-
Nature Reviews. Endocrinology Apr 2018Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal... (Review)
Review
Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.
Topics: Beckwith-Wiedemann Syndrome; Consensus; DNA Copy Number Variations; DNA Methylation; Humans; Molecular Diagnostic Techniques; Neoplasms, Germ Cell and Embryonal; Polymorphism, Single Nucleotide; Prenatal Diagnosis; Reproductive Techniques, Assisted
PubMed: 29377879
DOI: 10.1038/nrendo.2017.166 -
Frontiers in Pediatrics 2019Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder that presents with a wide spectrum of clinical features including overgrowth, abdominal wall... (Review)
Review
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.
PubMed: 32039119
DOI: 10.3389/fped.2019.00562 -
Cells Jun 2022In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 () knockout mouse models, we have learnt much about the structure of this... (Review)
Review
In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 () knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver-Russell and Beckwith-Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of -linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of defects in these patients.
Topics: Animals; Beckwith-Wiedemann Syndrome; Epigenomics; Genomic Imprinting; Humans; Insulin-Like Growth Factor II; Mice; Silver-Russell Syndrome
PubMed: 35741015
DOI: 10.3390/cells11121886 -
Cancers Nov 2022Placental mesenchymal dysplasia (PMD) is characterized by placentomegaly, aneurysmally dilated chorionic plate vessels, thrombosis of the dilated vessels, and large... (Review)
Review
Placental mesenchymal dysplasia (PMD) is characterized by placentomegaly, aneurysmally dilated chorionic plate vessels, thrombosis of the dilated vessels, and large grapelike vesicles, and is often mistaken for partial or complete hydatidiform mole with a coexisting normal fetus. Androgenetic/biparental mosaicism (ABM) has been found in many PMD cases. Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder with complex and diverse phenotypes and an increased risk of developing embryonal tumors. There are five major causative alterations: loss of methylation of imprinting control region 2 (:TSS-DMR) (ICR2-LOM), gain of methylation at ICR1 (/:IG-DMR) (ICR1-GOM), paternal uniparental disomy of 11 (pUPD11), loss-of-function variants of the gene, and paternal duplication of 11p15. Additional minor alterations include genetic variants within ICR1, paternal uniparental diploidy/biparental diploidy mosaicism (PUDM, also called ABM), and genetic variants of . ABM (PUDM) is found in both conditions, and approximately 20% of fetuses from PMD cases are BWS and vice versa, suggesting a molecular link. PMD and BWS share some molecular characteristics in some cases, but not in others. These findings raise questions concerning the timing of the occurrence of the molecularly abnormal cells during the postfertilization period and the effects of these abnormalities on cell fates after implantation.
PubMed: 36428656
DOI: 10.3390/cancers14225563 -
The Pan African Medical Journal 2023
Topics: Humans; Beckwith-Wiedemann Syndrome
PubMed: 37426460
DOI: 10.11604/pamj.2023.45.17.38741 -
Cancers Mar 2023CRC is an adult-onset carcinoma representing the third most common cancer and the second leading cause of cancer-related deaths in the world. EO-CRC (<45 years of age)...
CRC is an adult-onset carcinoma representing the third most common cancer and the second leading cause of cancer-related deaths in the world. EO-CRC (<45 years of age) accounts for 5% of the CRC cases and is associated with cancer-predisposing genetic factors in half of them. Here, we describe the case of a woman affected by BWSp who developed EO-CRC at age 27. To look for a possible molecular link between BWSp and EO-CRC, we analysed her whole-genome genetic and epigenetic profiles in blood, and peri-neoplastic and neoplastic colon tissues. The results revealed a general instability of the tumor genome, including copy number and methylation changes affecting genes of the WNT signaling pathway, CRC biomarkers and imprinted loci. At the germline level, two missense mutations predicted to be likely pathogenic were found in compound heterozygosity affecting the Cystic Fibrosis (CF) gene CFTR that has been recently classified as a tumor suppressor gene, whose dysregulation represents a severe risk factor for developing CRC. We also detected constitutional loss of methylation of the :TSS-DMR that leads to bi-allelic expression of the lncRNA and BWSp. Our results support the hypothesis that the inherited CFTR mutations, together with constitutional loss of methylation of the :TSS-DMR, initiate the tumorigenesis process. Further somatic genetic and epigenetic changes enhancing the activation of the WNT/beta-catenin pathway likely contributed to increase the growth advantage of cancer cells. Although this study does not provide any conclusive cause-effect relationship between BWSp and CRC, it is tempting to speculate that the imprinting defect of BWSp might accelerate tumorigenesis in adult cancer in the presence of predisposing genetic variants.
PubMed: 37046605
DOI: 10.3390/cancers15071944 -
Cancers Oct 2023Beckwith-Wiedemann syndrome (BWS) is a genetic imprinting disorder that most commonly presents as overgrowth, macroglossia, abdominal wall defects, lateralized...
Beckwith-Wiedemann syndrome (BWS) is a genetic imprinting disorder that most commonly presents as overgrowth, macroglossia, abdominal wall defects, lateralized overgrowth, and embryonal tumors [...].
PubMed: 37894306
DOI: 10.3390/cancers15204939 -
Frontiers in Genetics 2020Epigenetics has achieved a profound impact in the biomedical field, providing new experimental opportunities and innovative therapeutic strategies to face a plethora of... (Review)
Review
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 , 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 (), , and abnormally methylated DMR1 region. The second domain consists of cell proliferation and regulating-genes such as 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.
PubMed: 33101381
DOI: 10.3389/fgene.2020.563718