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Beckwith-Wiedemann syndrome

Authors
Brian Chung Hon-Yin, MD, FCCMG
Cheryl Shuman, MS, CGC
Sanaa Choufani, PhD
Rosanna Weksberg, MD, PhD, FRCPC, FCCMG, FACMG
Section Editor
Helen V Firth, DM, FRCP, DCH
Deputy Editor
Elizabeth TePas, MD, MS

INTRODUCTION

Beckwith-Wiedemann syndrome (BWS, MIM #130650) is a pediatric overgrowth disorder involving a predisposition to tumor development [1]. The clinical presentation is highly variable, and some cases lack the characteristic features originally described by Beckwith and Wiedemann [2,3]. BWS exhibits etiologic molecular heterogeneity, and some molecular alterations correlate with specific phenotypic features of BWS.

The epidemiology, genetics, pathogenesis, clinical manifestations, diagnosis, management, and prognosis of BWS are reviewed in this topic.

EPIDEMIOLOGY

BWS is a panethnic disorder with an estimated population prevalence of 1 in 13,700 [4]. This figure most likely represents an underestimate because milder phenotypes may not be ascertained. The prevalence is equal in males and females, with the notable exception of an increased frequency of female monozygotic twins versus male monozygotic twins [5]. BWS usually occurs sporadically (85 percent), but familial transmission occurs in approximately 15 percent of cases.

GENETICS AND PATHOGENESIS

Generally, both the maternally and paternally inherited alleles of each autosomal gene pair are expressed. Less than 100 genes across the genome are imprinted and expressed monoallelically in a parent of origin-specific manner (figure 1). That is, for a given imprinted gene pair, one parental allele is consistently expressed, whereas the other allele is silenced. Genomic imprinting is regulated by epigenetic mechanisms. These include noncoding RNAs and chemical modifications extrinsic to the primary nucleotide sequence, such as DNA methylation and histone modifications. Different DNA methylation and histone modification states underpin the expression or silencing of imprinted alleles. Thus, imprinted genes demonstrate differential DNA methylation. Imprinted genes occur in clusters referred to as imprinted domains and are regulated in cis (on the same chromosome) by imprinting centers (ICs). ICs are comprised of differentially methylated regions (DMRs) of DNA. (See "Overview of Mendelian inheritance", section on 'Parent-of-origin effects'.)

Deregulation of imprinted gene expression in the chromosome 11p15.5 region can result in the BWS phenotype [6-8]. The critical BWS genes in that region include insulin-like growth factor 2 (IGF2), H19, cyclin-dependent kinase inhibitor 1C (CDKN1C), potassium channel voltage-gated KQT-like subfamily member 1 (KCNQ1), and KCNQ1-overlapping transcript 1 (KCNQ1OT1, or long QT intronic transcript 1). A chromosome 11p15 molecular alteration is identified in only approximately 80 percent of individuals with BWS. This is due, in part, to somatic mosaicism for some of the molecular alterations.

                            

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Literature review current through: Nov 2016. | This topic last updated: Mon Feb 08 00:00:00 GMT 2016.
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