Beckwith-Wiedemann Spectrum Research Articles

Molecular and Clinical Features of Adrenocortical Tumors in Beckwith–Wiedemann Spectrum

Background/Objectives: Adrenocortical tumors (ACTs), including adrenocortical adenoma (ACA) and carcinoma (ACC), represent 0.3–0.4% of pediatric tumors. Beckwith–Wiedemann spectrum (BWSp) confer an increased risk of ACTs, but prognosis, management, and associated molecular characteristics are unclear. Methods: This paper combines a literature review of 54 published cases of BWSp-ACT with a report of one newly identified patient, totaling 55 cases with a confirmed BWSp clinical and/or molecular diagnosis. Results: Nineteen patients with ACA, 33 with ACC, and 3 with ACT of uncertain malignant potential (umACT) were included. Twenty patients had uniparental disomy of chromosome 11p15.5 (patUPD11), 11imprinting Center 2 Loss-of-methylation (IC2-LoM), and had 2 11p15 locus duplication. Eleven patients were diagnosed during cancer screening procedures, including two metastatic at diagnosis ACC. Conclusions: Almost half of ACC patients reached the minimum score for clinical BWSp diagnosis only after ACC onset, suggesting that the BWSp score has limited value for the early diagnosis in such a setting. Two patients with metastatic ACC had a histopathological Wieneke score ≤2, not correlating with clinical malignancy and confirming limitations of the current histopathological classification, as previously documented. Ultrasound screening failed identifying the ACC before metastasis in two cases, indicating an urgent need to develop new strategies for screening of ACTs in BWSp. Furthermore, some cases of metastatic ACC exhibited unexpectedly indolent behavior despite being malignant.

Low-level mosaic GCK mutations in children with diazoxide-unresponsive congenital hyperinsulinism.

Some children with diazoxide-unresponsive congenital hyperinsulinism (HI) lack any detectable disease-causing mutation in peripheral blood DNA. To examine whether somatic post-zygotic mutations of known HI genes are responsible for disease in children with diazoxide-unresponsive HI requiring surgery with histology not classified as focal or Localized Islet Nuclear Enlargement (LINE), and without detectable mutations by standard genetic testing of peripheral blood DNA. Next-generation sequencing (NGS) was performed on specimens of pancreas from 10 children with diazoxide-unresponsive HI. Four unique GCK mutations were identified at low levels of mosaicism ranging from 4.4-10.1% in pancreatic DNA from five of these 10 children. The GCK mutations were not detectable in peripheral blood DNA by NGS in three cases from which peripheral blood DNA was available for testing. All four GCK mutations have been previously published as activating HI mutations. The histology was consistent with diffuse-HI in four of the five cases with mosaic GCK mutations. In one of these, hypomethylation of IC2 on chromosome 11p was identified in pancreatic and peripheral blood DNA. Histology of the fifth case revealed minor islet abnormalities suggestive of Beckwith Wiedemann Spectrum (BWSp) although molecular analysis for 11pUPD was negative in pancreas. These results indicate that post-zygotic somatic GCK mutations are responsible for some cases of non-focal diazoxide-unresponsive hyperinsulinism.

Phenotypic spectrum and tumor risk in Simpson-Golabi-Behmel syndrome: Case series and comprehensive literature review.

Simpson-Golabi-Behmel syndrome (SGBS) is a rare congenital overgrowth condition characterized by macrosomia, macroglossia, coarse facial features, and development delays. It is caused by pathogenic variants in the GPC3 gene on chromosome Xq26.2. Here, we performed a comprehensive literature review and phenotyping of known patients with molecularly confirmed SGBS and reviewed a novel cohort of 22 patients. Using these data, we characterized the tumor risk for Wilms tumor and hepatoblastoma to suggest appropriate screening for this patient population. In addition, we discuss the phenotypic overlap between SGBS and Beckwith-Wiedemann Spectrum.

Molecular Basis and Diagnostic Approach to Isolated and Syndromic Lateralized Overgrowth in Childhood

To demonstrate a high-yield molecular diagnostic workflow for lateralized overgrowth (LO), a congenital condition with abnormal enlargement of body parts, and to classify it by molecular genetics. We categorized 186 retrospective cases of LO diagnosed between 2003 and 2023 into suspected Beckwith-Wiedemann spectrum, PIK3CA-related overgrowth spectrum (PROS), vascular overgrowth, or isolated LO, based on initial clinical assessments, to determine the appropriate first-tier molecular tests and tissue for analysis. Patients underwent testing for 11p15 epigenetic abnormalities or somatic variants in genes related to PI3K/AKT/mTOR, vascular proliferation, and RAS-MAPK cascades using blood or skin DNA. For cases with negative initial tests, a sequential cascade molecular approach was employed to improve diagnostic yield. This approach led to a molecular diagnosis in 54% of cases, 89% of cases consistent with initial clinical suspicions, and 11% reclassified. Beckwith-Wiedemann spectrum was the most common cause, with 43% of cases exhibiting 11p15 abnormalities. PIK3CA-related overgrowth spectrum had the highest confirmation rate, with 74% of clinically diagnosed patients showing a PIK3CA variant. Vascular overgrowth demonstrated significant clinical overlap with other syndromes. A molecular diagnosis of isolated LO proved challenging, with only 21% of cases classifiable into a specific condition. LO is underdiagnosed from a molecular viewpoint and to date has had no diagnostic guidelines, which is crucial for addressing potential cancer predisposition, enabling precision medicine treatments, and guiding management. This study sheds light on the molecular etiology of LO, highlighting the importance of a tailored diagnostic approach and of selecting appropriate testing to achieve the highest diagnostic yield.

Expanded phenotype and cancer risk in patients with Beckwith-Wiedemann spectrum caused by CDKN1C variants.

Beckwith-Wiedemann spectrum (BWSp) is caused by genetic and epigenetic alterations on chromosome 11 that regulate cell growth and division. Considering the diverse phenotypic landscape in BWSp, the characterization of the CDKN1C molecular subtype remains relatively limited. Here, we investigate the role of CDKN1C in the broader BWSp phenotype. Notably, patients with CDKN1C variants appear to exhibit a different tumor risk than other BWSp molecular subtypes. We performed a comprehensive literature review using the search term "CDKN1C Beckwith" to identify 113 cases of patients with molecularly confirmed CDKN1C-BWSp. We then assessed the genotype and phenotype in a novel cohort of patients with CDKN1C-BWSp enrolled in the BWS Research Registry. Cardinal and suggestive features were evaluated for all patients reported, and tumor risk was established based on available reports. The most common phenotypes included macroglossia, omphalocele, and ear creases/pits. Tumor types reported from the literature included neuroblastoma, acute lymphocytic leukemia, superficial spreading melanoma, and intratubular germ cell neoplasia. Overall, this study identifies unique features associated with CDKN1C variants in BWSp, enabling more accurate clinical management. The absence of Wilms tumor and hepatoblastoma suggests that screening for these tumors may not be necessary, while the neuroblastoma risk warrants appropriate screening recommendations.

A Novel Heterozygous Splice Donor Variant in TRIM28 Gene Causing Beckwith-Wiedemann Spectrum: Case Report and Literature Review

Beckwith-Wiedemann Syndrome (BWS) is an inborn growth disorder caused by molecular alterations in chromosome 11p15.5. Due to the varying clinical findings of patients with 11p15.5 disturbances, the syndromic entity was expanded to the Beckwith– Wiedemann spectrum (BWSp). BWSp describes a complex heterogeneous and multisystem disease spectrum. It can be diagnosed by clinical assessment and/or molecular testing. The clinical features comprise characteristic developmental anomalies, including midline abdominal defects, macroglossia, overgrowth, hemihypertrophy, and neonatal hypoglycemia. Patients with BWSp patients are predisposed to malignancy during their early childhood.

Co-occurrence of Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type 1B: coincidence or common molecular mechanism?

Imprinting disorders are congenital diseases caused by dysregulation of genomic imprinting, affecting growth, neurocognitive development, metabolism and cancer predisposition. Overlapping clinical features are often observed among this group of diseases. In rare cases, two fully expressed imprinting disorders may coexist in the same patient. A dozen cases of this type have been reported so far. Most of them are represented by individuals affected by Beckwith-Wiedemann spectrum (BWSp) and Transient Neonatal Diabetes Mellitus (TNDM) or BWSp and Pseudo-hypoparathyroidism type 1B (PHP1B). All these patients displayed Multilocus imprinting disturbances (MLID). Here, we report the first case of co-occurrence of BWS and PHP1B in the same individual in absence of MLID. Genome-wide methylation and SNP-array analyses demonstrated loss of methylation of the KCNQ1OT1:TSS-DMR on chromosome 11p15.5 as molecular cause of BWSp, and upd(20)pat as cause of PHP1B. The absence of MLID and the heterodisomy of chromosome 20 suggests that BWSp and PHP1B arose through distinct and independent mechanism in our patient. However, we cannot exclude that the rare combination of the epigenetic defect on chromosome 11 and the UPD on chromosome 20 may originate from a common so far undetermined predisposing molecular lesion. A better comprehension of the molecular mechanisms underlying the co-occurrence of two imprinting disorders will improve genetic counselling and estimate of familial recurrence risk of these rare cases. Furthermore, our study also supports the importance of multilocus molecular testing for revealing MLID as well as complex cases of imprinting disorders.

Dentoskeletal features and growth pattern in Beckwith-Wiedemann spectrum: is surgical tongue reduction always necessary?

ObjectivesThe 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 methodsOrthopantomography 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.ResultsEighteen 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.ConclusionsThese preliminary data suggest that early TSR does not improve craniofacial growth pattern and dentoskeletal features in BWSp children.Clinical relevanceReductive 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.

Should testing for mosaic genome-wide paternal uniparental disomy in Beckwith-Wiedemann spectrum (BWSp) be implemented in diagnostic testing?

Should testing for mosaic genome-wide paternal uniparental disomy in Beckwith-Wiedemann spectrum (BWSp) be implemented in diagnostic testing?

Investigation of 11p15.5 Methylation Defects Associated with Beckwith-Wiedemann Spectrum and Embryonic Tumor Risk in Lateralized Overgrowth Patients.

The Beckwith-Wiedemann spectrum (BWSp) ranges from isolated lateralized overgrowth (ILO) to classic phenotypes. In this broad clinical spectrum, an epigenetic alteration on chromosome 11p15.5 can be detected. The risk for embryonal tumors is high, especially in patients with lateralized overgrowth (LO). The aim of this study is to investigate epigenetic alterations in 11p15.5 and tumor risk in 87 children with LO. The methylation level of 11p15.5 was examined in the blood of all patients and in skin samples or buccal swabs from 40 patients with negative blood tests; 63.2% of patients were compatible with the ILO phenotype, 18.4% were atypical, and 18.4% were classic. The molecular diagnosis rate was 81.2% for the atypical and classic phenotypes, and 10.9% for the ILO phenotype. In patients with epigenetic alterations, LO was statistically significantly more severe than in test negatives. Tumors developed in six (6.9%) of the total 87 patients with LO; four belonged to the atypical or classical phenotype (12.5%) and two to ILO (3.5%). Three of the four patients with atypical/classical phenotypes had pUPD11, one had IC1-GOM alteration, and two ILO patients were negative. We conclude that LO patients should be monitored for tumor risk even if their epigenetic tests are negative.

Performance Metrics of the Scoring System for the Diagnosis of the Beckwith-Wiedemann Spectrum (BWSp) and Its Correlation with Cancer Development.

Different scoring systems for the clinical diagnosis of the Beckwith-Wiedemann spectrum (BWSp) have been developed over time, the most recent being the international consensus score. Here we try to validate and provide data on the performance metrics of these scoring systems of the 2018 international consensus and the previous ones, relating them to BWSp features, molecular tests, and the probability of cancer development in a cohort of 831 patients. The consensus scoring system had the best performance (sensitivity 0.85 and specificity 0.43). In our cohort, the diagnostic yield of tests on blood-extracted DNA was low in patients with a low consensus score (~20% with a score = 2), and the score did not correlate with cancer development. We observed hepatoblastoma (HB) in 4.3% of patients with UPD(11)pat and Wilms tumor in 1.9% of patients with isolated lateralized overgrowth (ILO). We validated the efficacy of the currently used consensus score for BWSp clinical diagnosis. Based on our observation, a first-tier analysis of tissue-extracted DNA in patients with <4 points may be considered. We discourage the use of the consensus score value as an indicator of the probability of cancer development. Moreover, we suggest considering cancer screening for negative patients with ILO (risk ~2%) and HB screening for patients with UPD(11)pat (risk ~4%).

Lateralized overgrowth as a guiding sign of abdominal neoplasms for pediatric orthopedic surgeons.

This study aims to increase the awareness of the association between lateralized overgrowth (LO) and abdominal tumor among the pediatric orthopedic community and to evaluate its incidence in our center. Between January 1997 and December 2021, a total of 166 patients with Wilms tumors and hepatoblastomas were retrospectively analyzed. Data including age, sex, initial clinical signs (hematuria, abdominal mass with or without general discomfort), type of asymmetric regional body overgrowth (isolated or in relation with any syndrome), and tumor stage at diagnosis were recorded. In addition, age at which asymmetric regional body overgrowth was described and age at the time of tumor diagnosis were noted. Of a total of 166 patients, 133 were diagnosed with Wilms tumors (nephroblastomas) and 33 were diagnosed with hepatoblastomas. In 94% of the cases, the initial clinical signs were an abdominal mass and/or hematuria. Overall, five (3%) patients presented with LO. Four patients with Wilms tumor presented it at the initial clinical examinations. In three of these cases (2.3%), we found it isolated and, in the remaining patient (0.75%), it was associated with Beckwith-Wiedemann spectrum. Only one patient affected from hepatoblastoma (3%) presented with an isolated LO at the time of tumor diagnosis. Our study results show an incidence of LO in relation to intra-abdominal tumors of 3%. The latest updates recommend genetic testing to identify subgroups with a higher risk for tumor development that are more likely to benefit from tumor protocol surveillance.

Familial Beckwith-Wiedemann syndrome in a multigenerational family: Forty years of careful phenotyping.

Beckwith-Wiedemann Spectrum (BWSp) is an overgrowth and cancer predisposition disorder characterized by a wide spectrum of phenotypic manifestations including macroglossia, abdominal wall defects, neonatal hypoglycemia, and predisposition to embryonal tumors. In 1981, Best and Hoekstra reported four patients with BWSp in a single family which suggested autosomal dominant inheritance, but standard clinical testing for BWSp was not available during this time. Meticulous phenotyping of this family has occurred over the past 40 years of follow-up with additional family members being identified and samples collected for genetic testing. Genetic testing revealed a pathogenic mutation in CDKN1C, consistent with the most common cause of familial BWSp. CDKN1C mutations account for just 5% of sporadic cases of BWSp. Here, we report the variable presentation of BWSp across the individuals affected by the CDKN1C mutation and other extended family members spanning multiple generations, all examined by the same physician. Additional phenotypes thought to be atypical in patients with BWSp were reported which included cardiac abnormalities. The incidence of tumors was documented in extended family members and included rhabdomyosarcoma, astrocytoma, and thyroid carcinoma, which have previously been reported in patients with BWSp. These observations suggest that in addition to the inheritance of the CDKN1C variant, there are modifying factors in this family driving the phenotypic spectrum observed. Alternative theories are suggested to explain the etiology of clinical variability including diffused mosaicism, anticipation, and the presence of additional variants tracking in the family. This study highlights the necessity of long-term follow-up in patients with BWSp and consideration of individual familial characteristics in the context of phenotype and/or (epi)genotype associations.

Further understanding of paternal uniparental disomy Beckwith-Wiedemann syndrome

Introduction Paternal uniparental disomy of chromosome 11 (upd(11)pat) accounts for up to 20% of molecularly confirmed Beckwith-Wiedemann spectrum (BWSp) cases. It belongs to the BWSp subgroup with the second highest tumour risk, and therefore needs particular awareness in research, diagnostics and clinical management. Areas covered We overview the contribution of paternal (mosaic) uniparental disomy of chromosome 11 (UPD, upd(11)pat) and mosaic paternal uniparental diploidy in patients with Beckwith-Wiedemann features. The review comprises the current knowledge on their formation and their molecular and clinical consequences. Accordingly, the consequences for diagnostic testing and clinical monitoring are compiled. Expert opinion The necessity to diagnostically identify and thus discriminate genome-wide paternal uniparental disomy, and upd(11)pat becomes obvious, due to the differences in the clinical course, disease prognosis and treatment. In particular, monitoring of tumour development by liquid biopsy might be a promising option in the future. From the research point of view, it should be addressed why 11p is prone to mitotic recombination and thus also provide to the role of upd(11) as second hit in tumorigenesis.

Tumor predisposition syndromes and nephroblastoma : Early diagnosis with imaging

The Beckwith-Wiedemann spectrum (BWSp) as well as the WT1-related syndromes, Denys-Drash syndrome (DDS) and WAGR spectrum (Wilms tumor, Aniridia, genitourinary anomalies and arange of developmental delays) are tumor predisposition syndromes (TPS) of Wilms tumor (WT). Patients with associated TPS are at higher risk of developing chronic kidney disease and bilateral and metachronous tumors as well as nephrogenic rests. Standard imaging diagnostics for WT include renal ultrasound and magnetic resonance imaging (MRI). In the current renal tumor studies Umbrella SIOP-RTSG 2016 and Randomet 2017, thoracic computed tomography (CT) is also recommended as standard. Positron emission tomography (PET)-CT and whole-body MRI, on the other hand, are not part of routine diagnostics. In recent publications, renal ultrasound is recommended every 3months until the age of 7years in cases of clinical suspicion or molecularly proven TPS. Patients with TPS and regular renal ultrasounds have smaller tumor volumes and lower tumor stages at WT diagnosis than patients without such ascreening. This allows areduction of therapy intensity and facilitates the performance of nephron sparing surgery, which is prognostically relevant especially in bilateral WT. Early diagnosis of WT in the context of TPS ensures the greatest possible preservation of healthy and functional renal tissue. Standardized screening by regular renal ultrasounds should therefore be firmly established in clinical practice. The initial diagnosis of TPS is clinical and requires askilled and attentive examiner in the presence of sometimes subtle clinical manifestations, especially in the case of BWSp. Clinical diagnosis should be followed by genetic testing, which should then be followed by sonographic screening.

Clinical and molecular characterization of patients affected by Beckwith-Wiedemann spectrum conceived through assisted reproduction techniques.

The prevalence of Beckwith–Wiedemann spectrum (BWSp) is tenfold increased in children conceived through assisted reproductive techniques (ART). More than 90% of ART‐BWSp patients reported so far display imprinting center 2 loss‐of‐methylations (IC2‐LoM), versus 50% of naturally conceived BWSp patients. We describe a cohort of 74 ART‐BWSp patients comparing their features with a cohort of naturally conceived BWSp patients, with the ART‐BWSp patients previously described in literature, and with the general population of children born from ART. We found that the distribution of UPD(11)pat was not significantly different in ART and naturally conceived patients. We observed 68.9% of IC2‐LoM and 16.2% of mosaic UPD(11)pat in our ART cohort, that strongly differ from the figure reported in other cohorts so far. Since UPD(11)pat likely results from post‐fertilization recombination events, our findings allows to hypothesize that more complex molecular mechanisms, besides methylation disturbances, may underlie BWSp increased risk in ART pregnancies. Moreover, comparing the clinical features of ART and non‐ART BWSp patients, we found that ART‐BWSp patients might have a milder phenotype. Finally, our data show a progressive increase in the prevalence of BWSp over time, paralleling that of ART usage in the last decades.

Molecular Basis of Beckwith-Wiedemann Syndrome Spectrum with Associated Tumors and Consequences for Clinical Practice.

Simple SummaryBeckwith–Wiedemann syndrome (BWS, OMIM 130650) is an inborn overgrowth disorder caused by molecular alterations in chromosome 11p15.5. These molecular changes affect so-called imprinted genes, i.e., genes which underlie a complex regulation which is linked to the parental origin of the gene copy. Thus, either the maternal gene copy is expressed or the paternal, but this balanced regulation is prone to disturbances. In fact, different types of molecular variants have been identified in BWS, resulting in a variable phenotype; thus, it was consented that the syndromic entity was extended to the Beckwith–Wiedemann spectrum (BWSp). Some molecular subgroups of BWSp are associated with an increased embryonic tumor risk and have different likelihoods for specific tumors. Therefore, the precise determination of the molecular subgroup is needed for precise monitoring and treatment, but the molecular diagnostic procedure has several limitations and challenges which have to be considered.Beckwith–Wiedemann syndrome (BWS, OMIM 130650) is a congenital imprinting condition with a heterogenous clinical presentation of overgrowth and an increased childhood cancer risk (mainly nephroblastoma, hepatoblastoma or neuroblastoma). Due to the varying clinical presentation encompassing classical, clinical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly, the syndromic entity was extended to the Beckwith–Wiedemann spectrum (BWSp). The tumor risk of up to 30% depends on the molecular subtype of BWSp with causative genetic or epigenetic alterations in the chromosomal region 11p15.5. The molecular diagnosis of BWSp can be challenging for several reasons, including the range of causative molecular mechanisms which are frequently mosaic. The molecular basis of tumor formation appears to relate to stalled cellular differentiation in certain organs that predisposes persisting embryonic cells to accumulate additional molecular defects, which then results in a range of embryonal tumors. The molecular subtype of BWSp not only influences the overall risk of neoplasia, but also the likelihood of specific embryonal tumors.

Abstract 5220: The consequences of 11p15 mosaicism in Beckwith-Wiedemann syndrome/spectrum: Epigenotypes associated with cancer development and necessity for universal tumor screening

Abstract Beckwith-Wiedemann Spectrum (BWSp) is the most common (epi)genetic cancer predisposition disorder. BWSp has a heterogeneous clinical presentation and is caused by epigenetic changes at two regions on chromosome 11p15. These epigenetic changes occur post-zygotically leading to a mosaic distribution among tissues. Clinical molecular testing usually starts with blood; however, we and others have demonstrated that positive molecular testing rates are increased if testing is performed on affected tissues. Clinical and molecular diagnosis is important because patients with BWS are at risk for development of embryonal tumors (Wilms tumor (WT), hepatoblastoma (HB), and neuroendocrine tumors). Formal surveillance guidelines were published in 2017 as part of a United States-based cancer predisposition effort that recommended alpha fetoprotein and complete abdominal ultrasound screening for all patients with BWSp until 4 years of age for HB and renal ultrasound screening until 7 years of age for WT. In contrast, the European-based BWS international consensus group (BWS-ICG) applied stratified cancer screening recommendations based on (epi)genotype. In the present study, we investigated cancer development rates and epigenotype profiles associated with cancer in patients diagnosed with BWSp. We present a series of patients with history of WT, HB, and/or neuroendocrine tumors to highlight that there can be differing BWSp epigenotype profiles in tumor and adjacent normal tissue compared to blood, demonstrating the presence of multiple cell populations with distinct epigenetic changes within patients. These distinct changes show that more than one epigenetic alteration in the chromosome 11p15 region can be present in a single tissue type. These findings suggest that the epigenetic classification in blood alone should not be used to stratify cancer risk in BWSp. Additionally, the mild BWSp clinical phenotype and low BWS-ICG clinical scores for these patients highlight that some patients present with few external features. Therefore, neither blood epigenotype nor external phenotype can help inform an individual’s unique tumor risk. This work further suggests that the BWS-ICG tumor risk stratification system cannot be applied to the full Beckwith-Wiedemann Spectrum due to the emerging epigenetic and phenotypic landscape of patients diagnosed with BWSp. These results support a recommendation of universal tumor screening for all patients diagnosed with even mild BWSp phenotypes and/or a 11p15 epigenetic abnormality. Citation Format: Kelly A. Duffy, Evan R. Hathaway, Mallory E. Byrne, Andrew M. George, Timothy Mcelroy, Suzanne P. MacFarland, Garrett M. Brodeur, Jennifer M. Kalish. The consequences of 11p15 mosaicism in Beckwith-Wiedemann syndrome/spectrum: Epigenotypes associated with cancer development and necessity for universal tumor screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5220.

Hepatoblastoma in molecularly defined, congenital diseases.

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.

Prevalence of (Epi)genetic Predisposing Factors in a 5-Year Unselected National Wilms Tumor Cohort: A Comprehensive Clinical and Genomic Characterization.

PURPOSEWilms tumor (WT) is associated with (epi)genetic predisposing factors affecting a growing number of WT predisposing genes and loci, including those causing Beckwith-Wiedemann spectrum (BWSp) or WT1-related syndromes. To guide genetic counseling and testing, we need insight into the prevalence of WT predisposing (epi)genetic factors.PATIENTS AND METHODSAll children diagnosed with WT in the Netherlands between 2015 and 2020 were referred to a clinical geneticist. Phenotypic data, disease characteristics, and diagnostic test results were collected. If no genetic predisposition was identified by targeted diagnostic testing, germline (trio-)whole-exome sequencing and BWSp testing on normal kidney-derived DNA were offered.RESULTSA total of 126 cases were analyzed of 128 identified patients. (Epi)genetic predisposing factors were present in 42 of 126 patients (33.3%) on the basis of a molecular diagnosis in blood-derived DNA (n = 26), normal kidney-derived DNA (n = 12), or solely a clinical diagnosis of BWSp (n = 4). Constitutional, heterozygous DIS3L2 variants were identified as a recurrent predisposing factor in five patients (4%), with a second somatic hit in 4 of 5 tumors. Twenty patients (16%) were diagnosed with BWSp while four additional patients without BWSp features harbored chromosome 11p15 methylation defects in normal kidney tissue. Remaining findings included WT1-related syndromes (n = 10), Fanconi anemia (n = 1), neurofibromatosis type 1 (n = 1), and a pathogenic REST variant (n = 1). In addition, (likely) pathogenic variants in adult-onset cancer predisposition genes (BRCA2, PMS2, CHEK2, and MUTYH) were identified in 5 of 56 (8.9%) patients with available whole-exome sequencing data. Several candidate WT predisposition genes were identified, which require further validation.CONCLUSION(Epi)genetic WT predisposing factors, including mosaic aberrations and recurrent heterozygous DIS3L2 variants, were present in at least 33.3% of patients with WT. On the basis of these results, we encourage standard genetic testing after counseling by a clinical geneticist.