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(a) Patient 1 in the BeckwithWiedemann syndrome (BWS) group as a newborn and (b) at the age of 3 years. Note the characteristic BWS facies.
Source publication
Aims:
To study the frequency of methylation abnormalities among Estonian patients selected according to published clinical diagnostic scoring systems for Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS).
Materials and methods:
Forty-eight patients with clinical suspicion of SRS (n = 20) or BWS (n = 28) were included in the stu...
Contexts in source publication
Context 1
... scores 7 and 8 at 1 and 5 min, respectively. During the first week of life, the child had feeding difficulties and several episodes of hypoglycemia treated with glucose infusion. Later, coarse fa- cial features, small omphalocele, macroglossia, hemi- hypertrophy, asymmetrical tongue, ear fistulas, inverted nipples, and exomphtalmos were noted (Fig. 1a). At the age of 2 months, the child was referred to the geneticist with a suspicion of BWS. The 11p15.5 region MS-MLPA analysis of DNA derived from patient's blood and skin cells and the CDKN1C gene sequencing and deletion/duplication analysis did not show any genetic or epigenetic alteration in the BWS region. Also, her chromosomal ...
Citations
... A study of 28 patients found that 12 were diagnosed with phenotypic characteristics of BWS, and presented hypomethylation of PLAGL1 and IGF2R, but these were not characterized as MLMDs [54]. ...
In vitro fertilization and somatic cell nuclear transfer are assisted reproduction technologies commonly used in humans and cattle, respectively. Despite advances in these technologies, molecular failures can occur, increasing the chance of the onset of imprinting disorders in the offspring. Large offspring syndrome/abnormal offspring syndrome (LOS/AOS) has been described in cattle and has features such as hypergrowth, malformation of organs, and skeletal and placental defects. In humans, Beckwith-Wiedemann syndrome (BWS) has phenotypic characteristics similar to those found in LOS/AOS. In both syndromes, disruption of genomic imprinting associated with loss of parental-specific expression and parental-specific epigenetic marks is involved in the molecular etiology. Changes in the imprinting pattern of these genes lead to loss of imprinting (LOI) due to gain or loss of methylation, inducing the emergence of these syndromes. Several studies have reported locus-specific alterations in these syndromes, such as hypomethylation in imprinting control region 2 (KvDMR1) in BWS and LOS/AOS. These LOI events can occur at multiple imprinted loci in the same affected individual, which are called multi-locus methylation defect (MLMD) events. Although the bovine species has been proposed as a developmental model for human imprinting disorders, there is little information on bovine imprinted genes in the literature, even the correlation of epimutation data with clinical characteristics. In this study, we performed a systematic review of all the multi-locus LOI events described in human BWS and LOS/AOS, in order to determine in which imprinted genes the largest changes in the pattern of DNA methylation and expression occur, helping to fill gaps for a better understanding of the etiology of both syndromes.
... Additionally, it has been shown that p57 is involved in the regulation of cytoskeletal dynamics, as well as in programmed cell death and cellular aging. Previous studies have shown that changes in p57 expression are relevant in the pathology of Beckwith-Wiedemann's syndrome [14], the cardiovascular system, and in the pathogenesis of prostate, liver, pancreatic, breast, and head and neck carcinoma [15]. The protein level of p57 is thought to be decreasing during tumor development, which is associated with the onset of aggressive phenotype and worse prognosis [16]. ...
Rhabdomyosarcoma (RMS) is a highly malignant cancer and is the most common soft tissue sarcoma in children and adolescents, but it is rare in adults (<1% of all adult malignancies). Altered expression and molecular abnormalities of cell-cycle-regulatory proteins are one of the most prominent features in RMS. Therefore, we evaluated the expression of cyclin-dependent kinase inhibitors p57 and p16, as well as p16 methylation status, along with clinicopathological characteristics and overall survival (OS) in RMS patients. This analysis was conducted on 23 pediatric and 44 adult patients. There was a male predominance in both groups and extremities were the most frequent tumor site. In adults, alveolar and pleomorphic types were almost equally represented. The majority of pediatric tumors were low grade, whereas, in adults, only one patient had a low-grade tumor. Seven pediatric (30.43%) and eight adult (18.18%) patients had a low p16 expression. The analysis of methylation status of the p16 promoter showed the presence of methylated allele only in one sample with pleomorphic histology. Six (26.1%) pediatric and 15 (34.1%) adult patients had low p57 expression, while in 17 (73.9%) pediatric and 29 (65.9%) adult patients it was assessed as high. Ninetyone percent of the pediatric patients and 32.6% of adults were alive at the end of the observational period. In adults, significant associations were found between OS and age (P = 0.020), gender (P = 0.027), tumor size (P < 0.001), lymph node status (P < 0.001), presence of metastases (P = 0.015), and p57 expression (P = 0.039). Stratification by histological type showed the correlation of low p57 expression (P = 0.030) and worse OS of patients with alveolar RMS. Uni-variate analysis identified age > 50 yrs. (HR 2.447), tumors > 5 cm (HR 21.31), involvement of regional lymph nodes (HR 3.96), the presence of metastases (HR 2.53), and low p57 expression (HR 2.11) as predictors of lower OS. Tumor size, regional lymph nodes involvement, and metastases were the independent predictors after multivariate analysis, while p57 did not predict OS in an independent way. In summary, although p57 was not confirmed to be an independent predictor of OS, our results indicate that its low expression may be the marker of aggressive phenotype and poor prognosis in adult RMS patients. Also, our findings suggest that epigenetic inactivation of p16 is not important in the pathogenesis of rhabdomyosarcoma.
... MLPA data analysis was performed with the Coffalyser software (MRC-Holland). A detailed description of the methods has been previously published [36] and is available also on the manufacturer's website (MRC-Holland, https://mlpa.com). ...
... Both cases of TS14 had a concurrent trisomy-one patient with triple X syndrome and the other with mosaic trisomy 14-in addition to maternal UPD(14) [42]. The only patient with TNDM had an atypical clinical presentation and isolated hypomethylation of the PLAGL1 and IGF2R genes [36]. The case of MDS was caused by a paternal heterozygous nonsense variant-c.21 ...
Imprinting disorders (ImpDis) represent a small group of rare congenital diseases primarily affecting growth, development, and the hormonal and metabolic systems. The aim of present study was to identify the prevalence of the ImpDis in Estonia, to describe trends in the live birth prevalence of these disorders between 1998 and 2016, and to compare the results with previously published data. We retrospectively reviewed the records of all Estonian patients since 1998 with both molecularly and clinically diagnosed ImpDis. A prospective study was also conducted, in which all patients with clinical suspicion for an ImpDis were molecularly analyzed. Eighty-seven individuals with ImpDis were identified. Twenty-seven (31%) of them had Prader–Willi syndrome (PWS), 15 (17%) had Angelman syndrome (AS), 15 (17%) had Silver–Russell syndrome (SRS), 12 (14%) had Beckwith–Wiedemann syndrome (BWS), 10 (11%) had pseudo- or pseudopseudohypoparathyroidism, four had central precocious puberty, two had Temple syndrome, one had transient neonatal diabetes mellitus, and one had myoclonus-dystonia syndrome. One third of SRS and BWS cases fulfilled the diagnostic criteria for these disorders, but tested negative for genetic abnormalities. Seventy-six individuals were alive as of January 1, 2018, indicating the total prevalence of ImpDis in Estonia is 5.8/100,000 (95% CI 4.6/100,000–7.2/100,000). The minimum live birth prevalence of all ImpDis in Estonia in 2004–2016 was 1/3,462, PWS 1/13,599, AS 1/27,198, BWS 1/21,154, SRS 1/15,866, and PHP/PPHP 1/27,198. Our results are only partially consistent with previously published data. The worldwide prevalence of SRS and GNAS-gene-related ImpDis is likely underestimated and may be at least three times higher than expected.
... SRS belongs to the group of rare diseases, its incidence is estimated to range between 1 in 3,000 to 1 in 100,000 (Price, Stanhope, Gar- rett, Preece, & Trembath, 1999). In the Estonian population an incidence of 1 in 70,000 has been determined ( Vals et al., 2015). MRKH as a comorbidity of SRS has been reported in five cases ( Abraham et al., 2015;Bellver-Pradas et al., 2001;Bliek et al., 2006;Bruce et al., 2010), among them three with ICR1 hypomethylation, and it is therefore recommended to investigate girls with SRS and primary amenorrhoea for MRKH ( Wakeling et al., 2017). ...
Background
Mayer–Rokitansky–Küster–Hauser syndrome (MRKH) is the second most common cause of primary amenorrhea and characterized by absence of the uterus and the upper part of the vagina. The etiology of MRKH is mainly unknown but a contribution of genomic alterations is probable. A molecular disturbance so far neglected in MRKH research is aberrant methylation at imprinted loci. In fact, MRKH has been reported in patients with the imprinting disorder Silver–Russell syndrome.
Methods
We report on a rare patient with MRKH and SRS due to an ICR1 hypomethylation in 11p15.5. On the basis of this observation we screened a large cohort of MRKH patients (n > 100) for aberrant methylation at nine imprinted loci.
Results
We failed to detect any epimutation, thus we conclude that imprinting defects at least at the currently known disease‐relevant imprinted loci do not contribute to the isolated MRKH phenotype. However, it cannot be excluded that altered methylation marks at other loci are involved in the etiology of MRKH.
Conclusion
The molecular basis for MRKH remains unclear in the majority of patients, but future studies on the association between MRKH and ICR1 hypomethylation/SRS will to enlighten the role of epigenetics in the etiology of MRKH.
... Other minor features are neonatal hypoglycemia, hemihyperplasia, and characteristic facial features. A rec- [Kotzot et al., 1995;Eggermann et al., 1997;Preece et al., 1997;Netchine et al., 2007;Abu-Amero et al., 2008;Binder et al., 2008] -Methylation abnormality at ICR1 in the 11p15 region hypomethylation in 37 -63% [Netchine et al., 2007;Binder et al., 2008;Bartholdi et al., 2009;Bruce et al., 2009;Abu-Amero et al., 2010;Turner et al., 2010;Vals et al., 2015b] hypermethylation 5 -10% [Gaston et al., 2001;Cooper et al., 2005Cooper et al., , 2007Sasaki et al., 2007] Methylation abnormality at ICR2 in the 11p15 region few cases with the hypomethylation of both ICRs [Begemann et al., 2011] hypomethylation in 50 -60% [Gaston et al., 2001;Cooper et al., 2005;Weksberg et al., 2010;Begemann et al., 2012b] Duplication in the 11p15 region (may involve ICR1 and/or ICR2) maternal 1 -2% [Eggermann et al., 2010a[Eggermann et al., , 2014b paternal microdeletions involving ICR1 (~5%) and microduplications of ICR2 (<1%) [Niemitz et al., 2004;Sparago et al., 2004;Bliek et al., 2009b;Demars et al., 2011;Begemann et al., 2012b;Vals et al., 2015a] Other chromosomal aberrations (including cryptic) 2% (the most frequent are 1q21 microdeletion, 12q24 microdeletion, ring chromosome 15, and deletion 15qter) [Bruce et al., 2010;Spengler et al., 2012;Fuke et al., 2013;Fokstuen and Kotzot, 2014;Azzi et al., 2015] rare cases, maternally inherited balanced translocations/inversions [Begemann et al., 2012b] UPD11 maternal single case [Bullman et al., 2008] paternal 20 -27% [Henry et al., 1991;Gaston et al., 2001;Cooper et al., 2005Cooper et al., , 2007 CDKN1C gene mutations gain-of-function mutation, single case [Brioude et al., 2013] loss-of-function mutations 8 -10%, familial 50 -68%, and sporadic cases 5 -31% [Cooper et al., 2005;Weksberg et 114 ognizable facial phenotype consists of prominent eyes, facial nevus flammeus, full lower face and anterior ear lobe creases and/or posterior helical pits in addition to macroglossia ( fig. 1 c, d). The craniofacial dysmorphic features are most apparent before the age of 3 years, and after the age of 5 years often only minor dysmorphism is present . ...
... The genes within the second imprinted domain (CDKN1C and KCNQ1) are regulated by centromeric ICR2, which is mainly involved in the etiology of BWS [Weksberg et al., 2010]. Hypomethylation of ICR1 is found in 37-63% of SRS cases depending on the clinical criteria used for defining cases [Netchine et al., 2007;Binder et al., 2008;Bartholdi et al., 2009;Bruce et al., 2009;Abu-Amero et al., 2010;Turner et al., 2010;Vals et al., 2015b]. A mosaic distribution of the 11p15 epimutation is present in nearly all SRS patients, and this is due to a postfertilization error. ...
... They found that 22% of patients with diagnosed epimutations had methylation defects of additional imprinted loci, and among patients with clinical features of an imprinting disorder but no molecular diagnosis, methylation anomalies were diagnosed in 8%, including missed and unexpected molecular diagnoses. Vals et al. [2015b] also detected the hypomethylation of PLAGL1 (6q24) and IGF2R (6q25) genes without 11p15 imprinting disorder and clinical features of 6q24-related transient neonatal diabetes mellitus in one patient with the highest BWS clinical scoring. ...
Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 clinically opposite growth-affecting disorders belonging to the group of congenital imprinting disorders. The expression of both syndromes usually depends on the parental origin of the chromosome in which the imprinted genes reside. SRS is characterized by severe intrauterine and postnatal growth retardation with various additional clinical features such as hemihypertrophy, relative macrocephaly, fifth finger clinodactyly, and triangular facies. BWS is an overgrowth syndrome with many additional clinical features such as macroglossia, organomegaly, and an increased risk of childhood tumors. Both SRS and BWS are clinically and genetically heterogeneous, and for clinical diagnosis, different diagnostic scoring systems have been developed. Six diagnostic scoring systems for SRS and 4 for BWS have been previously published. However, neither syndrome has common consensus diagnostic criteria yet. Most cases of SRS and BWS are associated with opposite epigenetic or genetic abnormalities in the 11p15 chromosomal region leading to opposite imbalances in the expression of imprinted genes. SRS is also caused by maternal uniparental disomy 7, which is usually identified in 5-10% of the cases, and is therefore the first imprinting disorder that affects 2 different chromosomes. In this review, we describe in detail the clinical diagnostic criteria and scoring systems as well as molecular causes in both SRS and BWS.
... The reported incidence of SRS varies from 1/3000 to 1/100000, depending on the definition used [11,12], making it difficult to determine the most relevant value. Indeed, some studies include only genetically proven cases of SRS, whereas others include patients born SGA with some features of SRS. ...
Purpose of review:
The purpose of review is to summarize new outcomes for the clinical characterization, molecular strategies, and therapeutic management of Silver-Russell syndrome (SRS).
Recent findings:
Various teams have described the clinical characteristics of SRS patients by genotype. A clinical score for the definition of SRS and for orienting molecular investigations has emerged. Insulin-like growth factor 2 (a major fetal growth factor) has been implicated in the pathophysiology of SRS, as the principle molecular mechanism underlying the disease is loss of methylation of the 11p15 region, including the imprinted insulin-like growth factor 2 gene. Maternal uniparental disomy of chromosome 7 and recently identified rare molecular defects have also been reported in patients with SRS. However, 40% of patients still have no molecular diagnosis.
Summary:
The definition of SRS has remained clinical since the first description of this condition, despite the identification of various molecular causes. The clinical issues faced by these patients are similar to those faced by other patients born small for gestational age (SGA), but patients with SRS require specific multidisciplinary management of their nutrition, growth, and metabolism, as they usually present an extreme form of SGA. Molecular analyses can confirm SRS, and are of particular importance for genetic counseling and prenatal testing.
Genomic imprinting is an epigenetic mechanism that leads to parent of origin-specific differential expression of a subset of genes. The identification of the array of mechanisms regulating monoallelic parent-of-origin specific expression has been instrumental in elucidating a wide range of functional epigenetic mechanisms. Imprinted genes are crucial for normal development. Alterations in the relative expression of these genes, sometimes due to perturbations in gene dosage, cause imprinting disorders. Imprinting disorders are rare and often characterized by clinical features that highlight problems in growth and neurobehavior. Beckwith–Wiedemann (BWS) and Russell–Silver syndromes (RSS), two imprinting disorders with opposite clinical manifestations (overgrowth and undergrowth respectively), can be caused by opposite molecular alterations affecting imprinted gene expression on human chromosome 11p15.5. Studies on the orthologous BWS–RSS genomic region in the mouse have shown that several imprinted genes demonstrate dosage-sensitive functions with important roles in the regulation of placental function and embryonic growth.
