While the antenatal onset of intracranial lesions associated with COL4A1 has been reported by us and others, this diagnosis has always been made after birth1–3 (Table S1). This is the first report of the diagnosis of a mutation in the COL4A1 gene in a fetus. A 35-year-old woman was referred after detection of a cystic lesion in the fetal posterior cranial fossa during ultrasound screening. She had no family history of anomalies or recent history of maternal or fetal trauma. Screening for TORCH and alloimmune antithrombocyte antibodies in maternal plasma, and polymerase chain reaction (PCR) for cytomegalovirus and quantitative fluorescent (QF)-PCR for trisomies 13, 18 and 21 in amniotic fluid were negative. Fetal neurosonography at 21 + 6 weeks' gestation revealed hyperechogenic walls of the lateral ventricles and left-sided periventricular echogenicity. A large germinal matrix hemorrhage extended with a wedge-shaped echogenic lesion into the left thalamus. The left cerebellar hemisphere was replaced by an echolucent area with displacement of the right cerebellar hemisphere (Figure 1a). At 23 + 4 weeks, fetal MRI confirmed the ultrasound findings. The posterior fossa mass had expanded and had the appearance of an organizing hematoma with destruction of the left cerebellar hemisphere (Figures 1b and c). Repeat ultrasound scans showed mild progressive dilatation, more obvious echogenicity of the lateral ventricles and wedge-shaped cystic evolution of the left thalamus (Figure S1a).
By 30 weeks' gestation the results of sequence analysis of the COL4A1 gene using fetal DNA isolated from amniotic fluid became known, showing a de-novo pathogenic missense mutation (G1103R). At 41 + 6 weeks a female infant was delivered vaginally with normal Apgar scores, birth weight (3355 g) and head circumference (34 cm). Neonatal MRI confirmed a wedge-shaped area of cavitation in the left basal ganglia. There was lack of myelination of the posterior limb of the internal capsule and absence of the left cerebellar hemisphere (Figures S1b and c). Ophthalmological investigation showed sporadic small retinal hemorrhages. Renal sonography was normal. The infant developed a hemiplegia.
Rates of fetal intracranial hemorrhage of 0.46 per 1000 deliveries and 0.9 per 1000 pregnancies have been reported at referral centers4. In an unknown proportion of fetuses, a Mendelian genetic disorder, associated with an increased risk for cerebral arteriopathy, can be detected. The COL4A1 gene encodes for the alpha-1 chain of type IV collagen, a basement membrane protein, which is expressed widely in all tissues, including the vasculature5. Mutations in the COL4A1 gene lead to an altered COL4A1 protein, which compromises the basement membrane of the vasculature, thus predisposing to hemorrhage. In 2005 Gould et al.6 were the first to report COL4A1 mutations in mice with perinatal hemorrhage and in human families with porencephaly. Since then COL4A1 mutations have been reported in association with a wide spectrum of symptoms, including familial porencephaly, intracranial aneurysms, muscle cramps, hemorrhagic stroke, infantile hemiparesis7–9 and intraventricular hemorrhage in preterm infants with parenchymal hemorrhage of antenatal onset2, 3, 10. More extensive supratentorial lesions, in combination with cerebellar injury, have recently been reported2. In our case, the combination of a supratentorial hemorrhage and a cerebellar lesion led to prenatal diagnosis of a COL4A1 mutation. Making this diagnosis has important implications for perinatal management and genetic counseling.
SUPPORTING INFORMATION ON THE INTERNET
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Table S1 Summary of prenatal ultrasound and magnetic resonance imaging findings in cases with a COL4A1 mutation.
Figure S1 (a) Prenatal ultrasound image at 32 + 4 weeks' gestation showing cystic evolution of the chogenic lesion into a porencephalic cyst. (b) Postnatal magnetic resonance imaging (T2SE-weighted), axial views. The left cerebellar hemisphere is absent. There is an area of cavitation in the left basal ganglia. (c) Myelination is only seen as low signal intensity in the right posterior limb of the internal capsule.