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      Neuroimaging Findings in Mowat-Wilson Syndrome: A Study of 54 Patients

      research-article
      , MD 1 , , MD 1 , 2 , , PhD 1 , 3 , , MD 1 , , MD 1 , , MD 4 , , MD, PhD 5 , 6 , , MD 7 , , MD, FACMG 8 , , PhD 9 , , MD 10 , 11 , , MD 12 , , MD 1 , 13 , , MD 14 , , MD, PhD 15 , , MD 16 , , MD 17 , 18 , , MD, PhD 14 , , MD 19 , , MD, MSc 1 , , MD 20 , , MD, MSc 21 , 22 , , MD 7 , , PhD 9 , , MD 23 , , MD 24 , , MD, PhD 13 , , MD 25 , 26 , , MD 27 , , MD 28 , , MD 29 , , MD 25 , 30 , , MD, PhD 31 , 32 , , MD 33 , , MD 27 , , MD 34 , , MD 27 , , MD 4 , , MD 35 , , MD 36 , , MD 37 , , MD 27 , , MD 38 , , MD 39 , , MD 40 , 41 , , MD 12 , , MD 42 , , MD 43 , , MD 44 , , MD 45 , , MD 25 , , MD 44 , , MD 46 , 47 , , MD 20 , , MD 48 , , MD 49 , 50 , , MD 51 , 52 , 53 , 54
      Genetics in medicine : official journal of the American College of Medical Genetics
      Mowat-Wilson syndrome, ZEB2, brain MRI, agenesis of corpus callosum, genotype-phenotype correlation
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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Purpose

          Mowat-Wilson syndrome (MWS) is a genetic disease characterized by distinctive facial features, moderate to severe intellectual disability and congenital malformations including Hirschsprung disease, genital and eye anomalies and congenital heart defects, caused by haploinsufficiency of the ZEB2 gene. To date, no characteristic pattern of brain dysmorphology in MWS has been defined.

          Methods

          Through brain MRI analysis, we delineate a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compare it with the features identified in a thorough review of published cases, and evaluate genotype-phenotype correlations.

          Results

          96% of patients had abnormal MRI. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), white matter abnormalities (reduction of thickness 40.7%, localized signal alterations 22.2%). Other consistent findings were large basal ganglia, cortical and cerebellar malformations. Most features were underrepresented in the literature. We also found ZEB2 variations leading to synthesis of a defective protein to be favourable for psychomotor development and some epilepsy features, but also associated with corpus callosum agenesis.

          Conclusion

          This study delineates the spectrum of brain anomalies in MWS and at the same time adds new insights in elucidating the role of ZEB2 in neurodevelopment.

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          Most cited references37

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          The role of the ZEB family of transcription factors in development and disease.

          The ZEB family of zinc finger transcription factors are essential players during normal embryonic development. One characteristic is that they induce epithelial to mesenchymal transition (EMT), a process that reorganizes epithelial cells to become migratory mesenchymal cells. E-cadherin is a major target gene of these transcriptional repressors, and this downregulation is considered a hallmark of EMT. In recent years, the involvement of the ZEB proteins in pathological contexts has been documented as well. Mutations in ZEB encoding genes cause severe syndromic malformations and evidence is mounting that links these factors to malignant tumor progression. In this review, we describe what is currently known on the molecular pathways these transcription factors are implicated in, and we highlight their roles in development and human diseases, with a focus on tumor malignancy.
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            Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes.

            The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field.
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              Hirschsprung disease, microcephaly, mental retardation, and characteristic facial features: delineation of a new syndrome and identification of a locus at chromosome 2q22-q23.

              We have identified six children with a distinctive facial phenotype in association with mental retardation (MR), microcephaly, and short stature, four of whom presented with Hirschsprung (HSCR) disease in the neonatal period. HSCR was diagnosed in a further child at the age of 3 years after investigation for severe chronic constipation and another child, identified as sharing the same facial phenotype, had chronic constipation, but did not have HSCR. One of our patients has an interstitial deletion of chromosome 2, del(2)(q21q23). These children strongly resemble the patient reported by Lurie et al with HSCR and dysmorphic features associated with del(2)(q22q23). All patients have been isolated cases, suggesting a contiguous gene syndrome or a dominant single gene disorder involving a locus for HSCR located at 2q22-q23. Review of published reports suggests that there is significant phenotypic and genetic heterogeneity within the group of patients with HSCR, MR, and microcephaly. In particular, our patients appear to have a separate disorder from Goldberg-Shprintzen syndrome, for which autosomal recessive inheritance has been proposed because of sib recurrence and consanguinity in some families.
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                Author and article information

                Journal
                9815831
                22061
                Genet Med
                Genet. Med.
                Genetics in medicine : official journal of the American College of Medical Genetics
                1098-3600
                1530-0366
                3 October 2016
                10 November 2016
                23 May 2017
                : 10.1038/gim.2016.176
                Affiliations
                [1 ]Clinical genetics Unit, Department of Obstetrics and Pediatrics, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
                [2 ]Department of Surgical, Medical, Dental and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Italy
                [3 ]Laboratory of Translational Research, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
                [4 ]Child Neurology and Psychiatry Unit, S Orsola Malpighi Hospital, University of Bologna, Italy
                [5 ]Department of Medical Genetics, Faculty of Medicine, King Abdulaziz University, Jeddah, SA
                [6 ]Department of Human Genetics, Medical Research Institute, University of Alexandria, Egypt
                [7 ] Neurophychiatric Department, Spedali Civili Brescia, Italy
                [8 ]Division of Genetic Medicine, University of Washington School of Medicine, Seattle, USA
                [9 ]Laboratory of Human Genetics; Galliera Hospital, Genoa, Italy
                [10 ]Department of Pediatrics, University Hospital of Copenhagen/Hvidovre, Denmark
                [11 ]Department of Clinical Genetics, Rigshospitalet, University Hospital of Copenhagen, Denmark
                [12 ]Department of Paediatrics, University of Torino, Torino, Italy
                [13 ]Pediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
                [14 ] Center for Human Genetics, Catholic University of Leuven, Belgium
                [15 ]Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
                [16 ]Neonatology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
                [17 ]Faculty of Medicine, University of Belgrade, Belgrade, Serbia
                [18 ]Department of Medical Genetics, University Children's Hospital, Belgrade, Serbia
                [19 ]Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
                [20 ]Clinical Neurophysiology Unit, IRCCS, E Medea Scientific Institute, Bosisio Parini, Lecco, Italy
                [21 ]Clinical Genetics, NE Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
                [22 ]Scientific Directorate, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
                [23 ]Center for Rare Diseases, Department of Clinical Genetics, University Hospital Copenhagen, Denmark
                [24 ]Neuropsychiatric Department, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
                [25 ]Génétique médicale, CHU, Bordeaux, France
                [26 ]INSERM U1211, Univ. Bordeaux, Bordeaux, France
                [27 ]Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy
                [28 ]Department of Pediatric Hematology&Oncology, Tepecik Training and Research Hospital, Izmir, Turkey
                [29 ]Medical Genetics Unit, Dolo Hospital, Venice, Italy
                [30 ]CHU Bordeaux, Centre de référence des anomalies du développement embryonnaire, Service de Génétique médicale, Bordeaux
                [31 ]Danish Epilepsy Centre, Dianalund, Denmark
                [32 ]Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
                [33 ]Institute for Human Genetics, University Hospital Magdeburg, Germany
                [34 ]Developmental Neurology Department, IRCCS Fondazione Istituto Neurologico “C. Besta,” Milan, Italy
                [35 ]Department of Pediatrics, H. San Pedro, La Rioja, Logrono, Spain
                [36 ]Clinical Neurophysiology and Epilepsy Center, Carlo Besta Neurological Institute, IRCCS
                [37 ]Genetics Unit, St Chiara Hospital, Trento, Italy
                [38 ]Department of Pediatrics, IRCCS San Matteo, Pavia, Italy
                [39 ]Department of Medical Genetics, Gaetano Rummo Hospital, Benevento, Italy
                [40 ]Department of Pediatrics, Hospital S. Gerardo, University of Milano-Bicocca, Monza, Italy
                [41 ]Department of Pediatrics, ASST Lariana, Como, Italy
                [42 ]Department of Pediatrics and Medical sciences, “Vittorio Emanuele” Hospital, University of Catania, Catania, Italy
                [43 ]Department of Pediatrics, University “La Sapienza,” Rome, Italy
                [44 ]Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil
                [45 ]Department of Genetics, Tours University Hospital, Tours, France
                [46 ]Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia, USA
                [47 ]Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, Virginia, USA
                [48 ]Institute of Genomic Medicine, Catholic University, Gemelli Hospital Foundation, Roma, Italy
                [49 ]Department of Pediatrics and Department of Neurology, University of Washington, Seattle, USA
                [50 ]Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, USA
                [51 ]Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA
                [52 ]Department of Neurology, University of Rochester Medical Center, Rochester, NY, USA
                [53 ]Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA
                [54 ]Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, NY, USA
                Author notes
                Address for correspondence: Dr. Livia Garavelli, Struttura Semplice Dipartimentale di Genetica Clinica, Arcispedale Santa Maria Nuova-IRCCS, Viale Risorgimento 80, 42123 Reggio Emilia, ITALY, Phone: 0039-0522-296244/296241, FAX: 0039-0522-296266, garavelli.livia@ 123456asmn.re.it
                Article
                EMS70054
                10.1038/gim.2016.176
                5438871
                27831545
                50897ca8-50c7-41b1-a3cd-514c8a4848a0

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                Article

                Genetics
                mowat-wilson syndrome,zeb2,brain mri,agenesis of corpus callosum,genotype-phenotype correlation

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