title: (Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome.
abstract: Beckwith-Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype-phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n=190), IC1 gain of methylation (IC1-GoM, n=31), chromosome 11p15 paternal uniparental disomy (UPD, n=87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n=10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (P<0.001). Exomphalos was more common in IC2/CDKN1C patients (P<0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (P<0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (P<0.001). Macroglossia was less common among UPD patients (P<0.001). Wilms' tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (P<0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P=0.009). In conclusion, (epi)genotype-phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening.
authors.affiliation: Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mussa
authors.affiliation: Laboratory of Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.affiliation: DiSTABiF, Second University of Naples, Italy.
authors.forename: Agostina
authors.initials: A
authors.lastname: De Crescenzo
authors.affiliation: DiSTABiF, Second University of Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Freschi
authors.affiliation: Laboratory of Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Calzari
authors.affiliation: Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, S. Gerardo Hospital, Monza, Italia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maitz
authors.affiliation: Rare Disease and Medical Genetics Unit, Bambino Gesù Children Hospital, Rome, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Macchiaiolo
authors.affiliation: Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Molinatto
authors.affiliation: Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Baldassarre
authors.affiliation: Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, S. Gerardo Hospital, Monza, Italia.
authors.forename: Milena
authors.initials: M
authors.lastname: Mariani
authors.affiliation: Department of Pediatric and Pediatric Neuropsychiatry, Sapienza University, Rome, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Tarani
authors.affiliation: Medical Genetics Unit, IRCCS Ca' Granda Foundation, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Bedeschi
authors.affiliation: Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Milani
authors.affiliation: Clinical Pediatric Genetics, Department of Pediatrics, University "Federico II", Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Melis
authors.affiliation: Rare Disease and Medical Genetics Unit, Bambino Gesù Children Hospital, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bartuli
authors.affiliation: Department of Biology, University of Naples Federico II, Naples, Italy.
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Cubellis
authors.affiliation: Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, S. Gerardo Hospital, Monza, Italia.
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Cirillo Silengo
authors.affiliation: Laboratory of Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy.|Department of Health Sciences, University of Milan, Milan, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
authors.affiliation: DiSTABiF, Second University of Naples, Italy.|Institute of Genetics and Biophysics 'A. Buzzati-Traverso'-CNR, Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Riccio
authors.affiliation: Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Ferrero
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D018392:Genomic Imprinting; D005838:Genotype; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D010641:Phenotype
chemical_list: C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57