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Clinical Epigenetics 2014Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder with variable expressivity and a predisposition to tumorigenesis, results from disordered expression...
BACKGROUND
Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder with variable expressivity and a predisposition to tumorigenesis, results from disordered expression and/or function of imprinted genes at chromosome 11p15.5. There are no generally agreed clinical diagnostic criteria, with molecular studies commonly performed to confirm diagnosis. In particular, methylation status analysis at two 11p15.5 imprinting control centres (IC1 and IC2) detects up to 80% of BWS cases (though low-level mosaicism may not be detected). In order to evaluate the relationship between the clinical presentation of suspected BWS and IC1/2 methylation abnormalities we reviewed the results of >1,000 referrals for molecular diagnostic testing.
RESULTS
Out of 1,091 referrals, 507 (46.5%) had a positive diagnostic test for BWS. The frequency of tumours was 3.4% in those with a molecular diagnosis of BWS. Previously reported genotype-phenotype associations with paternal uniparental disomy, IC1, and IC2 epimutation groups were confirmed and potential novel associations detected. Predictive values of previously described clinical diagnostic criteria were compared and, although there were differences in their sensitivity and specificity, receiver operating characteristic (ROC) analysis demonstrated that these were not optimal in predicting 11p15.5 methylation abnormalities. Using logistic regression, we identified clinical features with the best predictive value for a positive methylation abnormality. Furthermore, we developed a weighted scoring system (sensitivity 75.9%, and specificity 81.8%) to prioritise patients presenting with the most common features of BWS, and ROC analysis demonstrated superior performance (area under the curve 0.85, 95% CI 0.83 to 0.87) compared to previous criteria.
CONCLUSIONS
We suggest that this novel tool will facilitate selection of patients with suspected BWS for routine diagnostic testing and so improve the diagnosis of the disorder.
PubMed: 24982696
DOI: 10.1186/1868-7083-6-11 -
Genetics in Medicine : Official Journal... Nov 2019Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital...
PURPOSE
Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management.
METHODS
Three male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed.
RESULTS
SNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism.
CONCLUSION
SNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.
Topics: Beckwith-Wiedemann Syndrome; Chimerism; Chromosomes, Human, Pair 11; DNA Methylation; Genomic Imprinting; Genotype; Humans; Infant; Infant, Newborn; Male; Mosaicism; Phenotype; Polymorphism, Single Nucleotide; Uniparental Disomy
PubMed: 31147633
DOI: 10.1038/s41436-019-0551-9 -
Children (Basel, Switzerland) Mar 2024The study's aim was to determine the prevalence of depression and anxiety in children with Beckwith-Wiedemann syndrome (BWS) and their effects on social relationships...
The study's aim was to determine the prevalence of depression and anxiety in children with Beckwith-Wiedemann syndrome (BWS) and their effects on social relationships and family acceptance. The Pediatric Symptom Checklist-35 items (PSC-35), Screen for Child Anxiety Related Emotional Disorders (SCARED), and the Vineland Adaptive Behavior Scale Second Edition (VABS-II) were administered to the children. The parental Acceptance Rejection/Control Questionnaire (PARQ/Control) and Zarit Burden Inventory (ZBI) were administered to parents. In total, 6 patients and 10 parents were included. Patients showed a significant presence of internalizing behavior in PSC-35 (mean, 7.66 ± 3.67), anxiety symptoms (SCARED: mean, 46.33 ± 17.50) and socialization difficulties (mean, 90.83 ± 10.09). Parents reported a perceived good acceptance (mean, 56.33 ± 1.03) and a moderate control (mean, 24.17 ± 1.83), but the burden level was ranked moderate to severe (mean, 59.33 ± 16.78). It was found that the severity of the burden level reported by parents was related to internalizing behavior (OR = 2.000; 95% CI = 0.479-3.521; = 0.022) and anxiety symptoms (SCARED total score: OR = 3.000; 95% CI = 1.479-4.521; = 0.005) of children. During psychological counseling in the context of BWS treatment, it is important to identify specific resources that can support patients and families in dealing with stress and identify any critical areas that could hinder the adaptation process.
PubMed: 38539377
DOI: 10.3390/children11030342 -
Italian Journal of Pediatrics Apr 2020Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth disorder with variable clinical features and cancer predisposition. In this study, we aim to characterize the...
BACKGROUND
Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth disorder with variable clinical features and cancer predisposition. In this study, we aim to characterize the clinical features and molecular defects of BWS patients in China.
METHODS
Thirty-one patients with clinical suspicion of BWS were retrospectively recruited to the study from Shanghai Children's Hospital between January 2014 and December 2017. Clinical data, including demographics, clinical features, and molecular testing results were extracted and systematically analyzed.
RESULTS
Twenty-one patients with a BWS score ≥ 4 (6, IQR 4, 7) were clinically diagnosed with BWS, and 10 children with a BWS score ≥ 2 and < 4 (2, IQR 2, 3) were clinically suspected BWS patients. The most common cardinal feature of clinically diagnosed patients was macroglossia (71.4%) followed by lateralized overgrowth (33.3%) and exomphalos (14.3%), and the major suggestive features were umbilical hernia and/or diastasis recti (65.0%) and ear creases or pits (61.9%). Among 10 clinically suspected BWS patients, macroglossia and lateralized overgrowth were observed in 3 (30%) and 2 (20%) patients, and umbilical hernia and/or diastasis recti occurred in 7 (70.0%) patients. Seven (33.3%) clinically diagnosed patients and 3 (30%) suspected patients were identified with loss of methylation at KCNQ1OT1:TSS differentially methylated region (DMR; IC2 LOM), 5 (23.8%) clinically diagnosed BWS patients were identified with gain of methylation at H19/IGF2:IG-DMR (IC1 GOM), and 1 (4.8%) clinically diagnosed BWS patients was identified with paternal uniparental isodisomy 11 (pUPD11). The phenotype-genotype correlation analysis showed no significant difference among patients with IC2 LOM, IC1 GOM, and pUPD11.
CONCLUSIONS
The current study presents the first cohort study of BWS patients in mainland China. The clinical and molecular features of the patients are similar to those of other reported BWS patients in the Chinese population.
Topics: Beckwith-Wiedemann Syndrome; Child; Child, Preschool; China; Female; Genotype; Humans; Infant; Male; Phenotype; Retrospective Studies
PubMed: 32349794
DOI: 10.1186/s13052-020-0819-3 -
Journal of Clinical Medicine Sep 2022Due to associated maxillofacial growth anomalies and the impairment of oral functions, macroglossia may negatively impact the oral health-related quality of life...
Due to associated maxillofacial growth anomalies and the impairment of oral functions, macroglossia may negatively impact the oral health-related quality of life (OHRQoL) of people with Beckwith-Wiedemann syndrome (BWS). Therefore, the aim of this cross-sectional study was to determine the OHRQoL of Italian children and adolescents with BWS compared to healthy peers and to identify which symptoms related to macroglossia had the highest impact. A total of 48 patients with BWS and 48 age- and gender-matched controls completed the Italian version of OHIP-14 and a questionnaire on functional, oral and aesthetic outcomes. Parents of patients with BWS who had undergone tongue reduction surgery (TRS) answered additional questions related to surgery. The BWS group scored higher than controls on the total OHIP-14 and on the dimensions of oral function ( 0.036) and psychosocial impact ( 0.002), indicating a reduced OHRQoL. Neither gender nor age had an impact on OHRQoL. Scores were worse in children and adolescents treated with TRS, as most of them still had open bite malocclusion and speech difficulties. The OHRQoL of children and adolescents affected by BWS is worse than that of their healthy peers in spite of the surgical treatment of macroglossia.
PubMed: 36233553
DOI: 10.3390/jcm11195685 -
Radiology Case Reports Sep 2023Beckwith-Wiedemann syndrome (BWS) is a rare imprinting disorder and overgrowth syndrome with a prevalence of 1 in 10,000 live births. It is characterized by predilection...
Beckwith-Wiedemann syndrome (BWS) is a rare imprinting disorder and overgrowth syndrome with a prevalence of 1 in 10,000 live births. It is characterized by predilection for embryonal tumor growth, especially Wilms tumor (WT), and manifestations like lateralized overgrowth/hemihypertrophy, macroglossia, macrosomia, anterior abdominal wall defects, and hyperinsulinism. Our case is a 1 year of female child who presented with abdominal swelling and limb length discrepancies. A clinical diagnosis of BWS was made based on multifocal WT and hepatomegaly and nephromegaly detected on contrast-enhanced abdominal computed tomography and physical examination findings of lateralized overgrowth and umbilical hernia. A molecular genetic test was not available. The patient was started on preoperative chemotherapy with good tolerance. Clinical criteria can be used to diagnose WBS in a setting where confirmatory molecular testing is unavailable. This will considerably change approaches to management of presenting complications such as WT .
PubMed: 37520386
DOI: 10.1016/j.radcr.2023.06.025 -
Developmental Medicine and Child... Feb 2020Disruption of epigenetic modifications and the factors that maintain these modifications is rapidly emerging as a cause of developmental disorders. Here we summarize... (Review)
Review
Disruption of epigenetic modifications and the factors that maintain these modifications is rapidly emerging as a cause of developmental disorders. Here we summarize some of the major principles of epigenetics including how epigenetic modifications are: (1) normally reset in the germ line, (2) form an additional layer of interindividual variation, (3) are environmentally sensitive, and (4) change over time in humans. We also briefly discuss the disruption of growth and intellect associated with the Mendelian disorders of the epigenetic machinery and the classical imprinting disorders (such as Beckwith-Wiedemann syndrome, Silver-Russell syndrome, Prader-Willi syndrome, and Angelman syndrome), as well as suggesting some diagnostic considerations for the clinicians taking care of these patients. Finally, we discuss novel therapeutic strategies targeting epigenetic modifications, which may offer a safe alternative to up and coming genome editing strategies for the treatment of genetic diseases. This review provides a starting point for clinicians interested in epigenetics and the role epigenetic disruption plays in human disease. WHAT THIS PAPER ADDS: Clinicians are introduced to four main principles of epigenetics. Clinical features of imprinting disorders and Mendelian disorders of epigenetic machinery are presented.
Topics: Animals; Chromosome Disorders; Epigenesis, Genetic; Humans
PubMed: 31749156
DOI: 10.1111/dmcn.14398 -
Ugeskrift For Laeger Jun 2021We report a boy with congenital hemihyperplasia, umbilical hernia and temporary neonatal hypoglycemia, who was confirmed to have BWS caused by paternal uniparental...
We report a boy with congenital hemihyperplasia, umbilical hernia and temporary neonatal hypoglycemia, who was confirmed to have BWS caused by paternal uniparental disomy of chromosome 11p15.5. Additional phenotypic features comprising scoliosis, nephromegaly, focal partial epilepsy and delayed psychomotor development were coherent with the underlying genotype. This case emphasizes the importance of identifying the underlying genetic variant in order to acknowledge and manage the associated clinical complications and specific risk profile.
Topics: Beckwith-Wiedemann Syndrome; Hernia, Umbilical; Humans; Hyperplasia; Infant, Newborn; Kidney Diseases; Male; Uniparental Disomy
PubMed: 34120690
DOI: No ID Found -
Journal of Pediatric Surgery Dec 2013To present our experience in the care of infants with Beckwith-Wiedemann syndrome (BWS) who required pancreatectomy for the management of severe Congenital...
PURPOSE
To present our experience in the care of infants with Beckwith-Wiedemann syndrome (BWS) who required pancreatectomy for the management of severe Congenital Hyperinsulinism (HI).
METHODS
We did a retrospective chart review of patients with BWS who underwent pancreatectomy between 2009 and 2012.
RESULTS
Four patients with BWS and severe HI underwent pancreatectomy, 3 females and one male. Eight other BWS patients with HI could be managed medically. The diagnosis of BWS was established by the presence of mosaic 11p15 loss of heterozygosity and uniparental disomy in peripheral blood and/or pancreatic tissue. All patients had hypoglycemia since birth that did not respond to medical management with diazoxide or octreotide, and required glucose infusion rates of up to 30 mg/kg/min. Preoperative 18-F-DOPA PET/CT scans showed diffuse uptake of the radiotracer throughout an enlarged pancreas in three patients and a normal sized pancreas with a large area of focal uptake in the pancreatic body in one patient. None of the patients had mutations in the ABCC8 or KCNJ1 genes that are typically associated with diazoxide-resistant HI. Age at surgery was 1, 2, 4, and 12 months and the procedures were 85%, 95%, 90%, and 75% pancreatectomy, respectively, with the pancreatectomy extent tailored to HI severity. Pathologic analysis revealed marked diffuse endocrine proliferation throughout the pancreas that occupied up to 80% of the parenchyma with scattered islet cell nucleomegaly. One patient had a small pancreatoblastoma in the pancreatectomy specimen. The HI improved in all cases after the pancreatectomy, with patients being able to fast safely for more than 8 h. All patients are under close surveillance for embryonal tumors. One patient developed a hepatoblastoma at age 2.
CONCLUSION
The pathophysiology of HI in BWS patients is likely multifactorial and is associated with a dramatic increase in pancreatic endocrine tissue. Severe cases of HI that do not respond to medical therapy improve when the mass of endocrine tissue is reduced by subtotal or near-total pancreatectomy.
Topics: Beckwith-Wiedemann Syndrome; Congenital Hyperinsulinism; Female; Humans; Infant; Male; Pancreatectomy; Retrospective Studies; Severity of Illness Index; Treatment Outcome
PubMed: 24314195
DOI: 10.1016/j.jpedsurg.2013.05.016 -
Taiwanese Journal of Obstetrics &... Jun 2007Beckwith-Wiedemann syndrome (BWS, OMIM 130650) is characterized by macrosomia, macroglossia, visceromegaly, hemihypertrophy, abdominal wall defects, ear creases/pits,... (Review)
Review
Beckwith-Wiedemann syndrome (BWS, OMIM 130650) is characterized by macrosomia, macroglossia, visceromegaly, hemihypertrophy, abdominal wall defects, ear creases/pits, neonatal hypoglycemia, polyhydramnios, placentomegaly, placental mesenchymal dysplasia, cardiac defects, nevus flammeus, hemangiomata, and an increased frequency of embryonal tumors. This article provides an overview of BWS including the genetics, genetic diagnosis, genotype/epigenotype-phenotype correlations, association with assisted reproductive technology, and prenatal diagnosis. Omphalocele is an important sonographic marker for BWS. Prenatal detection of omphalocele, fetal overgrowth, polyhydramnios, increased abdominal circumference, placentomegaly and/or placental mesenchymal dysplasia should alert one to the possibility of BWS and prompt a genetic investigation and counseling for BWS.
Topics: Beckwith-Wiedemann Syndrome; Cyclin-Dependent Kinase Inhibitor p57; Female; Genotype; Hernia, Umbilical; Histone Methyltransferases; Histone-Lysine N-Methyltransferase; Humans; Insulin-Like Growth Factor II; Intracellular Signaling Peptides and Proteins; KCNQ1 Potassium Channel; Membrane Proteins; Nuclear Proteins; Potassium Channels, Voltage-Gated; Pregnancy; Prenatal Diagnosis; RNA, Long Noncoding; RNA, Untranslated; Reproductive Techniques, Assisted
PubMed: 17638616
DOI: 10.1016/S1028-4559(07)60002-3