Preclinical and Clinical Epigenetic-Based Reconsideration of Beckwith-Wiedemann Syndrome

Abstract

Epigenetics has achieved a profound impact in the biomedical field, providing new experimental opportunities and innovative therapeutic strategies to face a plethora of diseases. In the rare diseases scenario , Beckwith-Wiedemann syndrome (BWS) is a pediatric pathological condition characterized by a complex molecular basis, showing alterations in the expression of different growth-regulating genes. The molecular origin of BWS is associated with impairments in the genomic imprinting of two domains at the 11p15.5 chromosomal region. The first domain contains three different regions: insulin growth like factor gene ( IGF2 ), H19 , and abnormally methylated DMR1 region. The second domain consists of cell proliferation and regulating-genes such as CDKN1C gene encoding for cyclin kinase inhibitor its role is to block cell proliferation. Although most cases are sporadic, about 5–10% of BWS patients have inheritance characteristics. In the 11p15.5 region, some of the patients have maternal chromosomal rearrangements while others have Uniparental Paternal Disomy UPD(11)pat. Defects in DNA methylation cause alteration of genes and the genomic structure equilibrium leading uncontrolled cell proliferation, which is a typical tumorigenesis event. Indeed, in BWS patients an increased childhood tumor predisposition is observed. Here, we summarize the latest knowledge on BWS and focus on the impact of epigenetic alterations to an increased cancer risk development and to metabolic disorders. Moreover, we highlight the correlation between assisted reproductive technologies and this rare disease. We also discuss intriguing aspects of BWS in twinning. Epigenetic therapies in clinical trials have already demonstrated effectiveness in oncological and non-oncological diseases. In this review, we propose a potential “epigenetic-based” approaches may unveil new therapeutic options for BWS patients. Although the complexity of the syndrome is high, patients can be able to lead a normal life but tumor predispositions might impair life expectancy. In this sense epigenetic therapies should have a supporting role in order to guarantee a good prognosis.

Maxillo-Facial Morphology in Beckwith-Wiedemann Syndrome: A Preliminary Study on (epi)Genotype-Phenotype Association in Caucasians

“…Recent studies evidenced relevant (epi)genotype–phenotype association [ 2 , 8 , 29 , 30 ] and clinical and epigenetic differences based on racial/ethnic background [ 22 , 23 ]. Caucasian patients are more likely to present with classic traits of BWS (macroglossia, omphalocele) along with IC2-LoM, while non-Caucasian and Asian patients appear to be more prone to show less visually apparent features (nephromegaly, hyperinsulinism) reflecting UPD(11)pat and IC1-GoM subtypes [ 31 ].…”

“…We also applied a cluster analysis to explore whether skeletal divergence, cranio-facial growth pattern, skeletal class and facial profile might differentiate between the diverse molecular subtypes of BWS. While bivariate (epi)genotype-phenotype association has been reported in the literature [ 2 , 8 , 22 , 23 , 29 , 30 , 31 ], this is the first study to use multivariate statistical methods to classify patients according to dentoskeletal pattern. Interestingly, children were not separated based on this composite outcome.…”

Adrenocortical Tumors in Children With Constitutive Chromosome 11p15 Paternal Uniparental Disomy: Implications for Diagnosis and Treatment

“…ACTs have been reported in a BWS patient with concomitant neuroblastoma and hypomethylation at ICR2 (21). However, most studies associate ACT exclusively with 11p15 UPD (19,22,23). In addition to paternal 11p15 UPD, germline rearrangements at this region have also been observed in 12% of children with ACT without germline TP53 mutations (1), making abnormalities in these loci the most common recurrent constitutional driver events in wild type TP53 pediatric ACT.…”

Placental Mesenchymal Dysplasia and Beckwith–Wiedemann Syndrome

“…ICR2-LOM occurs on the maternal allele and induces the repression of CDKN1C , which encodes cyclin dependent kinase inhibitor p57 KIP2 , from the maternal allele [ 14 , 61 ]. The KCNQ1 variants, including SNVs and copy number variations (CNVs), on the maternal allele cause loss of transcription of KCNQ1 and lead to ICR2-LOM, resulting in repression of CDKN1C [ 18 , 19 ].…”

“…The KCNQ1 variants, including SNVs and copy number variations (CNVs), on the maternal allele cause loss of transcription of KCNQ1 and lead to ICR2-LOM, resulting in repression of CDKN1C [ 18 , 19 ]. ICR1-GOM occurs on the maternal allele and induces the expression of IGF2 , which encodes insulin-like growth factor 2, and the repression of H19 , a noncoding RNA, from the maternal allele [ 14 , 61 ]. SNVs or microdeletion of the Oct-binding site within ICR1 are found in approximately 20% of ICR1-GOM cases and cause ICR1-GOM, resulting in biallelic expression of IGF2 and biallelic repression of H19 [ 15 , 16 , 57 , 58 ].…”