Androgenetic chimerism as an etiology for Beckwith-Wiedemann syndrome: diagnosis and management.

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.

Altered microRNA expression profiles in large offspring syndrome and Beckwith-Wiedemann syndrome.

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.

Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome.

BACKGROUND AND OBJECTIVES: The emerging association of assisted reproductive techniques (ART) with imprinting disorders represents a major issue in the scientific debate on infertility treatment and human procreation. We studied the prevalence of Beckwith-Wiedemann syndrome (BWS) in children conceived through ART to define the specific associated relative risk. METHODS: Patients with BWS born in Piemonte, Italy, were identified and matched with the general demographic data and corresponding regional ART registry. RESULTS: Between 2005 and 2014, live births in Piemonte were 379 872, including 7884 from ART. Thirty-eight patients with BWS were born, 7 from ART and 31 naturally conceived. BWS birth prevalence in the ART group was significantly higher than that of the naturally conceived group (1:1126 vs 1:12 254, P < .001). The absolute live birth risk in the ART group was 887.9 per 1 000 000 vs 83.3 per 1 000 000 in the naturally conceived group, providing a relative risk of 10.7 (95% confidence interval 4.7-24.2). During the 1997-2014 period, 67 patients were diagnosed with BWS out of 663 834 newborns (1:9908 live births). Nine out of the 67 BWS patients were conceived through ART (13.4%), and 8 were molecularly tested, with 4 having an imprinting center 2 loss of methylation, 2 with 11p15.5 paternal uniparental disomy, and 2 negative results. CONCLUSIONS: ART entails a 10-fold increased risk of BWS and could be implicated in the pathogenesis of genomic events besides methylation anomalies. These data highlight the need for awareness of ART-associated health risk.

Epigenetic Alterations in Density Selected Human Spermatozoa for Assisted Reproduction.

Epidemiological evidence indicates that assisted reproductive technologies (ART) may be associated with several epigenetic diseases such as Beckwith-Wiedemann syndrome (BWS) or Silver-Russell syndrome (SRS). Selection of sperm by density-gradients in ART has improved DNA integrity and sperm quality; however, epigenetic alterations associated with this approach are largely unknown. In the present study, we investigated DNA methylation and histone retention profiles in raw sperm and selected sperm derived from the same individual and separated by using density-gradients. Results from a study group consisting of 93 males demonstrated that both global DNA methylation and histone retention levels decreased in density selected sperm. Compared to unselected raw sperm, histone transition rates decreased by an average of 27.2% in selected sperm, and the global methylation rate was 3.8% in unselected sperm and 3.3% in the selected sperm. DNA methylation and histone retention location profiling analyses suggested that these alterations displayed specific location patterns in the human genome. Changes in the pattern of hypomethylation largely occurred in transcriptional factor gene families such as HOX, FOX, and GATA. Histone retention increased in 67 genes, whereas it was significantly clustered in neural development-related gene families, particularly the olfactory sensor gene family. Although a causative relationship could not be established, the results of the present study suggest the possibility that sperm with good density also possess unique epigenetic profiles, particularly for genes involved in neural and olfactory development. As increasing evidence demonstrates that epigenetics plays a key role in embryonic development and offspring growth characteristics, the specific epigenetic alterations we observed in selected sperm may influence the transcriptional process and neural development in embryos.

Characterization of global loss of imprinting in fetal overgrowth syndrome induced by assisted reproduction.

Embryos generated with the use of assisted reproductive technologies (ART) can develop overgrowth syndromes. In ruminants, the condition is referred to as large offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including overgrowth, enlarged tongue, and abdominal wall defects. These characteristics recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth syndrome Beckwith-Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus in LOS, the most common epimutation in BWS. Although the first case of ART-induced LOS was reported in 1995, studies have not yet determined the extent of LOI in this condition. Here, we determined allele-specific expression of imprinted genes previously identified in human and/or mouse in day ∼105 Bos taurus indicus × Bos taurus taurus F1 hybrid control and LOS fetuses using RNAseq. Our analysis allowed us to determine the monoallelic expression of 20 genes in tissues of control fetuses. LOS fetuses displayed variable LOI compared with controls. Biallelic expression of imprinted genes in LOS was associated with tissue-specific hypomethylation of the normally methylated parental allele. In addition, a positive correlation was observed between body weight and the number of biallelically expressed imprinted genes in LOS fetuses. Furthermore, not only was there loss of allele-specific expression of imprinted genes in LOS, but also differential transcript amounts of these genes between control and overgrown fetuses. In summary, we characterized previously unidentified imprinted genes in bovines and identified misregulation of imprinting at multiple loci in LOS. We concluded that LOS is a multilocus LOI syndrome, as is BWS.

[Case of combination of Beckwith-Wiedemann syndrome with West syndrome].

Beckwith-Wiedemann syndrome (BWS) is etiologically connected with genetic/epigenetic growth dysregulation. The supposed localization of this disorder is a short arm of chromosome 11 (11p 15.5). Its prevalence is 1:13 per 700 newborns. West syndrome is an age-dependent epileptic syndrome related to a group of infantile epileptic encephalopathies and characterized by a triad of basic symptoms: series of infantile spasms, psychomotor retardation and severe paroxysmal EEG changes. The incidence of West syndrome is estimated at 1 case per 2,000-4,000 newborns. The article describes a rare clinical case: a combination of BWS with one of the types of infantile epileptic encephalopathies--West syndrome. A detailed analysis of the West syndrome progression in a female patient with BWS is given, the tactics of antiepileptic therapy is analyzed, and its complexity in terms of metabolic disorders caused by the presence of a genetic syndrome in a patient is shown. The results of a long catamnesis are described. The figures are the fragments of native electroencephalograms at the eruptive phase of West syndrome and against the background of a long-term remission. When describing the clinical case in detail, the authors actively discuss the obtained information and available literature data. The article also presents practical guidelines for the early detection of metabolic disorders in patients with infantile epileptic encephalopathies. In addition to anti-epileptic drugs, the authors propose to include a mandatory metabolic correction in the therapy complex for these patients.

The epidemiology of hepatoblastoma.

Few causes of hepatoblastoma have been conclusively identified, mainly due to the extreme rarity of the disease. Inherited conditions including Familial Adenomatous Polyposis and Beckwith-Wiedemann Syndrome dramatically raise risk of hepatoblastoma but account for few cases overall. A small number of case-control studies investigating risk factors for sporadic hepatoblastoma have been conducted to date. Although most of these studies feature fewer than 200 cases, several clues have emerged. Most notably there is a roughly 20-fold increased risk of hepatoblastoma among children with very low birth weight (<1,500 g) and a doubling of risk among those with moderately low birth weight (1,500-2,500 g). A modicum of evidence points to a possible role of parental tobacco use prior to or during pregnancy in the causation of hepatoblastoma as well.

Simultaneous occurrence of pancreatoblastoma and neuroblastoma in a newborn with beckwith-wiedemann syndrome.

Beckwith-Wiedemann syndrome is associated with an increased risk of tumors in the pediatric age. We report the case of a newborn with Beckwith-Wiedemann syndrome presenting the simultaneous occurrence of a cystic pancreatoblastoma and an adrenal neuroblastoma. Surgery was required to treat the pancreatoblastoma, and a "wait and see" policy was adopted for the neuroblastoma, which spontaneously regressed within a few months.

Intrauterine environment-genome interaction and children's development (3): Assisted reproductive technologies and developmental disorders.

In vitro fertilization (IVF) and other assisted reproductive technologies (ART) are widely used clinically as infertility treatments. Although ART procedures are generally considered safe, some studies have suggested an increase in the occurrence of major malformations and some other complications in babies conceived by ART. Further, it has recently been suggested that ART are associated with imprinting disorders in the offspring such as Beckwith-Wiedemann syndrome and Angelman syndrome. We review the human and animal studies investigating the outcome of ART pregnancies and discuss the potential risk of ART to pre- and perinatal development.

Diagnóstico prenatal del Síndrome de Beckwith-Wiedemann y su correlación posnatal / Prenatal diagnosis of Beckwith-Wiedemann Syndrome and postnatal correlation

El Síndrome de Beckwith-Wiedemann es un trastorno genético poco frecuente, que se diagnostica a través del ultrasonido, fundamentalmente por el hallazgo de macroglosia, macrosomía y onfalocele. En el caso que se presenta se encontraron dos criterios mayores, la sospecha de un tercer criterio mayor y uno menor. Durante el estudio prenatal se visualizó una posible lesión parenquimatosa renal que fue vista en el control postnatal.

[Epigenetic perspectives of safety in assisted reproductive technologies].

To date, a wide range of assisted reproductive technologies is available for patients with impaired fertility. In general, the current methods of reproductive medicine are considered safe and do not significantly increase the frequency of birth of children with diseases or congenital malformations. However, the evidence has been accumulating in literature on higher risk of genomic imprinting diseases (Beckwith-Wiedemann and Angelman syndromes) as a result of using assisted reproductive technologies. In most cases examined, the appearance of these syndromes was explained by defective methylation status of imprinted genes. It has been suggested that manipulations with gametes and embryos during the period of total epigenetic modification of their genomes may act as potential risk factors of assisted reproductive technologies. Moreover, overcoming many natural reproductive barriers may contribute to the development of some pathological phenotypes. The review summarizes current views on epigenetic risk factors associated with assisted reproductive technologies.

Placental mesenchymal dysplasia.

CONTEXT: Placental mesenchymal dysplasia is characterized by placentomegaly and may be mistaken for molar pregnancy both clinically and macroscopically because of the presence of "grapelike vesicles." It may be associated with a completely normal fetus, a fetus with growth restriction, or a fetus with features of Beckwith-Wiedemann syndrome. OBJECTIVE: To review the etiology, molecular pathology, gross and microscopic features, clinical presentation, complications, and differential diagnosis of placental mesenchymal dysplasia. DATA SOURCES: The PubMed and the Medline databases were systematically searched for articles between 1970 and 2006. The following keywords were used: placental mesenchymal dysplasia, mesenchymal hyperplasia, molar pregnancy, pseudomolar pregnancy, Beckwith-Wiedemann syndrome, and placentomegaly. Relevant references from review articles were also searched. CONCLUSIONS: Placental mesenchymal dysplasia should be considered in the differential diagnosis when the ultrasonographic findings show a cystic placenta. Close attention should be paid to fetal morphology for early recognition of fetal complications and to prevent unnecessary termination of pregnancy in cases associated with a normal fetus.

"Double-muscle" trait in cattle: a possible model for Wiedemann-Beckwith syndrome.

The Wiedemann-Beckwith syndrome (WBS) was first described in 1963 as a group of anomalies involving primarily macrosomia, macroglossia, and omphalocele. Histologic studies of WBS show nesidioblastosis of the pancreas, adrenocortical cytomegaly, and persistent metanephric blastema of the kidney. Multiple lines of evidence indicate that the human 11p15.5 region is the locus of abnormality in WBS. Insulin-like growth factor II (IGF-2) frequently has been considered a candidate gene, and expression of IGF-2 is known to be significantly delayed in fetal skeletal muscle of double-muscle (DM) cattle. Other candidate genes recently have been proposed for WBS. A number of recessive alleles in the bovine myostatin gene (GDF8, mapped to bovine chromosome 2 and apparently orthologous to the human 2q22 region) have been shown to be responsible for DM. Recently the first human case of deficient GDF8 function has been reported, confirming the importance of this gene. Bovine IGF-2 has been sequenced and localized to chromosome 25. The primary purpose of this study was to compare and contrast histologic findings in DM and WBS. Immunohistochemical staining confirms changes similar to nesidioblastosis in the pancreas. Other dysplastic changes of a cystic nature are seen in the adrenal. The renal histology of DM fetuses did not appear significantly different than controls.

Placental mesenchymal dysplasia is associated with high rates of intrauterine growth restriction and fetal demise: A report of 11 new cases and a review of the literature.

Placental mesenchymal dysplasia (PMD) is a rare condition of placentomegaly and abnormal chorionic villi often clinically mistakenly as partial hydatidiform mole. However, it is clinicopathologically distinct with high incidence of intrauterine growth restriction (IUGR) and fetal death. This study presents 11 new PMD cases and provides a meta-analysis of the associated IUGR and fetal death rates. The cases were identified between 1971 and 2005, mostly from consultation files. To our knowledge, 71 PMD cases have previously been reported; 15 of these were associated with Beckwith-Wiedemann syndrome (BWS). With the addition of our new results, among all cases without BWS, 50% had IUGR and 43% had intrauterine fetal demise (IUFD) or neonatal death. Females represented 82% of cases. Thus, PMD is associated with high IUGR and IUFD/neonatal death rates and disproportionally affects females. The cause and pathogenesis are yet unknown. The current understanding and hypotheses involving PMD are discussed.

Assisted reproductive therapies and imprinting disorders--a preliminary British survey.

BACKGROUND: Recent reports have suggested a higher risk of Beckwith-Wiedemann syndrome (BWS) and Angelman syndrome (AS) after assisted reproductive technologies (ARTs), but it is unclear whether this might also apply to other disorders of genomic imprinting. METHODS: We contacted families of children with BWS, AS, Prader-Willi syndrome (PWS) and transient neonatal diabetes mellitus (TNDM) to determine use of ART. RESULTS: A statistically significant increased frequency of ART in children with BWS was confirmed [2.9%, 95% confidence interval (CI) 1.4-6.3% vs 0.8% expected] but there was no significant association with PWS or TNDM. Consideration of the molecular subgroup of BWS and AS suggested the feasibility of association with ART. CONCLUSIONS: These differences may relate to variations in (i) the molecular mechanisms for disordered imprinting in the different disorders and (ii) the susceptibility of specific imprinting control regions to ART-associated methylation alterations (epimutations).

Assisted reproduction technology and defects of genomic imprinting.

It is estimated that approximately 1% of the newborn population of the British Isles are conceived following assisted reproduction technologies such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI). While the long term outcome of IVF children is mostly reassuring, some concerns remain. Specifically, recent studies have suggested a possible association between assisted conception and clinical conditions of genetic origin known as genomic imprinting defects. This has arisen from several different studies observing an excess of assisted conceptions among the rare clinical disorders of Beckwith-Wiedemann syndrome (BWS) and Angelman syndrome (AS). The numbers of such patients described in the studies to date are small but indicate a clear need for large-scale investigations to clarify the link between genomic imprinting defects and assisted conception as well as to establish the exact biological basis of any such link. In view of the strong public interest in this area of medicine, it behoves all professionals working in reproductive medicine and associated areas to be aware of these emerging data and be in a position to discuss them in as informed and responsible a manner with patients, as current data limitations permit.

Fetal origins of adult disease: a paediatric perspective.

Prepubertal children born SGA or VLBW premature exhibit marked insulin resistance. There are similarities between SGA and VLBW children in that both are exposed to sub-optimal environments that encompass undernutrition and/or malnutrition during the equivalent of the last trimester of pregnancy. Although both SGA and VLBW groups fail to reach genetic height potential and are recognized causes of short stature in childhood, there are differences between the groups with respect to the growth hormone and IGF-I axis.SGA children have elevated IGFI levels, possibly due to either hyperinsulinism or partial IGF-I resistance, whereas VLBW children have low IGF-I and IGFBP-3 levels suggestive of GH resistance. Thus the nature and timing of the early insult may lead to discordant changes to the metabolic and endocrine axes.IVF children are taller with increased IGF I, IGF II and IGFBP3 expression. These changes could be due to alterations in the environment of the periconceptual embryo resulting in changes in imprinting of genes involved in growth and development. The phenotypic, endocrine and metabolic consequences of alterations in the periconceptual, fetal and early neonatal periods is an area of intense investigation. Future research in this field is likely to focus on the mechanisms through which environmental changes lead to these programmed effects.

Genomic imprinting and assisted reproductive technology: connections and potential risks.

Assisted reproductive technology (ART) has become the standard of care for the treatment of many types of infertility. As a result, the numbers of children born after ART worldwide has escalated dramatically, and attention has turned to the potential risks of these procedures to the health and development of the children. In addition to the well-established risks of multiple gestations, recent reports have suggested a link between ART and rare disorders of imprinting including Beckwith-Wiedemann syndrome and Angelman syndrome. Here we review molecular mechanisms of genomic imprinting, consider how ART procedures could influence imprinting of gametes and embryos, and review the reports connecting imprinting disorders to ART. We highlight the importance of long-term follow-up of children born after ART, and emphasize the need for an improved understanding of the mechanisms of imprinting at the molecular level so that methods to prevent disruption of this critical epigenetic process can be developed.