Fetal intracerebral hemorrhage and COL4A1 mutation: promise and uncertainty

The first prenatal diagnosis of fetal intracranial hemorrhage (ICH) associated with COL4A1 gene mutation was reported recently1. Through an additional prenatal case, we would like to highlight several issues surrounding parental counseling and obstetric management that are raised by this diagnosis. A 29-year-old patient was referred to our center at 25 weeks’ gestation following detection on ultrasound of bilateral ventriculomegaly. Targeted neurosonography at 27 weeks’ gestation showed enlarged lateral ventricles with hyperechogenic walls and intraventricular blood clots. There was no relevant family history and the patient did not report any abdominal trauma during the pregnancy. Screening for TORCH and alloimmune thrombocytopenia was negative. Recent maternal cytomegalovirus infection was also excluded. A follow-up ultrasound scan at 28 weeks showed bilateral ventricular dilatation and hemorrhage, with massive right hemorrhage involving the subependymal area and the ventricle, and extending to the adjacent basal ganglia and parietal parenchyma (Figure 1). Magnetic resonance imaging confirmed the ultrasound findings. The hemorrhage appeared T1 hyperintense, slightly T2 hyperintense and markedly hypointense on T2*-weighted imaging (Figure 2). The parents were informed of the poor neurological prognosis and elected to terminate the pregnancy at 30 weeks’ gestation. There was no fetal thrombocytopenia at cordocentesis. Postmortem examination confirmed grade IV extensive ICH with the particular association of hemorrhagic lesions of different ages. Hemorrhages were also found in other organs (thymus, liver and adrenal glands). Following termination, fetal genomic DNA was amplified by polymerase chain reaction with 42 sets of primers to investigate the 52 exons and intron–exon boundaries of the COL4A1 gene, based on its reference sequence. A previously unreported G188E mutation of exon 10 in the COL4A1 gene was found. The parents were informed of this result and elected to undergo genetic testing. The mother was found to carry the same COL4A1 mutation. An ophthalmological examination revealed that she had retinal arterial tortuosity. During the patient’s subsequent pregnancy, the implications of genetic prenatal testing were discussed, including the possibility of an elective Cesarean section in case of an affected fetus. The parents opted for prenatal diagnosis. Amniocentesis was performed at 16 weeks’ gestation and the fetus was found to carry the same mutation. The pregnancy was uneventful and serial fetal cerebral ultrasonographic examinations were normal. A 3350-g girl was delivered by elective Cesarean section at 39 weeks. At the time of writing the child was 9 months old with normal development. Our case confirms that a COL4A1 mutation should be considered in cases of ICH when no other identifiable Figure 1 Ultrasound images of fetal intracranial hemorrhage at 28 weeks’ gestation demonstrating enlarged lateral ventricles with intraventricular hemorrhage and hyperechoic and irregular ventricular borders. (a) Axial view, showing involvement of left subependymal area (arrowhead) and hemorrhage (star) in the right ventricle and adjacent thalamus. (b) Right parasagittal view, showing massive hemorrhage (star) involving the thalamus and extending to the adjacent parietal parenchyma (arrow) with ependymal rupture.