title: Brain abnormalities in patients with Beckwith-Wiedemann syndrome.
abstract: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with variability in clinical manifestations and molecular causes. In most cases, patients with BWS have normal development. Cases with developmental delay are usually attributed to neonatal hypoglycemia or chromosome abnormalities involving copy number variation for genes beyond the critical BWS region at 11p15.5. Brain abnormalities have not previously been recognized within the BWS phenotypic spectrum. We report on seven cases of BWS associated with posterior fossa abnormalities. Of these, two cases presented with Blake's pouch cyst, two with Dandy-Walker variant (DWV; hypoplasia of the inferior part of the vermis), one with Dandy-Walker malformation (DWM) and one with a complex of DWM, dysgenesis of the corpus callosum and brain stem abnormality. In all these cases, molecular findings involved the centromeric imprinted domain on chromosome locus 11p15.5, which includes imprinting center 2 (IC2) and the imprinted growth suppressor gene, CDKN1C. Three cases had loss of methylation at IC2, two had CDKN1C mutations, and one had loss of methylation at IC2 and a microdeletion. In one case no mutation/methylation abnormality was detected. These findings together with previously reported correlations suggest that genes in imprinted domain 2 at 11p15.5 are involved in normal midline development of several organs including the brain. Our data suggest that brain malformations may present as a finding within the BWS phenotype when the molecular etiology involves imprinted domain 2. Brain imaging may be useful in identifying such malformations in individuals with BWS and neurodevelopmental issues.
authors.affiliation: Sarah Lawrence College, Bronxville, New York, USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Gardiner
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Sanaa
authors.initials: S
authors.lastname: Choufani
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shuman
authors.forename: Susan
authors.initials: S
authors.lastname: Blaser
authors.forename: Deborah
authors.initials: D
authors.lastname: Terespolsky
authors.forename: Sandra
authors.initials: S
authors.lastname: Farrell
authors.forename: Rosemary
authors.initials: R
authors.lastname: Reiss
authors.forename: Shoshana
authors.initials: S
authors.lastname: Wodak
authors.forename: Shuye
authors.initials: S
authors.lastname: Pu
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
authors.forename: Berivan
authors.initials: B
authors.lastname: Baskin
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000150:complications / Q000175:diagnosis* / Q000235:genetics; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics; D019175:DNA Methylation; D017809:Fatal Outcome; D005260:Female; D017353:Gene Deletion; D018392:Genomic Imprinting; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57