Beckwith-Wiedemann Syndrome


Overview: Beckwith-Wiedemann Syndrome (BWS) is a growth regulation disorder characterised by macrosomia (large body size) , macroglossia (large tongue), hemihyperplasia (some parts of the body are larger on one side) and kidney abnormalities - often diagnosed at birth. Children with BWS have an increased risk of developing childhood tumors (estimated at 7.5% of cases), usually before age 10: Wilms Tumor, Hepatoblastoma, Adrenocortical carcinoma, Rhabdomyosarcoma, and Neuroblastoma.

BWS is linked to genetic and epigenetic abnormalities of an area of chromosome 11 (11p15.5), which includes the CDKN1C and IGF2 genes. Most cases of BWS (about 85%) are sporadic (non-inherited, occurring by chance). Some cases of BWS (between 10-15%) are inherited in an autosomal dominant pattern. Overall incidence is estimated to be 1 out of 13,700 population (Weksberg et al, 2010).

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Pregnancy
  • Telomere
  • Pedigree
  • Kidney Cancer
  • Chromosome 11
  • Potassium Channels
  • KCNQ Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Pregnancy Complications
  • Translocation
  • Phenotype
  • Trisomy
  • Genotype
  • Alleles
  • RNA, Untranslated
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Membrane Proteins
  • Adolescents
  • Base Sequence
  • Chromosome Deletion
  • Rhabdomyosarcoma
  • Chromosome Mapping
  • Gene Deletion
  • Genetic Predisposition
  • Zinc Fingers
  • DNA Methylation
  • Beckwith-Wiedemann syndrome
  • Childhood Cancer
  • Newborns
  • Nuclear Proteins
  • Infant
  • Chromosome Aberrations
  • Long Noncoding RNA
  • Genomic Imprinting
  • Cyclin-Dependent Kinase Inhibitor p57
  • Mutation
  • Molecular Sequence Data
  • Repressor Proteins
  • IGF2
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (7)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

IGF2 11p15.5 GRDF, IGF-II, PP9974, C11orf43 Epigenetics
-IGF2 and Beckwith-Wiedemann Syndrome
CDKN1C 11p15.4 BWS, WBS, p57, BWCR, KIP2, p57Kip2 -CDKN1C and Beckwith-Wiedemann syndrome
KCNQ1OT1 11p15.5 LIT1, Kncq1, KvDMR1, KCNQ10T1, KCNQ1-AS2, KvLQT1-AS, NCRNA00012 -KCNQ1OT1 and Beckwith-Wiedemann syndrome
WT2 11p15.5 ADCR, MTACR1 -WT2 and Beckwith-Wiedemann syndrome
KCNQ1 11p15.5-p15.4 LQT, RWS, WRS, LQT1, SQT2, ATFB1, ATFB3, JLNS1, KCNA8, KCNA9, Kv1.9, Kv7.1, KVLQT1 -KCNQ1 and Beckwith-Wiedemann syndrome
NLRP7 19q13.42 HYDM, PAN7, NALP7, NOD12, PYPAF3, CLR19.4 -NLRP7 and Beckwith-Wiedemann syndrome
SLC22A18 11p15.4 HET, ITM, BWR1A, IMPT1, TSSC5, ORCTL2, BWSCR1A, SLC22A1L, p45-BWR1A -SLC22A18 and Beckwith-Wiedemann syndrome

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Useful Links (7 links)

Latest Publications

Li Y, Donnelly CG, Rivera RM
Overgrowth Syndrome.
Vet Clin North Am Food Anim Pract. 2019; 35(2):265-276 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Large offspring syndrome (LOS) is a fetal overgrowth condition in bovines most often observed in offspring conceived with the use of assisted reproductive technologies (ART). Phenotypes observed in LOS include, overgrowth, enlarged tongues, umbilical hernias, muscle and skeleton malformations, abnormal organ growth and placental development. Although LOS cases have only been reported to be associated with ART, fetal overgrowth can occur spontaneously in cattle (S-LOS). S-LOS refers to oversized calves that are born at normal gestation lengths. ART-induced LOS has been characterized as an epigenetic syndrome, more specifically, a loss-of-imprinting condition. We propose that S-LOS is also a loss-of-imprinting condition.

Mackay DJG, Bliek J, Lombardi MP, et al.
Discrepant molecular and clinical diagnoses in Beckwith-Wiedemann and Silver-Russell syndromes.
Genet Res (Camb). 2019; 101:e3 [PubMed] Related Publications
Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders associated with opposite molecular alterations in the 11p15.5 imprinting centres. Their clinical diagnosis is confirmed by molecular testing in 50-70% of patients. The authors from different reference centres for BWS and SRS have identified single patients with unexpected and even contradictory molecular findings in respect to the clinical diagnosis. These patients clinically do not fit the characteristic phenotypes of SRS or BWS, but illustrate their clinical heterogeneity. Thus, comprehensive molecular testing is essential for accurate diagnosis and appropriate management, to avoid premature clinical diagnosis and anxiety for the families.

Hattori H, Hiura H, Kitamura A, et al.
Association of four imprinting disorders and ART.
Clin Epigenetics. 2019; 11(1):21 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Human-assisted reproductive technologies (ART) are a widely accepted treatment for infertile couples. At the same time, many studies have suggested the correlation between ART and increased incidences of normally rare imprinting disorders such as Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS). Major methylation dynamics take place during cell development and the preimplantation stages of embryonic development. ART may prevent the proper erasure, establishment, and maintenance of DNA methylation. However, the causes and ART risk factors for these disorders are not well understood.
RESULTS: A nationwide epidemiological study in Japan in 2015 in which 2777 pediatrics departments were contacted and a total of 931 patients with imprinting disorders including 117 BWS, 227 AS, 520 PWS, and 67 SRS patients, were recruited. We found 4.46- and 8.91-fold increased frequencies of BWS and SRS associated with ART, respectively. Most of these patients were conceived via in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and showed aberrant imprinted DNA methylation. We also found that ART-conceived SRS (ART-SRS) patients had incomplete and more widespread DNA methylation variations than spontaneously conceived SRS patients, especially in sperm-specific methylated regions using reduced representation bisulfite sequencing to compare DNA methylomes. In addition, we found that the ART patients with one of three imprinting disorders, PWS, AS, and SRS, displayed additional minor phenotypes and lack of the phenotypes. The frequency of ART-conceived Prader-Willi syndrome (ART-PWS) was 3.44-fold higher than anticipated. When maternal age was 37 years or less, the rate of DNA methylation errors in ART-PWS patients was significantly increased compared with spontaneously conceived PWS patients.
CONCLUSIONS: We reconfirmed the association between ART and imprinting disorders. In addition, we found unique methylation patterns in ART-SRS patients, therefore, concluded that the imprinting disorders related to ART might tend to take place just after fertilization at a time when the epigenome is most vulnerable and might be affected by the techniques of manipulation used for IVF or ICSI and the culture medium of the fertilized egg.

Gaillot-Durand L, Brioude F, Beneteau C, et al.
Placental Pathology in Beckwith-Wiedemann Syndrome According to Genotype/Epigenotype Subgroups.
Fetal Pediatr Pathol. 2018; 37(6):387-399 [PubMed] Related Publications
OBJECTIVES: To evaluate the frequency of placental pathological lesions in Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder that exhibits etiologic molecular heterogeneity and variable phenotypic expression.
MATERIALS AND METHODS: The study included 60 BWS patients with a proven molecular diagnosis and a placental pathological examination. Placentomegaly, placental mesenchymal dysplasia (PMD), chorangioma/chorangiomatosis, and extravillous trophoblastic (EVT) cytomegaly were evaluated and their frequencies in the different molecular subgroups were compared. Immunohistochemistry and fluorescent in situ hybridization (FISH) were performed on EVT cytomegaly.
RESULTS: Placentomegaly was found in 70.9% of cases, PMD in 21.7%, chorangioma/chorangiomatosis in 23.3%, and EVT cytomegaly in 21.7%; there was no significant intergroup difference. EVT cytomegaly showed loss of p57 expression, increased Ki67 proliferating index, and polyploidy on FISH analysis.
CONCLUSIONS: There was no genotype/epigenotype-phenotype correlation concerning placental lesions in BWS. Diffuse EVT cytomegaly with polyploidy may represent a placental finding suggestive of BWS.

Shterenshis M, Roitblat Y, Ilani J, et al.
The 11p15.5 chromosomal region: When did the instability occur?
Med Hypotheses. 2018; 121:21-25 [PubMed] Related Publications
The disturbances of the 11p15.5 chromosomal region are associated with Beckwith-Wiedemann syndrome, Russell-Silver syndrome, Wilms tumor, IMAGe syndrome, and idiopathic hemihyperplasia. The aim of this research was to examine the hypothesis that 11p15.5 initially became unstable in the European population about 200 years ago. The medical literature from 1557 onwards, especially treatises on teratology, body asymmetry, and books of normal and pathologic anatomy, was searched for any mentioning of lateral body asymmetry, macroglossia and other possible visually detectable symptoms associated with the above-mentioned syndromes. The results indicate that lateral body asymmetry was not described before the first half of the 19th century, it was mentioned in the 1820s, and the first description of a true case was published in 1850. All first cases of hemihyperplasia were reported in continental Europe. Historical data suggest that the 11p15.5 chromosomal region became unstable in the first half of the 19th century. Our preliminary hypothesis is that de novo mutation occurred in continental Europe. Additional genetic research is needed to investigate the development of 11p15.5 instability during this period.

Fontana L, Bedeschi MF, Maitz S, et al.
Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders.
Epigenetics. 2018; 13(9):897-909 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.

Dagar V, Hutchison W, Muscat A, et al.
Genetic variation affecting DNA methylation and the human imprinting disorder, Beckwith-Wiedemann syndrome.
Clin Epigenetics. 2018; 10(1):114 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder with a population frequency of approximately 1 in 10,000. The most common epigenetic defect in BWS is a loss of methylation (LOM) at the 11p15.5 imprinting centre, KCNQ1OT1 TSS-DMR, and affects 50% of cases. We hypothesised that genetic factors linked to folate metabolism may play a role in BWS predisposition via effects on methylation maintenance at KCNQ1OT1 TSS-DMR.
RESULTS: Single nucleotide variants (SNVs) in the folate pathway affecting methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR), cystathionine beta-synthase (CBS) and methionine adenosyltransferase (MAT1A) were examined in 55 BWS patients with KCNQ1OT1 TSS-DMR LOM and in 100 unaffected cases. MTHFR rs1801133: C>T was more prevalent in BWS with KCNQ1OT1 TSS-DMR LOM (p < 0.017); however, the relationship was not significant when the Bonferroni correction for multiple testing was applied (significance, p = 0.0036). None of the remaining 13 SNVs were significantly different in the two populations tested. The DNMT1 locus was screened in 53 BWS cases, and three rare missense variants were identified in each of three patients: rs138841970: C>T, rs150331990: A>G and rs757460628: G>A encoding NP_001124295 p.Arg136Cys, p.His1118Arg and p.Arg1223His, respectively. These variants have population frequencies of less than 1 in 1000 and were absent from 100 control cases. Functional characterization using a hemimethylated DNA trapping assay revealed a reduced methyltransferase activity relative to wild-type DNMT1 for each variant ranging from 40 to 70% reduction in activity.
CONCLUSIONS: This study is the first to examine folate pathway genetics in BWS and to identify rare DNMT1 missense variants in affected individuals. Our data suggests that reduced DNMT1 activity could affect maintenance of methylation at KCNQ1OT1 TSS-DMR in some cases of BWS, possibly via a maternal effect in the early embryo. Larger cohort studies are warranted to further interrogate the relationship between impaired MTHFR enzymatic activity attributable to MTHFR rs1801133: C>T, dietary folate intake and BWS.

Tunster SJ, Van de Pette M, Creeth HDJ, et al.
Fetal growth restriction in a genetic model of sporadic Beckwith-Wiedemann syndrome.
Dis Model Mech. 2018; 11(11) [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Beckwith-Wiedemann syndrome (BWS) is a complex imprinting disorder involving fetal overgrowth and placentomegaly, and is associated with a variety of genetic and epigenetic mutations affecting the expression of imprinted genes on human chromosome 11p15.5. Most BWS cases are linked to loss of methylation at the imprint control region 2 (ICR2) within this domain, which in mice regulates the silencing of several maternally expressed imprinted genes. Modelling this disorder in mice is confounded by the unique embryonic requirement for

Johnson JP, Beischel L, Schwanke C, et al.
Overrepresentation of pregnancies conceived by artificial reproductive technology in prenatally identified fetuses with Beckwith-Wiedemann syndrome.
J Assist Reprod Genet. 2018; 35(6):985-992 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
OBJECTIVES: In vitro fertilization (IVF) has been linked to an increased risk for imprinting disorders in offspring. The data so far have predominantly been retrospective, comparing the rate of IVF conceptions in affected patients with controls. We describe a series of fetuses with omphalocele that were tested for Beckwith-Wiedemann syndrome (BWS) and subsequently ascertained as to whether pregnancies were conceived by assisted reproductive technologies (ART).
METHODS: Fetuses were tested for BWS by Southern blot, PCR based methods, and methylation analysis to identify the imprinting status at primarily the IC2 locus, KCNQ1OT1, as well as IC1, H19/IGF-2. Some fetuses were also tested for uniparental disomy of chromosome 11p.
RESULTS: We tested 301 fetuses with omphalocele for BWS. Forty samples were positive. Sixteen were from IVF pregnancies, for an overall rate of 40%. Such as high proportion of IVF pregnancies in a series of BWS-positive fetuses has not been described previously. Possible factors such as twinning and ascertainment bias are discussed.
CONCLUSION: We found about a 20-fold overrepresentation of IVF cases in fetuses with BWS/omphalocele when compared with the rate of ART pregnancies in the USA (p < .0001). Our series provides support for an association of IVF and BWS. Patients should be counseled about these risks and made aware of the availability of prenatal diagnosis for detection.

Elbracht M, Prawitt D, Nemetschek R, et al.
[Beckwith-Wiedemann Syndrome (BWS) Current Status of Diagnosis and Clinical Management: Summary of the First International Consensus Statement].
Klin Padiatr. 2018; 230(3):151-159 [PubMed] Related Publications
Beckwith-Wiedemann syndrome (BWS) belongs to the group of imprinting disorders and is characterized by variable clinical features, including overgrowth, macroglossia, abdominal wall defect, neonatal hypoglycemia, body asymmetry and an increased risk for embryonal tumors. In the majority of cases, molecular alterations of the Imprinting Center (IC) regions in the chromosomal region 11p15.5 can be detected, and a correlation of single clinical features with specific genomic and epigenetic changes is obvious. Therefore, the detailed molecular diagnosis is a prerequisite for a precise prediction of the tumor risk and the tumor spectrum. Furthermore, it is the basis for a well-directed genetic counselling of the families. Despite a huge number of comprehensive studies based on a large number of cases, standardized diagnostic criteria and advices for therapeutic management were missing. In the following, the recently published first international consensus guidelines drafted by 41 experts in the field of BWS from 11 European countries and the USA are summarized. Patients support groups had been included as well. In total, 72 consented recommendations for clinical and molecular diagnosis as well as for the clinical management of BWS have been published. They refer both to patients with the classical BWS phenotype and to those with "atypical" phenotypes which are summarized as BWS spectrum (BWSp). A modified clinical scoring system is now suggested, which represents the basis to initiate molecular diagnostics. Therapeutic recommendations comprise the major clinical questions in BWS/BWSp, i. e. early monitoring of an increased tumor risk, treatment of the macroglossia and the abdominal wall defects, and therapeutic interventions for hypoglycemia. However, though there was a broad consensus on the majority of therapeutic interventions, discussions on tumor monitoring are foreseeable. Thus, prospective studies to evaluate the consensus guidelines and their use are planned.

Pandita A, Gupta S, Gupta G, Panghal A
Beckwith-Weidemann syndrome with IC2 (KvDMR1) hypomethylation defect: a novel mutation.
BMJ Case Rep. 2018; 2018 [PubMed] Related Publications
The Beckwith-Wiedemann syndrome (BWS) is a rare genetic syndrome. However, this is one of the most common overgrowth syndromes. This is a genetically and clinically heterogeneous syndrome. Here, we report a case of Beckwith-Weidemann syndrome without macrosomia, visceromegaly and hemihyperplasia but having macroglossia, omphalocele and anterior linear ear lobe creases. The diagnosis was confirmed by gene analysis suggestive of imprinting centre 2 (KvDMR1) hypomethylation defect.

Brioude F, Kalish JM, Mussa A, et al.
Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.
Nat Rev Endocrinol. 2018; 14(4):229-249 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
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.

Bilgin B, Kabaçam S, Taşkıran E, et al.
Epigenotype and phenotype correlations in patients with Beckwith-Wiedemann syndrome.
Turk J Pediatr. 2018; 60(5):506-513 [PubMed] Related Publications
Bilgin B, Kabaçam S, Taşkıran E, Şimşek-Kiper PÖ, Alanay Y, Boduroğlu K, Utine GE. Epigenotype and phenotype correlations in patients with Beckwith-Wiedemann syndrome. Turk J Pediatr 2018; 60: 506-513. Beckwith-Wiedemann Syndrome (BWS) is one of the most common overgrowth syndromes. Cancer predisposition is an important feature of this clinically heterogeneous syndrome. Patients may have fetal and early childhood overgrowth, hemihyperplasia, macroglossia, facial dysmorphic features, abdominal wall defects, visceromegaly, and anomalies of the heart and the kidneys. Various previous investigations showed that heterogeneous molecular etiology may contribute to clinical variability and that epigenotype-phenotype correlations exist in BWS. This study was performed to detect the molecular etiology in 28 patients with BWS, to search for epigenotype-phenotype correlations and to provide appropriate individualized multidisciplinary approach. Four different molecular etiology groups were determined based on testing for copy number analysis and methylation status at 11p15. Sequencing for CDKN1C mutations were also performed. Groups were compared for various clinical findings. Differences between groups were not statistically significant owing to the small number of patients in individual groups. Statistical studies for epigenotype-phenotype correlations showed significance for only anterior ear lobe creases, visceromegaly and embryonal tumors. Additionally, one interesting patient had a mesenchymal tumor. Anticipating follow-up is clinically important in BWS.

Park KS, Mitra A, Rahat B, et al.
Loss of imprinting mutations define both distinct and overlapping roles for misexpression of IGF2 and of H19 lncRNA.
Nucleic Acids Res. 2017; 45(22):12766-12779 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Imprinted genes occur in discrete clusters that are coordinately regulated by shared DNA elements called Imprinting Control Regions. H19 and Igf2 are linked imprinted genes that play critical roles in development. Loss of imprinting (LOI) at the IGF2/H19 locus on the maternal chromosome is associated with the developmental disorder Beckwith Wiedemann Syndrome (BWS) and with several cancers. Here we use comprehensive genetic and genomic analyses to follow muscle development in a mouse model of BWS to dissect the separate and shared roles for misexpression of Igf2 and H19 in the disease phenotype. We show that LOI results in defects in muscle differentiation and hypertrophy and identify primary downstream targets: Igf2 overexpression results in over-activation of MAPK signaling while loss of H19 lncRNA prevents normal down regulation of p53 activity and therefore results in reduced AKT/mTOR signaling. Moreover, we demonstrate instances where H19 and Igf2 misexpression work separately, cooperatively, and antagonistically to establish the developmental phenotype. This study thus identifies new biochemical roles for the H19 lncRNA and underscores that LOI phenotypes are multigenic so that complex interactions will contribute to disease outcomes.

Li X, Lyu Y, Gao M, et al.
[Genetic analysis of two pediatric patients with Beckwith-Wiedemann syndrome].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2017; 34(6):831-834 [PubMed] Related Publications
OBJECTIVE: To explore the genetic cause for two children with omphalocele.
METHODS: The patients were examined, and the medical history of their families was collected. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) was performed to detect potential mutation in the patients.
RESULTS: Loss of methylation of imprinting center 2 (IC2) at the 11p15.5 region of the maternal chromosome was detected in both children.
CONCLUSION: The two patients were diagnosed with Beckwith-Wiedemann syndrome by MS-MLPA. The loss of methylation of IC2 probably underlies the disease in both patients.

Reed JA, Crotwell PL, Stein Q, et al.
Case Report of Infant With Features of Beckwith-Wiedemann Syndrome Diagnosed With Genome-wide Uniparental Disomy.
S D Med. 2017; 70(11):505-509 [PubMed] Related Publications
Uniparental disomy (UPD), where two copies of genetic material are from one parent, and none from the other, is a familiar cause of imprinting. We present a premature infant with organomegaly and congenital hyperinsulinism found to have complete UPD of paternal origin as determined by Mendelian inheritance error analysis.

Bedeschi MF, Calvello M, Paganini L, et al.
Sequence variants identification at the KCNQ1OT1:TSS differentially Methylated region in isolated omphalocele cases.
BMC Med Genet. 2017; 18(1):115 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
BACKGROUND: Omphalocele is a congenital midline ventral body wall defect that can exist as isolated malformation or as part of a syndrome. It can be considered one of the major and most frequent clinical manifestation of Beckwith-Wiedemann Syndrome (BWS) in case of loss of methylation at KCNQ1OT1: Transcription Star Site-Differentially Methylated Region (TSS-DMR) or in presence of CDKN1C mutations. The isolated form of the omphalocele accounts approximately for about the 14% of the total cases and its molecular etiology has never been fully elucidated.
METHODS: Given the tight relationship with BWS, we hypothesized that the isolated form of the omphalocele could belong to the heterogeneous spectrum of the BWS associated features, representing an endophenotype with a clear genetic connection. We therefore investigated genetic and epigenetic changes affecting BWS imprinted locus at 11p15.5 imprinted region, focusing in particular on the KCNQ1OT1:TSS DMR.
RESULTS: We studied 21 cases of isolated omphalocele detected during pregnancy or at birth and identified the following rare maternally inherited variants: i) the non-coding variant G > A at nucleotide 687 (NR_002728.3) at KCNQ1OT1:TSS-DMR, which alters the methylation pattern of the imprinted allele, in one patient; ii) the deletion c.624-629delGGCCCC at exon 1 of CDKN1C, with unknown clinical significance, in two unrelated cases.
CONCLUSIONS: Taken together, these findings suggest that KCNQ1OT1:TSS-DMR could be a susceptibility locus for the isolated omphalocele.

Chen Z, Hagen DE, Ji T, et al.
Global misregulation of genes largely uncoupled to DNA methylome epimutations characterizes a congenital overgrowth syndrome.
Sci Rep. 2017; 7(1):12667 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Assisted reproductive therapies (ART) have become increasingly common worldwide and numerous retrospective studies have indicated that ART-conceived children are more likely to develop the overgrowth syndrome Beckwith-Wiedemann (BWS). In bovine, the use of ART can induce a similar overgrowth condition, which is referred to as large offspring syndrome (LOS). Both BWS and LOS involve misregulation of imprinted genes. However, it remains unknown whether molecular alterations at non-imprinted loci contribute to these syndromes. Here we examined the transcriptome of skeletal muscle, liver, kidney, and brain of control and LOS bovine fetuses and found that different tissues within LOS fetuses have perturbations of distinct gene pathways. Notably, in skeletal muscle, multiple pathways involved in myoblast proliferation and fusion into myotubes are misregulated in LOS fetuses. Further, characterization of the DNA methylome of skeletal muscle demonstrates numerous local methylation differences between LOS and controls; however, only a small percent of differentially expressed genes (DEGs), including the imprinted gene IGF2R, could be associated with the neighboring differentially methylated regions. In summary, we not only show that misregulation of non-imprinted genes and loss-of-imprinting characterize the ART-induced overgrowth syndrome but also demonstrate that most of the DEGs is not directly associated with DNA methylome epimutations.

Rossi MN, Andresini O, Matteini F, Maione R
Transcriptional regulation of
Front Biosci (Landmark Ed). 2018; 23:83-108 [PubMed] Related Publications

Aref-Eshghi E, Schenkel LC, Lin H, et al.
Clinical Validation of a Genome-Wide DNA Methylation Assay for Molecular Diagnosis of Imprinting Disorders.
J Mol Diagn. 2017; 19(6):848-856 [PubMed] Related Publications
Genomic imprinting involves a DNA methylation-dependent and parent-of-origin-specific regulation of gene expression. Clinical assays for imprinting disorders are genomic locus, disorder, and molecular defect specific. We aimed to clinically validate a genome-wide approach for simultaneous testing of common imprinting disorders in a single assay. Using genome-wide DNA methylation arrays, epigenetic profiles from peripheral blood of patients with Angelman, Prader-Willi, Beckwith-Wiedemann, or Silver-Russell syndromes were compared to a reference cohort of 361 unaffected individuals. The analysis was of developmental delay and intellectual disabilities. This approach has allowed 100% sensitivity and specificity in detecting imprinting defects in all 28 patients and enabled identification of defects beyond the classically tested imprinted loci. Analysis of the cohort of patients with developmental delay and intellectual disabilities identified two patients with Prader-Willi syndrome, one with Beckwith-Wiedemann syndrome, and several other patients with DNA methylation defects in novel putative imprinting loci. These findings demonstrate clinical validation of a sensitive and specific genome-wide DNA methylation array-based approach for molecular testing of imprinting disorders to allow simultaneous assessment of genome-wide epigenetic defects in a single analytical procedure, enabling replacement of multiple locus-specific molecular tests while allowing discovery of novel clinical epigenomic associations and differential diagnosis of other epigenomic disorders.

Brzezinski J, Shuman C, Choufani S, et al.
Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines.
Eur J Hum Genet. 2017; 25(9):1031-1039 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome caused by a variety of molecular changes on chromosome 11p15.5. Children with BWS have a significant risk of developing Wilms tumours with the degree of risk being dependent on the underlying molecular mechanism. In particular, only a relatively small number of children with loss of methylation at the centromeric imprinting centre (IC2) were reported to have developed Wilms tumour. Discontinuation of tumour surveillance for children with BWS and loss of methylation at IC2 has been proposed in several recent publications. We report here three children with BWS reported to have loss of methylation at IC2 on clinical testing who developed Wilms tumour or precursor lesions. Using multiple molecular approaches and multiple tissues, we reclassified one of these cases to paternal uniparental disomy for chromosome 11p15.5. These cases highlight the current challenges in definitively assigning tumour risk based on molecular classification in BWS. The confirmed cases of loss of methylation at IC2 also suggest that the risk of Wilms tumour in this population is not as low as previously thought. Therefore, we recommend that for now, all children with a clinical or molecular diagnosis of BWS be screened for Wilms tumour by abdominal ultrasonography until the age of eight years regardless of the molecular classification.

White JC, Liu J, Nahar A
Simultaneous Presentation of Wilms Tumor and Immature Ovarian Teratoma in Beckwith-Wiedemann Syndrome.
J Pediatr Hematol Oncol. 2018; 40(1):e61-e63 [PubMed] Related Publications
The Beckwith-Wiedemann syndrome is a cancer predisposition syndrome characterized by a predilection to embryonal tumor growth, especially Wilms tumor, adrenocortical carcinomas, and hepatoblastomas. Genetic analysis of patients has revealed a link to the imprinted domain of the 11p15.5 chromosome and methylation status of the H19 locus and Igf-2. These genes have also been studied in other cancers, including ovarian teratomas. Our case is a patient with a simultaneous presentation of a Wilms tumor and immature ovarian teratoma and subsequently diagnosed with Beckwith-Wiedemann syndrome, which has not been previously described.

Giabicani É, Brioude F, Le Bouc Y, Netchine I
Imprinted disorders and growth.
Ann Endocrinol (Paris). 2017; 78(2):112-113 [PubMed] Related Publications
Fetal growth is a complex process. Its restriction is associated with morbidity and long-term metabolic consequences. Imprinted genes have a critical role in mammalian fetal growth. Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders with opposite fetal growth disturbance. SRS is leading to severe fetal and postnatal growth retardation with severe feeding difficulties during early childhood and long-term metabolic consequences and BWS is an overgrowth syndrome with an enhanced risk of tumors during childhood. Epigenetic (abnormal methylation at the imprinting center regions) or genetic (mutations, duplications, uniparental disomy [UPD]) including defects of imprinted genes on chromosome 11 (BWS and SRS), 7 (SRS) and more recently 14 (SRS) have been identified in these two syndromes. In humans, the 11p15 region contains genes important for the regulation of fetal and postnatal growth. This region includes two imprinted domains: the IGF2/H19 domain regulated by imprinting center region 1 (ICR1 or H19/IGF2:IG-DMR) and the CDKN1C/KCNQ1OT1 domain regulated by ICR2 (or KCNQ1OT1: TSS DMR).

Singh VB, Sribenja S, Wilson KE, et al.
Blocked transcription through KvDMR1 results in absence of methylation and gene silencing resembling Beckwith-Wiedemann syndrome.
Development. 2017; 144(10):1820-1830 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
The maternally methylated KvDMR1 ICR regulates imprinted expression of a cluster of maternally expressed genes on human chromosome 11p15.5. Disruption of imprinting leads to Beckwith-Wiedemann syndrome (BWS), an overgrowth and cancer predisposition condition. In the majority of individuals with BWS, maternal-specific methylation at KvDMR1 is absent and genes under its control are repressed. We analyzed a mouse model carrying a poly(A) truncation cassette inserted to prevent RNA transcripts from elongation through KvDMR1. Maternal inheritance of this mutation resulted in absence of DNA methylation at KvDMR1, which led to biallelic expression of

Duffy KA, Deardorff MA, Kalish JM
The utility of alpha-fetoprotein screening in Beckwith-Wiedemann syndrome.
Am J Med Genet A. 2017; 173(3):581-584 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Beckwith-Wiedemann syndrome (BWS) is one of the most common cancer predisposition disorders. As a result, BWS patients receive tumor screening as part of their clinical management. Until recently, this screening has been employed uniformly across all genetic and epigenetic causes of BWS, including the utilization of ultrasonography to detect abdominal tumors and alpha-fetoprotein (AFP) to detect hepatoblastoma. The advancements in our understanding of the genetics and epigenetics leading to BWS has evolved over time, and has led to the development of genotype/phenotype correlations. As tumor risk appears to correlate with genetic and epigenetic causes of BWS, several groups have proposed alterations to tumor screening protocols based on the etiology of BWS, with the elimination of AFP as a screening measure and the elimination of all screening measures in BWS patients with loss of methylation at the KCNQ1OT1:TSS-DMR 2 (IC2). There are many challenges to this suggestion, as IC2 patients may have additional factors that contribute to risk of hepatoblastoma including fetal growth patterns, relationship with assisted reproductive technologies, and the regulation of the IC2 locus. © 2017 Wiley Periodicals, Inc.

Chen KJ, Liu YM, Li CH, et al.
Prenatal diagnosis of paternal duplication of 11p15.5→14.3: Its implication of Beckwith-Wiedemann syndrome.
Taiwan J Obstet Gynecol. 2016; 55(6):877-880 [PubMed] Related Publications
OBJECTIVE: To characterize a prenatally detected chromosomal aberration with molecular cytogenetic approaches and explore its relationship with Beckwith-Wiedemann syndrome (BWS).
CASE REPORT: A 33-year-old woman, gravida 2, para 0, was referred to our prenatal clinic at 20+ weeks due to an abnormal amniocentesis karyotyping finding, which showed 46,XY,add(11)(q24.2)dn. The mother conceived through in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI), then embryo transfer. Fetal ultrasound revealed a left-sided congenital diaphragmatic hernia, overgrowth of the fetus, and an enlarged placenta. After genetic counseling and careful deliberation by the family, the pregnancy was subsequently terminated at 22+ weeks of gestation, delivering a fetus weighing 810 g (85
CONCLUSION: We presented a prenatally detected chromosomal aberration characterized by paternal duplication of chromosome 11p15.5, which strongly related to the phenotypic manifestation of BWS.

Luk HM
Clinical and molecular characterization of Beckwith-Wiedemann syndrome in a Chinese population.
J Pediatr Endocrinol Metab. 2017; 30(1):89-95 [PubMed] Related Publications
BACKGROUND: The objective of this study was to examine the clinical and molecular features, genotype-phenotype correlation and the efficacy of different diagnostic criteria for predicting a positive molecular test in Chinese Beckwith-Wiedemann syndrome (BWS) patients.
METHODS: A retrospective tertiary-wide study was performed in Hong Kong with 27 molecularly confirmed BWS patients between January 2010 and September 2015.
RESULTS: It was observed that 48.1% of the BWS cases were caused by loss of methylation at differentially methylated region 2 (DMR2-LoM) of the 11p15.5 region, 11.1% by gain of methylation at differentially methylated region 1 (DMR1-GoM) of the 11p15.5 region, 33.3% by paternal uniparental disomy 11 [upd (11)pat] and 7.5% by CDKN1C mutation. Two out of 27 (7.4%) had embryonal tumors. Both belonged to the DMR1-GoM subtype with one Wilm's tumor diagnosed at 3 months of age and the other, hepatoblastoma, diagnosed at 6 months of age. However, no genotype-phenotype correlation can be concluded by this cohort study. Finally, for different clinical diagnostic criteria, the Debaun and Tucker criteria and the Ibrahim et al. weighing score system have the best performance for predicting a positive molecular test in our Chinese BWS cohort.
CONCLUSIONS: It is the largest study of molecularly confirmed BWS in the Chinese. Their clinical and epigenetic features are comparable with other ethnic populations.

Khoshnam N, Robinson H, Clay MR, et al.
Calcifying nested stromal-epithelial tumor (CNSET) of the liver in Beckwith-Wiedemann syndrome.
Eur J Med Genet. 2017; 60(2):136-139 [PubMed] Related Publications
Calcifying nested stromal-epithelial tumor (CNSET) is a rare neoplasm. In the 31 reported cases, CNSET is predominantly found in young girls and women. Beckwith-Wiedemann syndrome (BWS) (OMIM #130650) is an overgrowth syndrome with an increased risk to develop cancer. Associations have been seen between BWS and embryonal tumors, especially Wilms tumor, hepatoblastoma, and adrenocortical carcinoma. Here we report on a female patient with BWS who presented with CNSET. Two other cases with the same association have been reported, with our case representing the third such reported in the literature. Although we recognize a potential reporting bias we speculate that CNSET may represent an unrecognized addition to the spectrum of BWS tumorigenesis.

Brioude F, Nicolas C, Marey I, et al.
Hypercortisolism due to a Pituitary Adenoma Associated with Beckwith-Wiedemann Syndrome.
Horm Res Paediatr. 2016; 86(3):206-211 [PubMed] Related Publications
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with an increased risk of cancer. Most BWS patients show a molecular defect in the 11p15 region that contains imprinted genes. BWS has been associated with malignant neoplasms during infancy. Descriptions of benign tumors, especially in adult patients, are rarer.
METHODS/RESULTS: We report the case of a BWS patient with pituitary adenoma caused by loss of methylation (LOM) at ICR2 (locus CDKN1C/KCNQ1OT1). The patient was referred to an endocrinology unit for suspicion of Cushing's disease due to a history of macroglossia and hemihyperplasia. Biological tests led to the diagnosis of ACTH-dependent hypercortisolism. MRI showed a microadenoma of the pituitary gland, confirming the diagnosis of Cushing's disease. DNA methylation analysis revealed LOM at ICR2 that was in a mosaic state in the patient's leukocytes, but was present in nearly all cells of the pituitary adenoma. The epigenetic defect was associated with a somatic USP8 mutation in the adenoma.
CONCLUSION: Pituitary adenoma rarely occurs in patients with BWS. However, BWS should be considered in cases of pituitary adenoma with minor and/or major signs of BWS. The association between ICR2 LOM and USP8 mutation in the adenoma is questionable. © 2016 S. Karger AG, Basel.

Bachmann N, Crazzolara R, Bohne F, et al.
Novel deletion in 11p15.5 imprinting center region 1 in a patient with Beckwith-Wiedemann syndrome provides insight into distal enhancer regulation and tumorigenesis.
Pediatr Blood Cancer. 2017; 64(3) [PubMed] Related Publications
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is an early-onset overgrowth disorder with a high risk for embryonal tumors. It is mainly caused by dysregulation of imprinted genes on chromosome 11p15.5; however, the driving forces in the development of tumors are not fully understood.
PROCEDURE: We report on a female patient presenting with macrosomia, macroglossia, organomegaly and extensive bilateral nephroblastomatosis. Adjuvant chemotherapy was initiated; however, the patient developed hepatoblastoma and Wilms tumor at 5 and 12 months of age, respectively. Subsequent radiofrequency ablation of the liver tumor and partial nephrectomy followed by consolidation therapy achieved complete remission.
RESULTS: Molecular genetic analysis revealed a maternally derived large deletion of the complete H19-differentially methylated region (H19-DMR; imprinting control region-1 [ICR1]), the whole H19 gene itself as well as large parts of the distal enhancer region within the imprinting cluster-1 (IC1). Extended analysis showed highly elevated insulin-like growth factor 2 (IGF2) expression, possibly explaining at least in part the distinct BWS features and tumor manifestations.
CONCLUSIONS: This study of a large maternal deletion encompassing the H19 gene and complete ICR1 is the first to demonstrate transcriptional consequences on IGF2 in addition to methylation effects resulting in severe overgrowth and occurrence of multiple tumors in a BWS patient. Studying this deletion helps to clarify the complex molecular processes involved in BWS and provides further insight into tumorigenesis.

Weksberg R, Shuman C, Beckwith JB
Beckwith-Wiedemann syndrome.
Eur J Hum Genet. 2010; 18(1):8-14 [PubMed] Article available free on PMC after 01/07/2020 Related Publications
Beckwith-Wiedemann syndrome (BWS) is a model disorder for the study of imprinting, growth dysregulation, and tumorigenesis. Unique observations in this disorder point to an important embryonic developmental window relevant to the observations of increased monozygotic twinning and an increased rate of epigenetic errors after subfertility/assisted reproduction.

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