LETTER TO THE EDITOR Novel Variant in COL4A1 Causes Extensive Prenatal Intracranial Hemorrhage and Porencephaly Stefanie Brock, MD 1,2 , Alex Michotte, MD 3 , Elisa Don e, MD 4 , Astrid Leus, MD 5 , Mieke Cannie, MD 5 , Kari De Pierre, MD 1 , Ramses Forsyth, MD, PhD 1 , Katrien Stouffs, PhD 2,7 , Kathelijn Keymolen, MD, PhD 7 , Boyan Dimitrov, MD, PhD 7 , Annelies Fieuw, PhD 7 , Anna C. Jansen, MD, PhD 2,6 , and Kim Van Berkel, MD 7 1 Department of Pathology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium 2 Neurogenetics Research Group, Vrije Universiteit Brussel (VUB), Brussels, Belgium 3 Department of Neurology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium 4 Department of Obstetrics and Gynaecology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium 5 Department of Radiology, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium 6 Pediatric Neurology Unit, Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium 7 Belgium Center for Reproduction and Genetics, UZ Brussel, Brussels, Belgium Correspondence to: Stefanie Brock, MD, Department of Pathology, Universitair Ziekenhuis Brussel (UZ Brussel), Laarbee- klaan 101, 1090 Brussels, Belgium; E-mail: Stefanie.brock@uzbrussel.be To the Editor: Collagen IVa (COL4A1) is a basement membrane pro- tein that is ubiquitously present in all tissues (1). Variants in the COL4A1 gene have been described in a spectrum of brain malformations including autosomal dominant porencephaly, schizencephaly, intracranial calcifications, small vessel dis- ease causing strokes and cerebral hemorrhages, and heredi- tary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC syndrome) (2). Cortical migration disorders and eye malformations have also been reported in mice and humans with COL4A1 variants (3). Prenatally detected porencephaly is associated with se- vere developmental delay, seizures and might be associated with other brain malformations including cortical dysplasia and polymicrogyria. These features can resemble congenital infections, ischemic insults or the complications of prenatal trauma (2). To date, more than 70 variants spread throughout the entire COL4A1 gene have been reported. Neuropathological features of patients with variants in COL4A1 and structural brain malformations have only rarely been described in the literature and are heterogeneous, including focal cortical dys- plasia, abnormal small blood vessels, and hemorrhages in the brain, respectively (4–7). Here, we present a correlation of imaging and neuro- pathological features of a fetal case with an early and severe presentation of porencephaly with a novel variant in COL4A1. The mother is a healthy 38-year-old G3P1A1. On pre- natal ultrasound at 22 gestational weeks the female fetus pre- sented with pericardial fluid and severe bilateral brain hemorrhage causing cerebral asymmetry with shifting of the falx to the left side, dilatation of the right anterior lateral ven- tricle and suspicion of choroid plexus hemorrhage (Fig. 1A, B). Fetal magnetic resonance imaging (MRI) at 22 weeks and postmortem MRI at 25 weeks showed extensive porence- phalic destruction of the brain parenchyma of the right hemi- sphere with shift of the midline to the left (Fig. 1C–F). Thalami and basal ganglia were no longer discernible. The corpus callosum was hypoplastic and the cavum septum pel- lucidum was absent. The left hemisphere showed several is- chemic zones with hemorrhagic transformation and a dilated and irregular lined lateral ventricle. Postmortem MRI revealed additional porencephaly in the temporal region on the left hemisphere and several areas of bleeding were noted in the posterior fossa. Noninvasive prenatal testing and molecular karyotype on amniotic fluid were normal. Screening for congenital infections and autoimmune-related platelet dysfunction were negative. Based on the extensive brain malformations, a poor prognosis including cerebral palsy, intellectual disability and epilepsy, was predicted and the pregnancy was terminated at 25 gestational weeks. Postmortem examination of the fetus showed no exter- nal malformations. Internal inspection and histological exam of the thoracic and abdominal organs were normal. No vascu- lar malformations or abnormal vessels were noted. Immuno- histochemical studies for smooth muscle actin and CD34 were normal in the kidneys and lungs. Neuropathological ex- amination was performed after fixation in 24% formaldehyde for 4 months. Macroscopic examination of the brain showed almost complete destruction of the right hemisphere with im- 807 V C 2021 American Association of Neuropathologists, Inc. All rights reserved. J Neuropathol Exp Neurol Vol. 80, No. 8, August 2021, pp. 807–810 doi: 10.1093/jnen/nlab026 Downloaded from https://academic.oup.com/jnen/article/80/8/807/6224198 by guest on 13 September 2021