Congenital Hydrocephalus‐Hydrencephaly in Five Siblings, with Autopsy Studies: a New Disease

Abstract

SUMMARY Following hydramnios, five female arthrorgypotic siblings were born around the 30th week of gestation, labour being further complicated by hydrocephalus. Full autopsy on two babies showed a diffuse destructive process in the brain and spinal cord, resulting in hydren‐cephaly in the forebrain, and gliosis elsewhere, the aqueduct of Sylvius being stenosed to produce hydrocephalus. Striking microscopic changes were the glomeruloid vessels in the brain, spinal cord and retina, and the intracytoplasmic inclusions in pericytes; focal necrosis with calcification was a third important finding. Other systems, apart from the deformed limbs and the small suprarenals, were normal. Investigation yielded no evidence of infection in the parents or babies. Various intra‐uterine infections known to produce malformations, including hydrencephaly, are considered and rejected. The condition, apparently not previously described, is thought to be of genetic origin, possibly a defect in the vascularization of the central nervous parenchyma. RÉSUMÉ Hydrocéphalie‐hydrencéphalie congénitales dans une fratrie de cing A la suite d'un hydramnios, cinq soeurs atteintes d'arthrogrypose sont nCes aux environs de la 30 éme semaine de gestation. Le travail fut compliquépar l'hydrocéphalie. Une autopsie complète de deux bébés révéla un processus destructif diffus du cerveau et de la moelle épiniére avec hydrencéphalie du cerveau antCrieur et gliose ailleurs. L'hydrocCphalie Ctait le résultat d'une stéose de l'aqueduc de Sylvius. Trois importantes découvertes ont CtC des modifications microscopiques frappantes des vaisseaux glomtrulaires du cerveau, de la moelle tpinitre et de la rCtine, des inclusions intracytoplasmiques dans les pkricytes et des ntcroses focales avec calcification. A l'excep‐tion. A l'exception de membres dCformCs et de surrtnales petites, les autres organes étaient normaux. L'anamnèse n'a apporté aucune indication d'infection chez les parents ou les bébés. Des infections intra‐utérines variées connues pour produire des malformations, incluant l'hydrencéphalie ont été envisagées et rejettes. Le tableau, qui ne semble pas avoir été décrit auparavant, parait être d'origine gCnktique, se traduisant peut être par un défaut de vascularisation du parenchyme du système nerveux central. ZUSAMMENFASSUNG Nach bestehendem Hydramnion wurden funf weibliche Geschwister mit Arthrogryposis um die 30 igste Schwangerschaftswoche geboren. Die Geburt wurde weiter durch Hydro‐cephalie kompliziert. Eine vollständige Autopsie an zwei Babies zeigte einen diffusen, destruktiven Prozeß im Gehirn und im Rückenmark, der Hydrencephalie im Vorderhirn und Gliosis an anderer Stelle zur Folge hatte. Der Hydrocephaus war bedingt durch eine Stenose des Aqueductus Sylvii. Drei wichtige Befunde waren besonders auffallend: Mikroskopische Veränderungen der glomeruloiden Gefäße im Gehirn, Rückenmark und in der Retina, Einschlußkörperchen im Cytoplasma der Pericyten und fokale Nekrose mit Verkalkungen. Außer deformierten Extremitäten und kleinen Nebennieren gab ...

The Fowler Syndrome-Associated Protein FLVCR2 Is an Importer of Heme

“…It is not clear how mutations in FLVCR2 are associated with Fowler syndrome. Fowler syndrome is a recessively inherited lethal disorder characterized by proliferative vasculopathy; brain stem, basal ganglia, and spinal cord ischemic lesions with calcification; and hydranencephaly-hydrocephaly (16). Five affected fetuses from three consanguineous families were found to have a common Thr430Arg mutation in FLVCR2.…”

“…Recently, mutations in the cell surface protein FLVCR2 (MFSD7C), an MFS transporter member, have been shown to be associated with Fowler syndrome (22,26), a proliferative vascular disorder of the brain (16). A previous study (6) suggested that FLVCR2 functions as a calcium-chelate transporter based on its expression in murine and human tissues involved in calcium homeostasis.…”

GPR124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood–brain barrier

“…Analogous to these genetically engineered rodent models, in humans there is a lethal prenatal condition known as proliferative vasculopathy and hydranencephalyhydrocephaly (PVHH), where affected fetuses share several striking similarities with Gpr124 −/− mice, including vascular glomeruloids in both the pallium and ventral spinal cord, enlarged cerebral ventricles, and a thin underdeveloped pallium (36). Although the mutations responsible for PVHH have not yet been identified, these studies suggest that GPR124 might be involved in this or a myriad of other neurovascular diseases associated with BBB breakdown or in the formation of glomeruloids associated with the most malignant forms of glioblastoma and gastrointestinal carcinomas (37,38).…”

Multiple thromboembolic events in fetofetal transfusion syndrome in triplets contributing to the understanding of pathogenesis of hydranencephaly in combination with polymicrogyria

“…An infectious genesis in the form of fetal encephalitis has been proposed as a possible origin of hydranencephaly [3]. Others attributed the pathologic changes to a proliferative vasculopathy [4]. Poisoning, maternal hypoxia, the hypothesis of an aplastic process, and, finally, a fetofetal transfusion syndrome especially in monochorionic twins have been identified as further factors of relevance in the genesis of hydranencephaly [5].…”