Diagnosis and Management of Beckwith-Wiedemann Syndrome

Abstract

Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder that presents with a wide spectrum of clinical features including overgrowth, abdominal wall defects, macroglossia, neonatal hypoglycemia, and predisposition to embryonal tumors. It is associated with genetic and epigenetic changes on the chromosome 11p15 region, which includes two imprinting control regions. Here we review strategies for diagnosing and managing BWS and delineate commonly used genetic tests to establish a molecular diagnosis of BWS. Recommended first-line testing assesses DNA methylation and copy number variation of the BWS region. Tissue mosaicism can occur in patients with BWS, posing a challenge for genetic testing, and a negative test result does not exclude a diagnosis of BWS. Further testing should analyze additional tissue samples or employ techniques with higher diagnostic yield. Identifying the BWS molecular subtype is valuable for coordinating patient care because of the (epi)genotype-phenotype correlations, including different risks and types of embryonal tumors.

DNA Methylation in the Diagnosis of Monogenic Diseases

“…A recent international consensus document has recognized the existence of a Beckwith-Wiedemann spectrum (BWSp) covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly [64]. The typical BWS molecular abnormalities affect one or both of two functional domains of the imprinted gene cluster located at chromosome 11p15.5-11p15.4 [65]. The telomeric domain harbors the insulin-like growth factor 2 (IGF2) gene that is expressed from the paternal allele and encodes a protein promoting fetal growth, and H19, which is expressed from the maternal allele and encodes a non-translated long non-coding RNA with growth inhibitory properties.…”

“…A molecular defect affecting imprinted genes in the chromosome region 11p15 can be detected iñ 85% of patients [64,65]. DNA methylation changes are the most frequent abnormalities.…”

“…Molecular diagnosis of BWS is obtained by detection of abnormal methylation of IC1, IC2 or both, and is most commonly reached by using MS-MLPA, which also recognizes CNVs [64,65]. A further microsatellite analysis is needed to confirm upd(11)pat, and Sanger sequencing is needed to detect possible clinical variants in IC1 and CDKN1C.…”

Medical Approaches in Adrenocortical Carcinoma

“…The Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth and tumor predisposition syndrome caused by genetic or epigenetic changes on chromosome 11p15, involving the IGF2 gene [17]. BWS is characterized by hemihypertrophy, macroglossia, macrosomia, organomegaly, hyperinsulinism, omphalocele/umbilical hernia as well as by the risk of developing embryonal tumors [18]. In particular, the overall risk of intra-abdominal tumor development is between 5 and 10% [19] and the most associated tumors in BWS are the Wilms tumor, hepatoblastoma, neuroblastoma and ACC [20].…”

Sex of donor cell and reprogramming conditions predict the extent and nature of imprinting defects in mouse iPSCs

“…These genes are important regulators in prenatal growth and development, as well as, in postnatal brain functions and metabolic pathways [reviewed in (Tucci et al, 2019)]. The dysregulation of imprinted genes has been associated with several developmental and behavioural disorders, such as Beckwith-Weidemann, Angelman and Prader-Willi syndromes (Cassidy et al, 2012; Maranga et al, 2020; Wang et al, 2019). Most imprinted genes are located in close proximity in defined genomic loci, called imprinted clusters.…”