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American Journal of Medical Genetics.... Sep 2022Beckwith-Wiedemann spectrum, Simpson-Golabi-Behmel syndrome, familial adenomatous polyposis and trisomy 18 are the most common congenital conditions associated with an... (Review)
Review
Beckwith-Wiedemann spectrum, Simpson-Golabi-Behmel syndrome, familial adenomatous polyposis and trisomy 18 are the most common congenital conditions associated with an increased incidence of hepatoblastoma (HB). In patients with these genetic disorders, screening protocols for HB are proposed that include periodic abdominal ultrasound and measurement of alpha-fetoprotein levels. Surveillance in these children may contribute to the early detection of HB and possibly improve their chances of overall survival. Therefore, physicians must be aware of the high HB incidence in children with certain predisposing genetic diseases.
Topics: Beckwith-Wiedemann Syndrome; Child; Genetic Diseases, X-Linked; Gigantism; Hepatoblastoma; Humans; Liver Neoplasms
PubMed: 35478319
DOI: 10.1002/ajmg.a.62767 -
Gaceta Medica de Mexico 2022Epigenetic and genomic imprinting alterations of the 11p15.5 region cause excessive or deficient growth, which result in Beckwith-Wiedemann syndrome (BWS) or...
INTRODUCTION
Epigenetic and genomic imprinting alterations of the 11p15.5 region cause excessive or deficient growth, which result in Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS), respectively.
OBJECTIVE
To evaluate the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) methylation analysis technique in the diagnosis of BWS and SRS.
METHODS
11p15.5 methylation and variants were evaluated in patients with clinical diagnosis of BWS and SRS using the MS-MLPA technique in peripheral blood DNA.
RESULTS
Paternal uniparental disomy and loss of maternal IC2 methylation were identified in two patients with BWS who had omphalocele and macroglossia, respectively. Paternal IC1hypomethylation was recorded in two patients with SRS of classic phenotype.
CONCLUSIONS
Adequate genotype-phenotype correlation was observed with the methylation defects that were identified, which confirms the usefulness of MLPA as a first-line study in patients diagnosed with BWS and SRS.
Topics: Humans; Silver-Russell Syndrome; Beckwith-Wiedemann Syndrome; Multiplex Polymerase Chain Reaction; DNA Methylation; Genomic Imprinting
PubMed: 36256576
DOI: 10.24875/GMM.M22000673 -
Radiology Case Reports Dec 2022Beckwith-Wiedemann syndrome (BWS) is a rare genetic disease, characterized by macrosomia, congenital malformations and tumor predisposition, associated with genetic and...
Beckwith-Wiedemann syndrome (BWS) is a rare genetic disease, characterized by macrosomia, congenital malformations and tumor predisposition, associated with genetic and epigenetic alterations in the 11p15 region. Most cases are diagnosed after birth, with prenatal diagnosis being difficult and depending on the identification of specific ultrasound anomalies, namely macrosomia, macroglossia, omphalocele and renal dysplasia. Case 1: Ultrasound diagnosis at 13 weeks of isolated omphalocele with normal array. At 20 weeks, there were shortened fetal long bones, foot deformity, macroglossia, corpus callosum hypoplasia and bilateral nephromegaly. Due to the polymalformative syndrome, a termination of pregnancy (TOP) was performed. The anatomopathological study of the placenta identified mesenchymal dysplasia. The search for the methylation pattern of the 11p15 region by MS-MLPA was normal and the molecular study of the gene identified a likely pathogenic variant, inherited from the mother. Case 2: Morphological ultrasound at 21 weeks revealed macrosomia, macroglossia, omphalocele, bilateral renal dysplasia, and hydramnios. The cytogenetic study, after amniocentesis, was normal (46,XX karyotype). TOP was performed. The anatomopathological study of the fetus confirmed the described malformations and the one concerning the placenta identified placentomegaly. The search for the methylation pattern of the 11p15 region by MS-MLPA revealed abnormal methylation. These results confirmed the diagnosis of BWS in both cases. Prenatal ultrasound suspicion of this pathology is extremely important to guide the conduct in pregnancy and/or the prevention of perinatal complications. Shortened fetal long bones and foot deformity complement the broad spectrum of this syndrome. Positive molecular tests allow confirming the diagnosis, assessing the risk of recurrence and guiding the surveillance of future pregnancy.
PubMed: 36281281
DOI: 10.1016/j.radcr.2022.09.066 -
Srpski Arhiv Za Celokupno Lekarstvo 2011In 1963 Beckwith presented a report on the first patient with extreme cytomegaly of adrenal cortex, hyperplasia of kidneys and pancreas and Leydig cell hyperplasia....
INTRODUCTION
In 1963 Beckwith presented a report on the first patient with extreme cytomegaly of adrenal cortex, hyperplasia of kidneys and pancreas and Leydig cell hyperplasia. Wiedemann completed description of the new syndrome by adding umbilical hernia and macroglossia. The diagnosis is made based on the clinical signs of omphalocele or some other umbilical deformity, macroglossia, congenital asymmetry, visceromegaly (liver, pancreas, and kidneys).
CASE OUTLINE
A 16-month-old male child was admitted for examination because of macroglossia. He underwent examination on several occasions by an endocrinologist due to recurrent hypoglycaemic crisis. The patient was observed by a paediatric neurophysicatrist for disorders of mental development. Hypoglycaemia, muscular hypotonia of the anterior abdominal wall with umbilical hernia and macroglossia were observed by clinical examination. Inratraoral examination revealed macroglossia with microstomia, suckling and swallowing difficulties, hypotonia of the perioral muscles with increased salivation. It was therefore decided to perform surgical reduction of the prominent tongue and develop good condition for nutrition, speech function and the development of orofacial system.
CONCLUSION
The diagnosis of macroglossia is based on subjective clinical criteria such as the morphology and amount of protrusion of the tongue, difficulty in articulating sounds, breathing, and hypersalivation. Some authors have suggested that the tongue size may be analyzed radiographically with a cephalogram. Treatment of macroglossia is controversial because of the absence of objective clinical criteria.
Topics: Beckwith-Wiedemann Syndrome; Humans; Infant; Macroglossia; Male
PubMed: 21858977
DOI: 10.2298/sarh1106366k -
Archives of Pathology & Laboratory... Sep 2014Placental mesenchymal dysplasia is a rare placental lesion characterized by stem villous cystic dilation and vesicle formation, placentomegaly, and vascular... (Review)
Review
Placental mesenchymal dysplasia is a rare placental lesion characterized by stem villous cystic dilation and vesicle formation, placentomegaly, and vascular abnormalities. It can be associated with growth restriction, stillbirth, Beckwith-Wiedemann syndrome, and some chromosomal abnormalities, and needs to be distinguished from its main differential diagnosis, hydatidiform mole.
Topics: Beckwith-Wiedemann Syndrome; Chromosome Aberrations; Diagnosis, Differential; Female; Fetal Growth Retardation; Humans; Hydatidiform Mole; Mesoderm; Placenta; Placenta Diseases; Pregnancy
PubMed: 25171710
DOI: 10.5858/arpa.2013-0399-RS -
American Journal of Medical Genetics.... Jul 2019Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum. There is an increased prevalence of monozygotic twinning in BWS....
Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum. There is an increased prevalence of monozygotic twinning in BWS. Given the epigenetic nature and phenotypic spectrum that defines BWS, twins are often discordant for clinical features, and clinicians are faced with the challenge of diagnosing and managing these twins. We present a cohort of multiple pregnancies in which one or more child from each pregnancy was diagnosed with BWS. We conducted a chart review of monochorionic and dichorionic gestations. Clinical scores for monochorionic twins demonstrated phenotypic discordance between the proband and twin. Based on linear regression analysis, a higher clinical score in the proband correlated with larger phenotypic discordance between twin siblings. Despite phenotypic discordance, however, we observed a consistent additive clinical score for a pregnancy (proband's plus twin's scores from a pregnancy). This idea of a finite degree of affectedness for a pregnancy implies a finite number of epigenetically affected cells. This further corroborates the idea that timing of monozygotic monochorionic twinning correlates with the disruption of establishment and/or maintenance of imprinting. The difference in clinical score between a proband and their twin may be due to diffused mosaicism, whereby there is an asymmetric distribution of affected cells among the multiple fetuses in a monozygotic monochorionic pregnancy, leading to a spectrum of variably affected phenotypes. Based on these findings, we recommend an algorithm for a conservative approach to clinically evaluate all children in a monozygotic multiple gestation affected by BWS.
Topics: Algorithms; Beckwith-Wiedemann Syndrome; Cohort Studies; DNA Methylation; Disease Management; Diseases in Twins; Female; Genomic Imprinting; Humans; Infant; Male; Mosaicism; Phenotype; Pregnancy; Severity of Illness Index; Twins, Dizygotic; Twins, Monozygotic
PubMed: 31067005
DOI: 10.1002/ajmg.a.61164 -
The Veterinary Clinics of North... Jul 2019Large offspring syndrome (LOS) is a fetal overgrowth condition in bovines most often observed in offspring conceived with the use of assisted reproductive technologies... (Review)
Review
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.
Topics: Animals; Beckwith-Wiedemann Syndrome; Cattle; Cattle Diseases; Female; Growth Disorders; Humans; Pregnancy; Reproductive Techniques, Assisted
PubMed: 31103180
DOI: 10.1016/j.cvfa.2019.02.007 -
Epigenetics Sep 2019The use of assisted reproductive technologies (ART) can induce a congenital overgrowth condition in humans and ruminants, namely Beckwith-Wiedemann syndrome (BWS) and...
The use of assisted reproductive technologies (ART) can induce a congenital overgrowth condition in humans and ruminants, namely Beckwith-Wiedemann syndrome (BWS) and large offspring syndrome (LOS), respectively. Shared phenotypes and epigenotypes have been found between BWS and LOS. We have observed global misregulation of transcripts in bovine foetuses with LOS. microRNAs (miRNAs) are important post-transcriptional gene expression regulators. We hypothesize that there is miRNA misregulation in LOS and that this misregulation is shared with BWS. In this study, small RNA sequencing was conducted to investigate miRNA expression profiles in bovine and human samples. We detected 407 abundant known miRNAs and predicted 196 putative miRNAs from the bovine sequencing results and identified 505 abundant miRNAs in human tongue. Differentially expressed miRNAs (DE-miRNAs) were identified between control and LOS groups in all tissues analysed as well as between BWS and control human samples. DE-miRNAs were detected from several miRNA clusters including DLK1-DIO3 genomic imprinted cluster in LOS and BWS. DNA hypermethylation was associated with downregulation of miRNAs in the DLK1-DIO3. mRNA targets of the DE-miRNAs were predicted and signalling pathways associated with control of organ size (including the Hippo signalling pathway), cell proliferation, apoptosis, cell survival, cell cycle, and cell adhesion were found to be enriched with these genes. Yes associated protein 1 (YAP1) is the core effector of the Hippo signalling pathway, and increased level of active (non-phosphorylated) YAP1 protein was detected in skeletal muscle of LOS foetuses. Overall, our data provide evidence of miRNA misregulation in LOS and BWS.
Topics: Animals; Beckwith-Wiedemann Syndrome; Cattle; Cattle Diseases; DNA Methylation; Down-Regulation; Female; Gene Expression Profiling; Gene Regulatory Networks; Genomic Imprinting; Humans; Male; MicroRNAs; Reproductive Techniques, Assisted; Sequence Analysis, RNA
PubMed: 31144574
DOI: 10.1080/15592294.2019.1615357 -
Journal of Personalized Medicine Oct 2021Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is a rare overgrowth syndrome with tumor predisposition resulting from the abnormal expression or function of imprinted...
BACKGROUND
Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is a rare overgrowth syndrome with tumor predisposition resulting from the abnormal expression or function of imprinted genes of the chromosome 11p15.5 imprinting gene cluster. The aim of this study was to identify the epigenotype-phenotype correlations of these patients using quantitative DNA methylation analysis.
METHODS
One hundred and four subjects with clinically suspected BWS were enrolled in this study. All of the subjects had been referred for diagnostic testing which was conducted using methylation profiling of -associated imprinting center (IC) 1 and -associated IC2 in high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between the quantitative DNA methylation status and clinical manifestations of the enrolled subjects were analyzed.
RESULTS
Among the 104 subjects, 19 had IC2 hypomethylation, 2 had IC1 hypermethylation, and 10 had paternal uniparental disomy (pUPD). The subjects with IC2 hypomethylation were characterized by significantly more macroglossia but less hemihypertrophy compared to the subjects with pUPD ( < 0.05). For 19 subjects with IC2 hypomethylation, the IC2 methylation level was significantly different ( < 0.05) between the subjects with and without features including macroglossia (IC2 methylation level: 11.1% vs. 30.0%) and prenatal or postnatal overgrowth (8.5% vs. 16.9%). The IC2 methylation level was negatively correlated with birth weight score ( < 0.01, = 19) and birth height score ( < 0.05, = 13). For 36 subjects with clinically diagnosed BWS, the IC2 methylation level was negatively correlated with the BWS score ( = -0.592, < 0.01). The IC1 methylation level showed the tendency of positive correlation with the BWS score without statistical significance ( = 0.137, > 0.05).
CONCLUSIONS
Lower IC2 methylation and higher IC1 methylation levels were associated with greater disease severity in the subjects with clinically diagnosed BWS. Quantitative DNA methylation analysis using the MassARRAY assay could improve the detection of epigenotype-phenotype correlations, which could further promote better genetic counseling and medical care for these patients.
PubMed: 34834418
DOI: 10.3390/jpm11111066 -
Molecular Genetics & Genomic Medicine Oct 2021Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth syndrome characterized by congenital malformations and predisposition to embryonic tumors. Loss of methylation of... (Review)
Review
BACKGROUND
Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth syndrome characterized by congenital malformations and predisposition to embryonic tumors. Loss of methylation of imprinting center 2 (IC2) is the most frequent alteration and rarely associated with tumors compared to paternal uniparental disomy of chromosome 11 (UPD(11)pat) and gain of methylation of imprinting center 1.
METHODS
Our study aimed to describe the clinical, histopathological and genetic characteristics of two patients and establish genotype-phenotype correlations. The clinical diagnosis was based on the criteria defined by the international expert consensus of BWS. Molecular study of 11p15.5 methylation status was assessed using methylation-specific-multiplex ligation probe amplification (MS-MLPA).
RESULTS
Patients were aged 12 months and 3 months and fulfilled the clinical score of BWS. MS-MLPA showed molecular alterations consisting of loss of methylation in IC2 (IC2-LOM) at the maternal allele for one patient and a mosaic UPD(11)pat for the second patient in whom follow-up at 6months revealed adrenocortical carcinoma (ACC) with low grade of malignancy. Molecular subtypes guide the follow-up and tumor surveillance, our major concern.
CONCLUSION
We have to take into account the psychological impact of a possible tumor whatever the underlying mechanism is. Nevertheless, the tumor risk remains high for UPD(11)pat. Our study extended the phenotype of BWS with absence of macrosomia in Tunisian patients, contrasting with literature, and added a supplementary case of ACC in the tumor spectrum of BWS patients with UPD(11)pat.
Topics: Beckwith-Wiedemann Syndrome; Biopsy; Epigenesis, Genetic; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genomic Imprinting; Humans; Immunohistochemistry; Infant; Male; Phenotype; Retrospective Studies; Symptom Assessment; Tomography, X-Ray Computed; Treatment Outcome; Tunisia
PubMed: 34510813
DOI: 10.1002/mgg3.1796