The first prenatal diagnosis of fetal intracranial hemorrhage (ICH) associated with COL4A1 gene mutation was reported recently. 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 causes are found. Together with COL4A2, COL4A1 is an important component of the Type IV collagen in basement membranes, including the vascular basement membrane. Gould et al. reported that in both mice and humans a mutation in the COL4A1 gene predisposes both newborns and adults to ICH owing to the increased fragility of the brain vessels. Recently, several cases of young patients presenting with either recent ICH or porencephalic lesions have been reported[5, 6]. These lesions were sequelae of previous ICH and were related to a COL4A1 mutation. Therefore COL4A1 gene mutation appears to play a role in a substantial proportion of young patients with ICH, and it is likely that this mutation accounts for some cases of ICH observed in fetuses.
Prenatal identification of this autosomal dominant genetic disease raises important issues regarding parental information (i.e. identification of the carrier and his or her own risk for stroke), genetic counseling for future pregnancies, management of delivery of an affected fetus and the provision of information for the rest of the family if the mutation is inherited from one of the parents. Indeed, identification of COL4A1 mutation during the prenatal period raises both ethical and medical questions. First, the parents should be informed that one of them is likely to carry the same mutation (excluding de novo mutation). Parental consent for this predictive genetic testing requires complete and clear information. Owing to the absence of a consistent correlation between genotype and phenotype, as for the mutation found in our case, and the wide range of clinical expression of this disease, possible psychological consequences of being diagnosed with this mutation need to be anticipated. Adult carriers may be asymptomatic or present with a variable phenotype including neurological features such as migraine, epilepsy, stroke or hemiparesis[6, 7]. Systemic features including ocular, renal and muscular involvement may also be observed[6, 7]. Secondly, the legitimacy of a genetic prenatal diagnosis for future pregnancies is questionable, given the wide phenotypic spectrum. Besides the difficulty in predicting the long-term outcome of a fetus that carries a COL4A1 mutation, the risk of ICH in case of vaginal delivery needs to be taken into account. Gould et al. reported on a mouse model with a COL4A1 mutation. They showed that cerebral hemorrhage occurred in all 20 mutated mice pups after normal delivery, whereas none of the 26 surgically delivered mutated pups had a severe cerebral hemorrhage. Nevertheless, we agree with others that Cesarean delivery would not be sufficient to prevent the occurrence of ICH in this situation. However, one could readily expect that this risk would be greater in cases of vaginal delivery. In addition, the question of a possible increased risk for maternal ICH during expulsive efforts at the time of delivery must also be taken into account when the mother carries the mutation.
Recent identification of COL4A1 mutation as an etiology for fetal ICH has uncovered issues in both genetic counseling and obstetric management. Moreover, in cases of ICH diagnosed in the neonatal period, one should consider the possibility of a COL4A1 mutation before automatically attributing it to obstetric trauma. We hope that the reporting of further cases will increase our knowledge of the natural history of perinatal cerebral COL4A1-related lesions.