产前筛查孕妇游离雌三醇水平低下对X连锁鱼鳞病患儿的预警作用

Early warning of low maternal unconjugated estriol level by prenatal screening for fetus with X-linked ichthyosis

目的探讨妊娠中期孕妇血清游离雌三醇(uE_(3))水平对X连锁鱼鳞病(XLI)患儿的预警作用。方法收集2016年9月至2021年6月于河南省人民医院和潍坊医学院附属医院行产前诊断提示Xp22.31微缺失(XLI的典型表现)的胎儿56例,同期确诊为21三体综合征的胎儿70例及18三体综合征的胎儿26例,回顾性分析孕妇妊娠中期的血清学筛查资料,包括游离雌三醇(uE_(3))、甲胎蛋白(AFP)和人绒毛膜促性腺激素(hCG)的中位数倍数(MoM)值。采用羊水细胞染色体核型分析和基因组拷贝数变异(CNV)检测对Xp22.31微缺失胎儿进行产前诊断并行家系成员验证及致病性分析,并随访母儿结局。结果56例妊娠Xp22.31微缺失胎儿的孕妇中,43例行妊娠中期血清学筛查,其中42例异常(男性胎儿39例,女性胎儿3例)。39例男性胎儿母亲的血清uE_(3)的MoM值[0.06(0.00~0.21)]低于正常值,且显著低于21三体综合征胎儿[0.71(0.26~1.27)]及18三体综合征胎儿[0.36(0.15~0.84)],差异有统计学意义(Z=99.96,P<0.001);其AFP、hCG的MoM值均在正常值范围内。56例携带Xp22.31微缺失的胎儿中,男性胎儿45例,女性胎儿11例,缺失片段均累及STS基因。家系验证分析发现,遗传自母亲(49例)或父亲(1例)者占89%(50/56),新发突变占11%(6/56)。随访发现,56例中活产48例(男性38例,女性10例),引产8例(男性7例,女性1例)。38例男性新生儿中,37例于1~3月龄出现皮肤鳞屑样变,1例随访至出生后4个月无临床表现;10例女性新生儿无明显临床表现。结论孕妇血清学筛查uE_(3)的MoM值显著降低可能提示男性胎儿患XLI的风险增加。对于孕妇血清学筛查uE_(3)水平偏低或者有XLI家族史的孕妇,除进行染色体核型分析外,建议联合基因组CNV检测进行产前诊断。

Objective To analyze the characteristic of prenatal serological screening in fetus with X-linked ichthyosis(XLI),and to explore the relationship between unconjugated estriol(uE_(3))levels and XLI.Methods A total of 56 fetuses with Xp22.31 microdeletion indicated by prenatal diagnosis and 70 fetuses diagnosed with trisomy 21 and 26 fetuses with trisomy 18 in Henan Provincial People's Hospital and Affiliated Hospital of Weifang Medical College from September 2016 to June 2021 were collected.The multiples of median(MoM)values of uE_(3),alpha-fetoprotein(AFP),and human chorionic gonadotropin(hCG)during the second trimester of pregnancy were retrospectively analyzed.Prenatal diagnosis was made by amniotic fluid karyotype analysis and genome copy number variant analysis,parent genetic verification and pathogenicity analysis were performed,and maternal and infant outcomes were followed up.Results Of 56 pregnant women with fetal Xp22.31 microdeletion,43 underwent serological screening during the second trimester of pregnancy,of which 42 were abnormal(39 male fetuses and 3 female fetuses).The median uE_(3) MoM value of 39 male fetuses[0.06(0.00-0.21)]was lower than the normal value and significantly lower than that of fetuses with trisomy 21[0.71(0.26-1.27)]and fetuses with trisomy 18[0.36(0.15-0.84)],the difference was statistically significant(Z=99.96,P<0.001).While the MoM values of AFP and hCG were all within the normal range.Among the 56 fetuses carrying Xp22.31 microdeletion,45 were male fetuses and 11 were female fetuses,and the deletion fragments all involved STS gene.Eighty-nine percent(50/56)were inherited from mother(49 cases)or father(1 case),and 11%(6/56)were de novo mutations.Follow-up showed 48 live births(38 males and 10 females)and 8 chose to terminate pregnancy(7 males and 1 female).Among the 38 male newborns,37 presented with scaly skin changes from 1 to 3 months of age,and one had no clinical manifestations until 4 months after birth.Ten female newborns had no obvious clinical manifestations.Conclusions The decrease levels of uE_(3) MoM on maternal serological screening is closely related to the higher risk of XLI in male fetuses.For pregnant women with low uE_(3) in serological screening or with family history of ichthyosis,in addition to chromosomal karyotype analysis,joint detection of genomic copy number variant analysis should be recommended.