Brain and Placental Pathology in Fetal COL4A1 Related Disease

Abstract

Introduction Although fetal brain injury due to COL4A1 gene mutation is well documented, fetal central nervous system (CNS) and placental histopathology lack description. We report CNS and placental pathology in fetal cases with symptomatic COL4A1 mutation. Methods We retrieved four autopsy cases of COL4A1 related disease, confirmed by genetic sequencing after fetal brain injury was detected. Results One case was a midgestation fetus with residua of ventricular zone hemorrhage and normal placental villi. Three cases were 30-32 week gestation fetuses: two demonstrated CNS small vessel thrombosis, with CNS injury. Both demonstrated high grade placental fetal vascular malperfusion (FVM). One additionally showed villous dysmorphism, the other demonstrated mild villous immaturity. The fetus whose placenta demonstrated high grade FVM was growth restricted. A fourth fetus demonstrated schizencephaly with a CNS arteriopathy with smooth muscle cell degeneration and cerebral infarcts; the placenta demonstrated severe villous dysmorphism and low grade FVM. Discussion These cases confirm that small vessel disease is important in producing intracranial pathology in COL4A1mutation. We report an arteriopathy distinct from microvascular thrombosis and demonstrate that placental pathology is common in fetal COL4A1 related disease. This tentatively suggests that placental pathology may contribute to CNS abnormalities by affecting circulatory sufficiency.

Prenatal Diagnosis of COL4A1 Mutations in Eight Cases: Further Delineation of the Neurohistopathological Phenotype

“…Maurice et al 22 published a retrospective study aiming to establish the prevalence of COL4A1 and COL4A2 mutations in fetuses presenting a characteristic pattern of cerebral injury. They proposed a fetal phenotype associated with the disease that they characterized by severe and/or multifocal hemorrhagic lesions that can be supratentorial or infratentorial with multifocal ischemic and hemorrhagic lesions of different ages, associated with schizencephaly or porencephaly.…”

“…5,35 Indeed, both lesions are found in association with COL4A1 and COL4A2 gene mutations. 2,3,5,22,32,36…”

“…3,12,13,15,17 Literature evidence about COL4A1 mutation manifestations before birth is growing. 9,[18][19][20][21][22][23] In 2012, Lichtenbelt et al published the first case report of a prenatal COL4A1 mutation in a fetus of 21,6 weeks with ultrasound findings of cerebral hemorrhage. 21 Maurice et al 22 published a retrospective study aiming to evaluate the prevalence of COL4A1 and COL4A2 mutations in fetuses presenting a characteristic pattern of cerebral injury including multifocal supra-and infratentorial and ischemic-hemorrhagic lesions associated with schizencephaly or porencephaly.…”

“…9,[18][19][20][21][22][23] In 2012, Lichtenbelt et al published the first case report of a prenatal COL4A1 mutation in a fetus of 21,6 weeks with ultrasound findings of cerebral hemorrhage. 21 Maurice et al 22 published a retrospective study aiming to evaluate the prevalence of COL4A1 and COL4A2 mutations in fetuses presenting a characteristic pattern of cerebral injury including multifocal supra-and infratentorial and ischemic-hemorrhagic lesions associated with schizencephaly or porencephaly. Recently, Schannon et al 23 studied a series of 4 COL4A1 mutated fetuses and their placentas correlating the vascular placental malperfusion lesions with cerebral involvement.…”

Stroke in Children

“…22 A study of placental pathology in COL4A1 suggests an explanation for the novel finding of fetal growth restriction. 23 Establishing a prenatal diagnosis may result in safer delivery as these children are at risk for hemorrhage at birth. Two retrospective studies differentiated phenotypes of moyamoya, demonstrating that patients with neurofibromatosis type 1 had a more benign course, presenting with unilateral disease and fewer strokes compared with other types of moyamoya.…”