Neuroimaging findings in Mowat-Wilson syndrome: a study of 54 patients.
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.



Through brain magnetic resonance imaging (MRI) analysis, we delineated a neuroimaging phenotype in 54 MWS patients with a proven ZEB2 defect, compared it with the features identified in a thorough review of published cases, and evaluated genotype-phenotype correlations.



Ninety-six percent of patients had abnormal MRI results. The most common features were anomalies of corpus callosum (79.6% of cases), hippocampal abnormalities (77.8%), enlargement of cerebral ventricles (68.5%), and 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 favorable for psychomotor development and some epilepsy features but also associated with corpus callosum agenesis.



This study delineated the spectrum of brain anomalies in MWS and provided new insights into the role of ZEB2 in neurodevelopment.Genet Med advance online publication 10 November 2016.
Clinical Genetics Unit, Department of Obstetrics and Pediatrics, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Livia
L
Garavelli
Clinical Genetics Unit, Department of Obstetrics and Pediatrics, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.|Department of Surgical, Medical, Dental, and Morphological Sciences with interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.
Ivan
0000-0002-0113-783X
I
Ivanovski
Laboratory of Translational Research, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Stefano Giuseppe
0000-0002-5033-7854
SG
Caraffi
Clinical Genetics Unit, Department of Obstetrics and Pediatrics, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Daniela
0000-0002-4464-1593
D
Santodirocco
Clinical Genetics Unit, Department of Obstetrics and Pediatrics, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Marzia
0000-0001-7070-7472
M
Pollazzon
Child Neurology and Psychiatry Unit, S Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.
Duccio Maria
0000-0002-1367-6419
DM
Cordelli
Department of Medical Genetics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.|Department of Human Genetics, Medical Research Institute, University of Alexandria, Alexandria, Egypt.
Ebtesam
E
Abdalla
Neurophychiatric Department, Spedali Civili Brescia, Italy.
Patrizia
P
Accorsi
Division of Genetic Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
Margaret P
0000-0001-9817-5121
MP
Adam
Laboratory of Human Genetics, Galliera Hospital, Genoa, Italy.
Chiara
0000-0001-7508-3953
C
Baldo
Department of Pediatrics, University Hospital of Copenhagen/Hvidovre, Copenhagen, Denmark.|Department of Clinical Genetics, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Allan
A
Bayat
Department of Paediatrics, University of Torino, Torino, Italy.
Elga
0000-0003-2392-7223
E
Belligni
Clinical Genetics Unit, Department of Obstetrics and Pediatrics, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.|Pediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.
Federico
F
Bonvicini
Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium.
Jeroen
0000-0002-0734-5154
J
Breckpot
Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.
Bert
0000-0002-9743-4205
B
Callewaert
Neonatology Unit, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
Guido
G
Cocchi
Faculty of Medicine, University of Belgrade, Belgrade, Serbia.|Department of Medical Genetics, University Children's Hospital, Belgrade, Serbia.
Goran
G
Cuturilo
Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium.
Koenraad
K
Devriendt
Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.
Mary Beth
0000-0002-7353-6178
MB
Dinulos
Clinical Genetics Unit, Department of Obstetrics and Pediatrics, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Olivera
O
Djuric
Clinical Neurophysiology Unit, IRCCS, E Medea Scientific Institute, Lecco, Italy.
Roberta
0000-0001-6739-804X
R
Epifanio
Clinical Genetics, NE Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Francesca
F
Faravelli
Scientific Directorate, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Debora
0000-0001-6723-8505
D
Formisano
Neurophychiatric Department, Spedali Civili Brescia, Italy.
Lucio
L
Giordano
Laboratory of Human Genetics, Galliera Hospital, Genoa, Italy.
Marina
0000-0001-5682-1789
M
Grasso
Center for Rare Diseases, Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark.
Sabine
S
Grønborg
Neuropsychiatric Department, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Alessandro
A
Iodice
Pediatric Unit, Department of Medical and Surgical Sciences for Mothers, Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.
Lorenzo
0000-0003-0370-7872
L
Iughetti
Génétique Médicale, CHU, Bordeaux, France.|INSERM U1211, Univ. Bordeaux, Bordeaux, France.
Didier
D
Lacombe
Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Massimo
M
Maggi
Department of Pediatric Hematology &Oncology, Tepecik Training and Research Hospital, Izmir, Turkey.
Baris
B
Malbora
Medical Genetics Unit, Dolo Hospital, Venice, Italy.
Isabella
0000-0001-7633-1381
I
Mammi
Génétique Médicale, CHU, Bordeaux, France.|CHU Bordeaux, Centre de Référence des Anomalies du Développement Embryonnaire, Service de Génétique Médicale, Bordeaux, France.
Sebastien
0000-0002-8942-6731
S
Moutton
Danish Epilepsy Centre, Dianalund, Denmark.|Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
Rikke
R
Møller
Institute for Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
Petra
P
Muschke
Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Manuela
0000-0002-0434-4172
M
Napoli
Developmental Neurology Department, IRCCS Fondazione Istituto Neurologico "C. Besta," Milan, Italy.
Chiara
C
Pantaleoni
Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Rosario
0000-0001-7335-5847
R
Pascarella
Child Neurology and Psychiatry Unit, S Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.
Alessandro
0000-0002-5592-9015
A
Pellicciari
Department of Pediatrics, H. San Pedro, Logrono, Spain.
Maria Luisa
0000-0003-0247-7147
ML
Poch-Olive
Clinical Neurophysiology and Epilepsy Center, Carlo Besta Neurological Institute, IRCCS, Milano, Italy.
Federico
0000-0001-6799-2911
F
Raviglione
Genetics Unit, St Chiara Hospital, Trento, Italy.
Francesca
0000-0001-5969-8464
F
Rivieri
Neuroradiology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy.
Carmela
0000-0002-8427-7941
C
Russo
Department of Pediatrics, IRCCS San Matteo, Pavia, Italy.
Salvatore
S
Savasta
Department of Medical Genetics, Gaetano Rummo Hospital,Benevento, Italy.
Gioacchino
0000-0001-5477-0711
G
Scarano
Department of Pediatrics, Hospital S. Gerardo, University of Milano-Bicocca, Monza, Italy.|Department of Pediatrics, ASST Lariana, Como, Italy.
Angelo
A
Selicorni
Department of Paediatrics, University of Torino, Torino, Italy.
Margherita
M
Silengo
Department of Pediatrics and Medical sciences, ''Vittorio Emanuele" Hospital, University of Catania, Catania, Italy.
Giovanni
0000-0003-1385-5588
G
Sorge
Department of Pediatrics, University ''La Sapienza,'' Rome, Italy.
Luigi
L
Tarani
Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
Luis Gonzaga
LG
Tone
Department of Genetics, Tours University Hospital, Tours, France.
Annick
0000-0002-5999-5300
A
Toutain
Génétique Médicale, CHU, Bordeaux, France.
Aurelien
0000-0002-3457-5684
A
Trimouille
Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
Elvis Terci
ET
Valera
Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia, USA.|Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia, USA.
Samantha Schrier
0000-0001-9194-0644
SS
Vergano
Clinical Neurophysiology Unit, IRCCS, E Medea Scientific Institute, Lecco, Italy.
Nicoletta
0000-0003-0204-4587
N
Zanotta
Institute of Genomic Medicine, Catholic University, Gemelli Hospital Foundation, Roma, Italy.
Marcella
M
Zollino
Department of Pediatrics and Department of Neurology, University of Washington, Seattle, Washington, USA.|Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
William B
0000-0002-7681-2844
WB
Dobyns
Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA.|Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.|Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, New York, USA.|Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, USA.
Alex R
AR
Paciorkowski
D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004827:Epilepsy / Q000473:pathology; D019066:Facies; D005260:Female; D005838:Genotype; D057895:Haploinsufficiency; D006627:Hirschsprung Disease / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D059906:Neuroimaging; D010641:Phenotype; D000074165:Zinc Finger E-box Binding Homeobox 2 / Q000235:genetics
C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2