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Journal of Pediatric Surgery Nov 2023Children with omphalocele have an increased prevalence of Beckwith Wiedemann syndrome (BWS) and thus a suspected increased risk of developing embryonal tumors, e.g....
AIM OF THE STUDY
Children with omphalocele have an increased prevalence of Beckwith Wiedemann syndrome (BWS) and thus a suspected increased risk of developing embryonal tumors, e.g. Wilms tumor, hepatoblastoma, neuroblastoma and rhabdomyosarcoma. The aim of this study was to examine the prevalence of BWS and the risk of embryonal tumors amongst patients born with omphalocele.
METHODS
A population-based cohort was used, including all children born in Sweden 1/1 1997-31/12 2016. Patients with omphalocele were identified through the Swedish National Patient Register and the Swedish Medical Birth Register. For each case of omphalocele ten age and sex matched individuals unexposed for omphalocele were randomly selected for comparison. Data on BWS and embryonal tumors were collected from the Swedish National Patient Register and the Swedish National Cancer Register.
MAIN RESULTS
Out of 207 cases of omphalocele, 15 (7.2%) were diagnosed with BWS. None of the children with omphalocele had yet developed any kind of embryonal tumor (median follow-up time 8 years). None of the 2070 controls were diagnosed with BWS but 3 (0.1%) of them had developed embryonal tumors during a median follow-up time of 10 years.
CONCLUSIONS
In this study the prevalence of BWS amongst children born with omphalocele is in the lower range of previously reported figures. Also, the prevalence of embryonal tumors amongst children with BWS is lower than expected and the risk of embryonal tumors in children with omphalocele and BWS might not be as high as previously stated. This must be taken into consideration when counseling parents prenatally.
TYPE OF STUDY
National register cohort study.
LEVEL OF EVIDENCE
II.
PubMed: 37355432
DOI: 10.1016/j.jpedsurg.2023.05.021 -
Brain Sciences May 2023About 90% of children diagnosed with classic BWS have macroglossia, and 40% of them are submitted to surgical tongue reduction. The purpose of our article is to present...
About 90% of children diagnosed with classic BWS have macroglossia, and 40% of them are submitted to surgical tongue reduction. The purpose of our article is to present a case study of a 5-month-old child with BWS who was treated with an original therapy for stimulation of oral areas innervated by the trigeminal nerve. The therapy included stimulation of the upper and lower lip and muscles of the floor of the mouth. The treatment was provided by a therapist once a week. In addition, the child was stimulated every day at home by his mother. After 3 months, a significant improvement in oral alignment and function was achieved. Preliminary observations of therapy application for stimulation regions innervated by the trigeminal nerve in children with Beckwith-Wiedemann syndrome seem promising. The original therapy for stimulation of oral areas innervated by the trigeminal nerve is a good alternative to existing methods of surgical tongue reduction in children with BWS and macroglossia.
PubMed: 37239301
DOI: 10.3390/brainsci13050829 -
Cancers Apr 2023Patients with Beckwith-Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to...
Patients with Beckwith-Wiedemann syndrome (BWS), an epigenetic imprinting disorder involving alterations in genes at the 11p15 chromosomal location, are predisposed to develop hepatoblastomas (HBs), which are rare embryonal liver tumors. Tumors can develop after a BWS diagnosis or, conversely, can be the presenting feature leading to a subsequent diagnosis. While HBs are the cardinal tumors of BWS, not all patients with the BWS spectrum will develop HBs. This observation has led to many hypotheses, including genotype-associated risk, tissue mosaicism, and tumor-specific second hits. To explore these hypotheses, we present the largest cohort of patients with BWS and HBs to date. Our cohort comprised 16 cases, and we broadened our sample size by searching the literature for all cases of BWS with HBs. From these isolated case studies, we amassed another 34 cases, bringing the total number to 50 cases of BWS-HB. We observed that paternal uniparental isodisomy (upd(11)pat) was the most common genotype, representing 38% of cases. The next most common genotype was IC2 LOM, representing 14% of cases. Five patients had clinical BWS without a molecular diagnosis. To investigate the potential mechanism of HBs in BWS, we analyzed normal liver and HB samples from eight cases and isolated tumor samples from another two cases. These samples underwent methylation testing, and 90% of our tumor samples underwent targeted cancer next-generation sequencing (NGS) panels. These matched samples provided novel insights into the oncogenesis of HBs in BWS. We found that 100% of the HBs that underwent NGS panel testing had variants in the gene. We further identified three distinct groups of BWS-HB patients based on epigenotype. We also demonstrated epigenotype mosaicism, where 11p15 alterations can differ between the blood, HB, and normal liver. In light of this epigenotype mosaicism, tumor risk assessment based on blood profiling may not be accurate. Therefore, universal screening is recommended for all patients with BWS.
PubMed: 37174013
DOI: 10.3390/cancers15092548 -
Clinical Oral Investigations Aug 2023The role of tongue reduction surgery (TRS) in preventing excessive mandibular growth and anterior open bite in children with Beckwith-Wiedemann Spectrum (BWSp) is still...
OBJECTIVES
The role of tongue reduction surgery (TRS) in preventing excessive mandibular growth and anterior open bite in children with Beckwith-Wiedemann Spectrum (BWSp) is still controversial. This cross-sectional study aimed at comparing craniofacial growth pattern in children affected by BWSp either treated or not treated with early TRS for severe macroglossia. Considering the invasive nature of such surgery, the present study could help in clarifying the need for TRS to reduce or prevent growth disturbances.
MATERIALS AND METHODS
Orthopantomography and lateral skull x-ray images were taken either from surgically treated or non-surgically treated patients, aged 5 to 8 years, to compare dentoskeletal features and craniofacial growth by cephalometric analysis. Molecular testing results were collected from their medical records.
RESULTS
Eighteen BWSp patients were consecutively recruited: 8 underwent TRS at 14.9 ± 2.2 months of age, while 10 did not. Anterior open bite and dental class III were more frequently observed in the surgically treated group, but none showed skeletal class III. No statistically significant differences were observed in growth pattern, but children treated with TRS showed a tendency towards both maxillary and mandibular prognathism with protruding lower lip. Growth pattern seemed to be not related to molecular subtypes.
CONCLUSIONS
These preliminary data suggest that early TSR does not improve craniofacial growth pattern and dentoskeletal features in BWSp children.
CLINICAL RELEVANCE
Reductive glossectomy may not be justified for preventing or avoiding oro-facial deformities in BWSp; therefore, early monitoring of maxillofacial development of each affected child has a great clinical significance.
Topics: Child; Humans; Beckwith-Wiedemann Syndrome; Open Bite; Cross-Sectional Studies; Tongue; Macroglossia
PubMed: 37162568
DOI: 10.1007/s00784-023-05043-w -
Frontiers in Endocrinology 2023Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and... (Review)
Review
Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic β-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.
Topics: Infant; Infant, Newborn; Humans; Child; Congenital Hyperinsulinism; Beckwith-Wiedemann Syndrome; Insulin Secretion; Glucose
PubMed: 37065762
DOI: 10.3389/fendo.2023.1013874 -
Cancers Mar 2023CRC is an adult-onset carcinoma representing the third most common cancer and the second leading cause of cancer-related deaths in the world. EO-CRC (<45 years of age)...
CRC is an adult-onset carcinoma representing the third most common cancer and the second leading cause of cancer-related deaths in the world. EO-CRC (<45 years of age) accounts for 5% of the CRC cases and is associated with cancer-predisposing genetic factors in half of them. Here, we describe the case of a woman affected by BWSp who developed EO-CRC at age 27. To look for a possible molecular link between BWSp and EO-CRC, we analysed her whole-genome genetic and epigenetic profiles in blood, and peri-neoplastic and neoplastic colon tissues. The results revealed a general instability of the tumor genome, including copy number and methylation changes affecting genes of the WNT signaling pathway, CRC biomarkers and imprinted loci. At the germline level, two missense mutations predicted to be likely pathogenic were found in compound heterozygosity affecting the Cystic Fibrosis (CF) gene CFTR that has been recently classified as a tumor suppressor gene, whose dysregulation represents a severe risk factor for developing CRC. We also detected constitutional loss of methylation of the :TSS-DMR that leads to bi-allelic expression of the lncRNA and BWSp. Our results support the hypothesis that the inherited CFTR mutations, together with constitutional loss of methylation of the :TSS-DMR, initiate the tumorigenesis process. Further somatic genetic and epigenetic changes enhancing the activation of the WNT/beta-catenin pathway likely contributed to increase the growth advantage of cancer cells. Although this study does not provide any conclusive cause-effect relationship between BWSp and CRC, it is tempting to speculate that the imprinting defect of BWSp might accelerate tumorigenesis in adult cancer in the presence of predisposing genetic variants.
PubMed: 37046605
DOI: 10.3390/cancers15071944 -
Journal of Medical Case Reports Apr 2023Pediatric adrenocortical tumors include both benign adenomas and highly virulent malignant tumors. However, they are very rare among children. The aim of this study is... (Review)
Review
BACKGROUND
Pediatric adrenocortical tumors include both benign adenomas and highly virulent malignant tumors. However, they are very rare among children. The aim of this study is to evaluate the clinicopathological data of children presenting with adrenocortical tumors and assess their survival in a South Asian population.
CASE PRESENTATION
This is a retrospective cohort study that includes patients diagnosed with adrenocortical tumors from August 2020 to August 2022 followed-up at Lady Ridgeway Hospital. Seven children were diagnosed with adrenal cortical tumors. Their ages ranged from 10 months to 6.5 years. Five of them were boys. All displayed signs of peripheral precocious puberty. One boy phenotypically had features of Beckwith-Wiedemann syndrome. The median time for diagnosis after the onset of symptoms was 4.4 months. The preoperative diagnosis was based on clinical manifestations, elevated dehydroepiandrosterone sulfate levels, and suprarenal masses on computed tomography. All five boys had right-sided suprarenal masses, while the two girls had them on the left side. All underwent surgery for tumor resection. The diagnosis was confirmed based on the histopathology of the adrenal specimens. Four children had a Wieneke score of 4 or more, suggesting the possibility of adrenocortical carcinoma; however, only two of them behaved as malignant tumors. To date, two children have developed local recurrences within a very short period.
CONCLUSION
Adrenocortical tumors are uncommon in children, and treatment options are limited. To identify early recurrences, routine clinical, radiological, and biochemical examinations at least once every 6-8 weeks is important.
Topics: Male; Female; Child; Humans; Infant; Retrospective Studies; Sri Lanka; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Recurrence
PubMed: 37046342
DOI: 10.1186/s13256-023-03890-5 -
Journal of Medical Genetics Sep 2023Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse.
BACKGROUND
Studies suggest that Wilms tumours (WT) are caused by underlying genetic (5%-10%) and epigenetic (2%-29%) mechanisms, yet studies covering both aspects are sparse.
METHODS
We performed prospective whole-genome sequencing of germline DNA in Danish children diagnosed with WT from 2016 to 2021, and linked genotypes to deep phenotypes.
RESULTS
Of 24 patients (58% female), 3 (13%, all female) harboured pathogenic germline variants in WT risk genes ( and ). Only one patient had a family history of WT (3 cases), segregating with the variant. Epigenetic testing revealed one (4%) additional patient (female) with uniparental disomy of chromosome 11 and Beckwith-Wiedemann syndrome (BWS). We observed a tendency of higher methylation of the BWS-related imprinting centre 1 in patients with WT than in healthy controls. Three patients (13%, all female) with bilateral tumours and/or features of BWS had higher birth weights (4780 g vs 3575 g; p=0.002). We observed more patients with macrosomia (>4250 g, n=5, all female) than expected (OR 9.98 (95% CI 2.56 to 34.66)). Genes involved in early kidney development were enriched in our constrained gene analysis, including both known (, ) and candidate () WT predisposition genes. WT predisposing variants, BWS and/or macrosomia (n=8, all female) were more common in female patients than male patients (p=0.01).
CONCLUSION
We find that most females (57%) and 33% of all patients with WT had either a genetic or another indicator of WT predisposition. This emphasises the need for scrutiny when diagnosing patients with WT, as early detection of underlying predisposition may impact treatment, follow-up and genetic counselling.
Topics: Male; Female; Humans; F-Box-WD Repeat-Containing Protein 7; Fetal Macrosomia; Genomic Imprinting; Wilms Tumor; Genotype; Beckwith-Wiedemann Syndrome; DNA Methylation; Disease Susceptibility; Kidney Neoplasms; Germ Cells
PubMed: 37019617
DOI: 10.1136/jmg-2022-108982 -
Clinical Epigenetics Mar 2023Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A...
BACKGROUND
Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking.
RESULTS
Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype-phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues.
CONCLUSIONS
Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants contribute to MLID.
Topics: DNA Methylation; Genomics; Genotype; High-Throughput Nucleotide Sequencing
PubMed: 36859312
DOI: 10.1186/s13148-023-01453-5