C A P F Alves1, O Sherbini2, F D'Arco3, D Steel4,5, M A Kurian4,5, F C Radio6, G B Ferrero7, D Carli7, M Tartaglia6, T B Balci8,9, N N Powell-Hamilton10, S A Schrier Vergano11,12, H Reutter13, J Hoefele14, R Günthner14,15, E R Roeder16, R O Littlejohn16, D Lessel17, S Lüttgen17, C Kentros18, K Anyane-Yeboa18, C B Catarino19, S Mercimek-Andrews20,21, J Denecke22, M J Lyons23, T Klopstock19,24,25, E J Bhoj26, L Bryant26, A Vanderver27,2. 1. From the Division of Neuroradiology (C.A.P.F.A.) alvesc@chop.edu. 2. Department of Neurology (O.S., A.V.), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 3. Departments of Radiology (F.D.). 4. Neurology (D.S., M.A.K.), Great Ormond Street Hospital for Children, London, UK. 5. Molecular Neurosciences (D.S., M.A.K.), Zayed Centre for Research into Rare Diseases in Children, UCL GOS-Institute of Child Health, London, UK. 6. Genetics and Rare Diseases Research Division (F.C.R., M.T.), Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy. 7. Department of Public Health and Pediatrics (G.B.F., D.C.),University of Torino, Turin, Italy. 8. MedicalGenetics Programof Southwestern Ontario (T.B.B.), London Health Sciences Centre, London, Ontario, Canada. 9. Department of Paediatrics (T.B.B.),Western University, London, Ontario, Canada. 10. Division of Medical Genetics (N.N.P.-H.), Nemours Childrenșs Hospital, Wilmington, Delaware. 11. Division of Medical Genetics and Metabolism (S.A.S.V.), Childrenșs Hospital of The Kingșs Daughters, Norfolk, Virginia. 12. Department of Pediatrics (S.A.S.V.), Eastern Virginia Medical School, Norfolk, Virginia. 13. Division of Neonatology and Pediatric Intensive Care (H.R.), Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University Nürnberg-Erlangen, Erlangen, Germany. 14. Institute of Human Genetics (J.H., R.G.). 15. Department of Nephrology (R.G.), Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany. 16. Department of Pediatrics and Molecular and Human Genetics (E.R.R., R.O.L.), Baylor College of Medicine, San Antonio, Texas. 17. Institute of Human Genetics (D.L., S.L.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 18. Division of Clinical Genetics (C.K., K.A.-Y.), Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian, New York, New York. 19. Friedrich-Baur-Institute (C.B.C., T.K.), Department of Neurology, University Hospital, Ludwig-Maximilian University Munich, Munich, Germany. 20. Department of Medical Genetics (S.M.-A.), Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada. 21. Department of Medical Genetics (S.M.-A.), The Hospital for Sick Children, Toronto, Ontario, Canada. 22. Department of Pediatrics (J.D.), University Medical Center Eppendorf, Hamburg, Germany. 23. Greenwood Genetic Center (M.J.L.), Greenwood, South Carolina. 24. German Center for Neurodegenerative Diseases (T.K.), Munich, Germany. 25. Munich Cluster for Systems Neurology (T.K.), Munich, Germany. 26. Department of Radiology, Division of Human Genetics (E.J.B., L.B.). 27. Department of Pediatrics, and Division of Neurology (A.V.), Department of Pediatrics, Childrenșs Hospital of Philadelphia, Philadelphia, Pennsylvania.
Abstract
BACKGROUND AND PURPOSE: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B (H3F3) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants. MATERIALS AND METHODS: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range. RESULTS: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation. CONCLUSIONS: Imaging phenotypes in germline H3F3-affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles.
BACKGROUND AND PURPOSE: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B (H3F3) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants. MATERIALS AND METHODS: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range. RESULTS: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation. CONCLUSIONS: Imaging phenotypes in germline H3F3-affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles.
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