胎儿反复脑实质出血及囊性脑白质软化灶形成生后确诊为COL4A1基因突变1例

Postnatally confirmed COL4A1 mutation in a fetus with recurrent intraparenchymal hemorrhage and cystic leukomalacia

本文报告了1例胎儿期反复出现多发脑实质出血合并囊性脑白质软化灶形成,生后脐血基因检测为COL4A1基因新发突变的胎儿。该胎儿胎龄25周时超声发现脑实质内及小脑半球多处新鲜出血灶,定期复查超声及神经系统MRI,可见反复多发脑实质出血伴出血后多发脑白质囊性软化灶形成。羊水染色体荧光原位杂交及染色体微阵列分析未见异常。该胎儿于胎龄37周+3剖宫产出生,生后1和5 min Apgar评分均为10分,但生后出现反复呼吸暂停。生后6 d神经系统MRI提示新发脑实质出血伴脑白质软化灶形成。生后90 d随访时,该患儿四肢肌张力仍偏低,此后失访。全外显子组测序提示患儿COL4A1基因c.4738G>A(NM_001845.4;p.G1580S)新发杂合突变,其父母均未携带。由本例认为,对颅内出血的胎儿进行产前诊断时,特别是对胎儿期反复出现脑实质出血伴有出血后脑白质软化形成者,应考虑COL4A1基因突变可能。明确此基因诊断有助于客观分析胎儿预后,指导分娩方式。

We report a fetus with recurrent intraparenchymal hemorrhage and cystic leukomalacia during pregnancy who was postnatally detected with a de novo mutation in the COL4A1 gene by genetic testing of umbilical cord blood.Multiple fresh hemorrhagic foci were detected in the fetal brain parenchyma and cerebellar hemisphere by ultrasound at 25 gestational weeks.Regular re-examination of the nervous system's ultrasound and magnetic resonance imaging(MRI)indicated recurrent multiple intraparenchymal hemorrhages followed by cystic leukomalacia.However,karyotyping and chromosomal microarray analysis of amniotic fluid showed no abnormality.The newborn was born by cesarean section at 37+3 gestational weeks with an Apgar score of 10 at 1 and 5 min.Repeated apnea occurred after birth.MRI detected new intraparenchymal hemorrhage and cystic leukomalacia on the six-day of life.The infant's limb muscle tone remained low on the 90-day follow-up.The patient was lost to follow up.Whole-exome sequencing of the cord blood identified a de novo heterozygous mutation-c.4738G>A in the COL4A1 gene(NM_001845.4;p.G1580S)neither parent carried.It suggests that the genetic test of the COL4A1 mutation should be considered for fetuses with intracranial hemorrhage in the prenatal diagnosis,especially those with recurrent fetal intraparenchymal hemorrhage followed by cystic leukomalacia.Genetic tests could help analyze the fetal prognosis,and guide the delivery mode.