- Brian Chung Hon-Yin, MD, FCCMG
Brian Chung Hon-Yin, MD, FCCMG
- Clinical Associate Professor
- University of Hong Kong
- Cheryl Shuman, MS, CGC
Cheryl Shuman, MS, CGC
- University of Toronto
- The Hospital for Sick Children
- Sanaa Choufani, PhD
Sanaa Choufani, PhD
- Research Associate
- The Hospital for Sick Children
- Rosanna Weksberg, MD, PhD, FRCPC, FCCMG, FACMG
Rosanna Weksberg, MD, PhD, FRCPC, FCCMG, FACMG
- University of Toronto
- Senior Associate Scientist
- The Hospital for Sick Children
Beckwith-Wiedemann syndrome (BWS, MIM #130650) is a pediatric overgrowth disorder involving a predisposition to tumor development . 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.
BWS is a panethnic disorder with an estimated population prevalence of 1 in 10,300 to 13,700 [4,5]. 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 . BWS usually occurs sporadically (85 percent), but familial transmission occurs in approximately 15 percent of cases. Assisted reproductive technology (ART) is associated with an increased risk of imprinting disorders, with a 10-fold increased risk of BWS seen in live births from ART compared with natural conception in one Italian study .
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 exclusively or preferentially expressed, whereas the other allele is silenced or weakly expressed. 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 protein tail modifications. Different DNA methylation and histone modification states underpin the expression or silencing of imprinted alleles. Thus, imprinted alleles 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 "Inheritance patterns of monogenic disorders (Mendelian and non-Mendelian)", section on 'Parent-of-origin effects (imprinting)'.)
Deregulation of imprinted gene expression in the chromosome 11p15.5 region can result in the BWS phenotype [8-10]. 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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- GENETICS AND PATHOGENESIS
- CLINICAL MANIFESTATIONS
- Prenatal and perinatal
- Metabolic abnormalities
- Structural anomalies
- PHENOTYPE-(EPI)GENOTYPE CORRELATIONS
- Tumor development
- Cleft palate
- Developmental delay
- Severe BWS phenotype
- Positive family history
- Female monozygotic twins
- Subfertility/assisted reproductive technology
- Genetic testing
- Prenatal diagnosis
- DIFFERENTIAL DIAGNOSIS
- Evaluation following initial diagnosis
- Treatment of manifestations
- Genetic counseling