Send to

Choose Destination
Eur J Hum Genet. 2016 Feb;24(2):183-90. doi: 10.1038/ejhg.2015.88. Epub 2015 Apr 22.

(Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome.

Author information

Department of Pediatric and Public Health Sciences, University of Torino, Torino, Italy.
Laboratory of Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, Milan, Italy.
DiSTABiF, Second University of Naples, Italy.
Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, S. Gerardo Hospital, Monza, Italia.
Rare Disease and Medical Genetics Unit, Bambino Gesù Children Hospital, Rome, Italy.
Department of Pediatric and Pediatric Neuropsychiatry, Sapienza University, Rome, Italy.
Medical Genetics Unit, IRCCS Ca' Granda Foundation, Ospedale Maggiore Policlinico, Milan, Italy.
Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Clinical Pediatric Genetics, Department of Pediatrics, University "Federico II", Naples, Italy.
Department of Biology, University of Naples Federico II, Naples, Italy.
Department of Health Sciences, University of Milan, Milan, Italy.
Institute of Genetics and Biophysics 'A. Buzzati-Traverso'-CNR, Naples, Italy.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center