(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome: a paradigm for genomic medicine

Abstract

Beckwith-Wiedemann syndrome (BWS) is the commonest overgrowth cancer predisposition disorder and represents a model for human imprinting dysregulation and tumorigenesis. BWS features can variably combine and present a widely variable range of severity in the phenotypic expression. This wide spectrum is paralleled at molecular level by complex (epi)genetic defects on chromosome 11p15.5 leading to disrupted expression of imprinted genes controlling growth and cellular proliferation. In this review, we outline the spectrum of clinical manifestations of BWS analyzing their (epi)genotype-phenotype correlations. The differences observed in the phenotypic profiles of BWS molecular subtypes allow a composite view of this syndrome with implications on clinical care, diagnosis, follow-up, and management, and provide directions for future disease monitoring.

Cell signaling pathways in the adrenal cortex: Links to stem/progenitor biology and neoplasia

“…IGF2 and also H19 , a long non-coding RNA, are imprinted genes inversely regulated by methylation of imprinting control region 1 (ICR1) (also called imprinting center 1, IC1, or differentially methylated region 1, DMR1) at the human 11p15 locus (mouse chromosome 7). Disruption of this locus occurs in sporadic ACC in pediatric and adult populations as well as in cases of Beckwith–Wiedemann syndrome (BWS), a fetal overgrowth disease associated with pediatric ACC (Assié et al, 2014; Mussa et al, 2016b; Pinto et al, 2015; Zheng et al, 2016). …”

“…BWS is molecularly characterized by alterations at chromosome 11p15 that involve mutation or deletion of imprinted genes, methylation alterations, or paternal uniparental disomy (UPD) (reviewed by Mussa et al, 2016b). Aberrations frequently result in a gain of imprinting (hypermethylation) at the ICR1 locus, either by aberrant methylation of the maternal chromosome, or paternal UPD, which results in overexpression of IGF2.…”

“…In particular, discoveries of the underpinnings of the genetic syndromes that predispose patients to adrenocortical adenomas (ACAs) and/or carcinomas, such as Beckwith-Widemann syndrome (BWS) and Carney complex (CNC), have allowed insights to signaling pathways central to both neoplasia and homeostasis (Mussa et al, 2016b; Stratakis et al, 1996). This review will focus on the contribution of cell signaling pathways as it pertains to stem/progenitor biology and neoplasia, especially cancer.…”

Fetal growth patterns in Beckwith–Wiedemann syndrome

“…Few data are currently available on fetal and neonatal growth in BWS, being cancer predisposition the main focus of the available clinical reports (12)(13)(14)(15)(16)(17) given the implications for tumor screening (18)(19)(20). The recent understanding of molecular bases of BWS allowed to define specific correlations between (epi)genotype and phenotype (12)(13)(14)(15)(16)21). However, still data on growth pattern are largely insufficient: previous reports sought a widely variable prevalence of fetal and neonatal macrosomia in affected cohorts, probably reflecting collection biases, different prevalence of the molecular anomalies, and variable definition of growth excess.…”

Retrospective evaluation of a decision‐support algorithm (MIPOGG) for genetic referrals for children with neuroblastic tumors

“…CPS, pathogenic variants in cancer susceptibility genes, and constitutional segmental chromosomal alterations, that were identified as being clearly or potentially associated with neuroblastic tumor development, are presented in Table . Predominant phenotypic features associated with each of these genetic diseases and their association with neuroblastic tumors are also illustrated in this table.…”