and standard karyotyping analysis were used to detect common aneuploidies.Genomic DNA was extracted using Qiagen DNA Blood Mini kits following the manufacturer's protocol.The DNA samples were run on Cyto Scan TM HD Array using the manufacturer's protocol(n=44).Array is scanned and generates intensity(CEL)file data.Then the probe level analysis on CEL file data is performed in CHAS software(Affymetrix,California,USA).The CNVs detected were further aligned with known CNVs listed in database at home and databases publically available online,such as the database of DGV,DECIPHER,OMIM,ISCA and UCSC.4.There were 7 studies with 52 fetuses with CCAM using maternal steroids administration included in this meta-analysis.Individual patient data were extracted based on a standard form.Random effect models were performed to estimate the fetal surgery rate,survival rate and hydrops resolution rate adjusted for study specific random effect.Univariate logistic models were respectively performed to examine associations between different outcomes and eligible variables adjusted for the within-study clustering.5.The medical records of 22 treated patients with prenatally diagnosed CCAM in Maternal and Child Health Hospital of Foshan during 2011-2017 were reviewed.Results:1.Among 320 thousand pregnant women,108 cases were diagnosed as CCAM during prenatal diagnosis by ultrasonography,the incidence rate was 3.4/10 000.The influencing factors of pregnancy outcome included residence,abnormal pregnancy history and combing with hydrothorax and ascites or not.2.The overall pooled prevalence was 4.01/10000(1.14/10000-16.09/10000)fetuses.The CCAM prevalence was high in north(7.93/10000)and central(8.93/10000)areas,and low in south areas(2.81/10000).3.Of the 44 fetal CCAM cases using CMA analysis,7 cases were diagnosed as BPS after delivery,then 37 cases of CCAM samples were included.CMA detected pathogenic CNVs in 3 fetuses,and the detection rate was 8.1%(3/37).Well-known microdeletion or microduplication syndromes including HNPP syndrome and diabetes(RCAD)syndrome and CMT1A syndrome were identified in three cases.In addition,23 CNVs were co-existed in more than 2 samples,3 co-existed CNVs contain pathogenic genes.The 6p25.3,7q34 microdeletions and Xp22.33 microduplications may be associated with CCAM.DUSP22,PRSS1,SHOX were possible candidate genes for fetal CCAM.We have noticed that 4 samples were detected 7q34(142266306-142493)deletion,which including OM1M gene PRSS1.4.The estimated hydrops resolution rate,fetal surgery rate and survival rate was 68.6%,11.5%and 79.5%,respectively.Microcystic CCAM lesion was associated with fetal survival and hydrops resolution.Multi-course of steroid was associated with lower fetal survival.5.There were 22 antenatal diagnosed CCAM cases,4 for open fetal surgery and 7 for ex-utero intrapartum therapy(EXIT).Two fetal demises occurred after open fetal surgery.Conclusion:1.The prevalence of CCAM was 3.4/10000 fetuses in Guangzhou and Foshan.The influencing factors of pregnancy outcome included residence,abnormal pregnancy history and combing with hydrothorax and ascites or not.2.The overall pooled prevalence was 4.01/10000.The CCAM prevalence was high in north and central areas,and low in south areas.3.Among the 37 CCAM samples,the CMA identified pathogenic copy number variations in 3 fetuses,leading to a pathogenic detection rate of 8.1%(3/37).Well-known microdeletion or microduplication syndromes including HNPP syndrome and RCAD syndrome and CMT1A syndrome were identified in three cases.4 samples were detected 7q34(142266306-142493)deletion,including OMIM gene PRSS1.According to the gene function,we hypothesized that PRSS1 gene deletion or mutation,may leads to the occurrence of congeniml cystic adenomatoid malformation.4.Maternal steroids administration is preferable for microcystic CCAM.The non-responders should be closely monitored and underwent fetal surgery if necessary.5.Open fetal surgery is associated with premature rupture of membranes and at risk of fetal loss.The prognosis of ex-utero intrapartum therapy is good.