Mutations in COL4A1 were first associated with cerebral microangiopathy (OMIM 607595) and familial porencephaly (OMIM 75780). The expanded phenotypic spectrum includes fetal, neonatal and adult intracranial hemorrhages and small vessel disease, hemorrhagic and ischemic stroke, nephropathy, muscle cramps and ophthalmologic anomalies. The underlying pathophysiology of microvascular disease is attributed to the role of type IV collagen in the protein network of the basement membrane, particularly of the basement membranes surrounding the blood vessels, renal glomeruli and ocular structures.
The mother was a 32-year-old G1P0 woman with a past medical history of left common femoral DVT and extensive bilateral non-occlusive saddle emboli in the pulmonary arteries at age 25 years, for which she completed a 2 year course of anticoagulation. Risk factors for DVT at the time included smoking and oral contraception which had been initiated several months earlier. There was no family history of DVT and standard coagulation studies were negative. LMWH was initiated from 6 WG. Detailed fetal ultrasound at 19 WG was unremarkable. Follow up for missed views noted a possible pericardial effusion. The fetus continued to be monitored and at 27 WG, ultrasound revealed fetal anemia and IUGR. At 30.8 WG, fetal MRI showed measurements consistent with 25.2 WG and abnormal basal ganglia with loss of the right caudate head. There were cystic foci in the left frontal lobe, possibly left temporal lobe and in the right cerebellar hemisphere. Foci of hemorrhage were present on the susceptibility weighted MR image and there was multifocal diffusion restriction suggestive of ongoing ischemia. The placenta appeared bulky and edematous. After being informed of the findings and prognosis, the couple decided to terminate the pregnancy.
A neuropathological examination revealed micrencephaly and multiple intravascular thrombi and sequelae within the brain, associated with hemorrhage and infarction (Figure 1). Specifically, there were multiple foci of cortical dysgenesis with leptomeningeal heterotopias, multiple deep hemorrhages and bland infarcts of varying age, multiple and organizing deep vein thrombi. Thrombosis was not seen in other fetal organs apart from the brain. The eyes showed cataractous lenses and microvascular proliferation of the inner retina. Immunohistochemical staining for type IV collagen revealed tangled blood vessels extending into the ocular vitreous (Figure 2). The placental weight was below the 5th percentile. Thrombi in the fetal circulation of the placenta (Figure 3) resulted in a pattern of clustered avascular villi referred to as fetal thrombotic vasculopathy (FTV) (Figure 4). Causes of FTV include cord compression, right heart failure, vascular injury due to placental infection or prolonged meconium exposure or hypercoagulability. There was no evidence of cord compression, right heart block or acute chorioamnionitis in this case, leaving hypercoagulability within the fetal circulation as the chief hypothesis to explain the brain and placental findings.
Clinical whole-exome sequencing by Baylor College of Medicine identified a heterozygous c.2879G>T (p.G960V) novel, likely pathogenic variant in the COL4A1 gene of the fetus. This variant was present in the mother; however, the reference allele was clearly predominant, suggesting that the mother is apparently mosaic for this variant (Figure 5).
We hereby describe a fetus with microvascular disease affecting the intracranial vessels, retinae and placenta, consistent with previous reports of severe prenatal presentation of COL4A1-related disorders. This was inherited from the mother who showed mosaicism for the COL4A1 mutation and a remarkable past medical history of DVT/PE at a young age. This may be a supporting evidence for COL4A1 as a risk factor for idiopathic DVT/PE in young adults.