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.

GestaltMML: Enhancing Rare Genetic Disease Diagnosis through Multimodal Machine Learning Combining Facial Images and Clinical Texts.

Individuals with suspected rare genetic disorders often undergo multiple clinical evaluations, imaging studies, laboratory tests and genetic tests, to find a possible answer over a prolonged period of time. Addressing this "diagnostic odyssey" thus has substantial clinical, psychosocial, and economic benefits. Many rare genetic diseases have distinctive facial features, which can be used by artificial intelligence algorithms to facilitate clinical diagnosis, in prioritizing candidate diseases to be further examined by lab tests or genetic assays, or in helping the phenotype-driven reinterpretation of genome/exome sequencing data. Existing methods using frontal facial photos were built on conventional Convolutional Neural Networks (CNNs), rely exclusively on facial images, and cannot capture non-facial phenotypic traits and demographic information essential for guiding accurate diagnoses. Here we introduce GestaltMML, a multimodal machine learning (MML) approach solely based on the Transformer architecture. It integrates facial images, demographic information (age, sex, ethnicity), and clinical notes (optionally, a list of Human Phenotype Ontology terms) to improve prediction accuracy. Furthermore, we also evaluated GestaltMML on a diverse range of datasets, including 528 diseases from the GestaltMatcher Database, several in-house datasets of Beckwith-Wiedemann syndrome (BWS, over-growth syndrome with distinct facial features), Sotos syndrome (overgrowth syndrome with overlapping features with BWS), NAA10-related neurodevelopmental syndrome, Cornelia de Lange syndrome (multiple malformation syndrome), and KBG syndrome (multiple malformation syndrome). Our results suggest that GestaltMML effectively incorporates multiple modalities of data, greatly narrowing candidate genetic diagnoses of rare diseases and may facilitate the reinterpretation of genome/exome sequencing data.

A Novel Macroglossia Severity Index for Beckwith-Wiedemann Syndrome.

OBJECTIVE/ SUMMARY BACKGROUND DATA: We propose the first classification scheme for macroglossia in patients with Beckwith-Wiedemann Syndrome (BWS), the BWS Index of macroGlossia (BIG). METHODS: Patients with molecularly confirmed BWS seen from 2004-2023 were included to develop this system. Relationships among BIG scores, tongue reduction surgery, BWS clinical score, percent mosaicism, and polysomnography findings were examined. RESULTS: Patients were classified from BIG0 to BIG3. BIG0 includes those without macroglossia; BIG1 includes those with macroglossia not protruding beyond the teeth/alveolus; BIG2 includes those with tongue protrusion past the teeth/alveolus to the lips but that can be contained within the mouth; and BIG3 includes those with tongues that protrude beyond the teeth/alveolus and lips but that cannot be closed within the mouth. Of the 459 patients with molecularly confirmed BWS, 266 (58.0%) patients were scored. One hundred and eleven (41.7%) were BIG0, 44 (16.5%) were BIG1, 90 (33.8%) were BIG2, and 21 (7.9%) were BIG3. As scores increased, patients had an increased incidence of tongue reduction surgery (BIG0: 0% versus BIG1: 20.5% versus BIG2: 51.1% versus BIG3: 100%; r=0.66, P <0.01). Higher BIG scores were associated with elevated BWS clinical scores (r=0.68, P <0.01) and increased tissue mosaicism (r=0.50, P <0.01) as well as trends towards worse obstructive apnea-hypopnea indices (r=0.29, P =0.02) and lower SpO 2 nadirs (r=-0.29, P =0.02). CONCLUSION: In this large series of patients with Beckwith-Wiedemann Syndrome, increased BIG score correlates with undergoing tongue reduction surgery and increased phenotypic severity. Adoption of the BIG scoring system may facilitate communication and risk stratification across institutions.

Trends in Blood Mosaicism and Clinical Phenotype Score in Patients with Beckwith-Wiedemann Syndrome Evaluated for Tongue Reduction Surgery.

INTRODUCTION: Most patients with Beckwith-Wiedemann syndrome (BWS) have macroglossia with some requiring tongue reduction surgery (TRS). This study reports correlations between levels of affected cells (mosaicism) and BWS clinical score in patients evaluated for TRS. We also show correlations of clinical score and mosaicism with obstructive sleep apnea (OSA) severity. METHODS: Blood mosaicism levels and BWS clinical score were recorded in patients with macroglossia referred to plastic surgery for evaluation. Associations among blood mosaicism, BWS clinical score, TRS, and OSA were assessed with appropriate statistics. RESULTS: Of the 225 patients included, BWS blood testing was available in 128 (56.9%). Mosaicism levels were higher in those who underwent TRS compared to those who did not (85.9 85.9 (56.5-95.9)% vs. 29.7 (2.8-73.1)%, p<0.001). BWS clinical score was also higher in those requiring TRS (9.0 (8.0-11.0) versus 7.0 (6.0-9.0), p<0.001). There was a positive correlation between clinical score and obstructive apnea-hypopnea index (r=0.320, p=0.011). Receiver operating characteristic curve analysis showed a clinical score ≥11 had 100% specificity and 36.4% sensitivity for detecting patients requiring TRS. Blood mosaicism ≥80% had 63.6% sensitivity and 83.6% specificity for predicting surgery. A combined criteria of BWS clinical score ≥11 or mosaicism ≥80% had 72.7% sensitivity and 83.6% specificity for predicting TRS. CONCLUSION: Blood mosaicism levels and higher BWS clinical scores appear associated with a greater frequency of having surgery in patients with macroglossia referred for surgical evaluation. Elevations in BWS clinical scoring are associated with increased OSA severity while increased blood mosaicism is not.

Cancer predisposition signaling in Beckwith-Wiedemann Syndrome drives Wilms tumor development.

BACKGROUND: Wilms tumor (WT) exhibits structural and epigenetic changes at chromosome 11p15, which also cause Beckwith-Wiedemann Syndrome (BWS). Children diagnosed with BWS have increased risk for WT. The aim of this study is to identify the molecular signaling signatures in BWS driving these tumors. METHODS: We performed whole exome sequencing, methylation array analysis, and gene expression analysis on BWS-WT samples. Our data were compared to publicly available nonBWS data. We categorized WT from BWS and nonBWS patients by assessment of 11p15 methylation status and defined 5 groups- control kidney, BWS-nontumor kidney, BWS-WT, normal-11p15 nonBWS-WT, altered-11p15 nonBWS-WT. RESULTS: BWS-WT samples showed single nucleotide variants in BCORL1, ASXL1, ATM and AXL but absence of recurrent gene mutations associated with sporadic WT. We defined a narrow methylation range stratifying nonBWS-WT samples. BWS-WT and altered-11p15 nonBWS-WT showed enrichment of common and unique molecular signatures based on global differential methylation and gene expression analysis. CTNNB1 overexpression and broad range of interactions were seen in the BWS-WT interactome study. CONCLUSION: While WT predisposition in BWS is well-established, as are 11p15 alterations in nonBWS-WT, this study focused on stratifying tumor genomics by 11p15 status. Further investigation of our findings may identify novel therapeutic targets in WT oncogenesis.

Overgrowth syndromes, diagnosis and management.

PURPOSE OF REVIEW: This review will focus on the current knowledge of the diagnosis and management of overgrowth syndromes with specific focus on mosaic conditions and treatment strategies. RECENT FINDINGS: With the implementation of massively parallel sequencing, the genetic etiology of many classically described overgrowth syndromes have been identified. More recently, the role of mosaic genetic changes has been well described in numerous syndromes. Furthermore, the role of imprinting and methylation, especially of the 11p15 region, has been shown to be instrumental for growth. Perhaps most importantly, many overgrowth syndromes carry an increased risk of neoplasm formation especially in the first 10 years of life and possibly beyond. The systematic approach to the child with overgrowth will aide in timely diagnosis and efficiently align them with appropriate screening strategies. In some cases, precision medical interventions are available to target the perturbed growth signaling pathways. SUMMARY: The systematic approach to the child with overgrowth aids in the standardization of the diagnostic pathway for these young patients, thereby expediting the diagnostic timeline, enabling rigorous monitoring, and delivering tailored therapeutic interventions.

Introduction to the Beckwith-Wiedemann Syndrome and Cancer Special Issue.

Beckwith-Wiedemann syndrome (BWS) is a genetic imprinting disorder that most commonly presents as overgrowth, macroglossia, abdominal wall defects, lateralized overgrowth, and embryonal tumors [...].

(Epi)genotype and Timing of Tongue Reduction Predict Safety and Long-Term Outcomes in Beckwith-Wiedemann Syndrome.

INTRODUCTION: Macroglossia is a cardinal feature of Beckwith-Wiedemann syndrome (BWS) with a clinical spectrum where the indication and timing for surgery remain to be validated. This study leverages a cohort of molecularly characterized patients with BWS to correlate epigenetic diagnosis with phenotype and treatment outcome. METHODS: Patients with BWS seen in consultation for macroglossia from 2009-2022 were reviewed for phenotype, molecular diagnosis, tongue reduction status, timing of surgery (early = under 12 months), and perioperative complications. RESULTS: Two hundred thirty-seven patients were included. Imprinting control region 2 loss of methylation (IC2 LOM) was the most common epigenotype (61%). Paternal uniparental isodisomy for chromosome 11 (pUPD11) comprised a larger proportion of patients undergoing tongue reduction (18%) than those not undergoing surgery (8%, p = 0.024) and was associated with need for repeat surgery (OR 4.49, 95% CI 1.06-18.98, p = 0.041). Complications including wound dehiscence, ventilator associated pneumonia, and unplanned extubation were more common in patients undergoing early surgery (20%) than late surgery (4%, OR 5.70, 95% CI 1.14-28.55, p = 0.034). CONCLUSIONS: This study presents one of the largest cohorts correlating molecular diagnosis with clinical course of macroglossia treatment in BWS. Macroglossia in patients with pUPD11 is associated with higher rates of reoperation. Relief of obstructive sleep apnea with early tongue reduction must be weighed against risk of perioperative complications, most of which are non-surgical. This study highlights how molecular diagnosis advances clinical care by risk stratifying clinical outcomes in a center providing integrated multidisciplinary care for the BWS population.

Associations between the timing of tongue reduction surgery, (Epi)genotype, and dentoskeletal development in patients with Beckwith-Wiedemann syndrome.

Tongue reduction surgery is often pursued to manage the adverse effects of macroglossia in patients with Beckwith-Wiedemann syndrome (BWS). This study characterized dental outcomes in patients with BWS based on surgical timing and molecular diagnosis. A retrospective study was designed to include patients with BWS over the age of two who had clinical or radiographic documentation of dental development. Patients were grouped by history of tongue reduction surgery and surgical timing (early: <12 months). One hundred three patients were included (55 no tongue reduction, 18 early, 30 late). Patients who underwent late surgery had lower odds of class I occlusion (OR 0.11, 95% CI 0.02-0.58, p = 0.009) and higher odds of anterior open bite (OR 7.5, 95% CI 1.14-49.4, p = 0.036). Patients with clinical diagnoses and negative molecular testing had anterior open bite less frequently than patients with imprinting center 2 loss of methylation and paternal uniparental isodisomy of 11p15.5 (p = 0.009). Compared to reference values, patients who had tongue reductions had an increased mandibular plane angle (32.0 ± 4.5° versus 36.9 ± 5.0°, p = 0.001), indicative of hyperdivergent growth. The results of this study help to understand the complex nature of dentoskeletal growth in BWS and shed insight on how surgical timing and molecular diagnosis influence prognosis.

Imprinting disorders.

Imprinting disorders (ImpDis) are congenital conditions that are characterized by disturbances of genomic imprinting. The most common individual ImpDis are Prader-Willi syndrome, Angelman syndrome and Beckwith-Wiedemann syndrome. Individual ImpDis have similar clinical features, such as growth disturbances and developmental delay, but the disorders are heterogeneous and the key clinical manifestations are often non-specific, rendering diagnosis difficult. Four types of genomic and imprinting defect (ImpDef) affecting differentially methylated regions (DMRs) can cause ImpDis. These defects affect the monoallelic and parent-of-origin-specific expression of imprinted genes. The regulation within DMRs as well as their functional consequences are mainly unknown, but functional cross-talk between imprinted genes and functional pathways has been identified, giving insight into the pathophysiology of ImpDefs. Treatment of ImpDis is symptomatic. Targeted therapies are lacking owing to the rarity of these disorders; however, personalized treatments are in development. Understanding the underlying mechanisms of ImpDis, and improving diagnosis and treatment of these disorders, requires a multidisciplinary approach with input from patient representatives.

Adult experiences in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth and epigenetic disorder caused by changes on chromosome 11p15. The primary features requiring management in childhood include macroglossia, omphalocele, lateralized overgrowth, hyperinsulinism, and embryonal tumors. Management guidelines have not been developed for adults with BWS and there have been few studies to assess the clinical needs of these patients. Furthermore, there have been few studies on the psychosocial implications of BWS in children or adults. Here, we present a descriptive summary of data gathered from two separate adult BWS cohorts. The first, a patient-based survey cohort, includes self-reported health information and recollections about BWS experiences, while the second provides results of a medical record-based assessment from patients in an overgrowth registry. Results highlight the clinical features and medical issues affecting two large independent cohorts of adults with BWS while noting similarities. Open-ended questions asked of the survey cohort yielded themes to guide future qualitative studies. Finally, the study demonstrated the reliability of patient-reported data and the utility of international partnerships in this context.

Occurrence of Hepatoblastomas in Patients with Beckwith-Wiedemann Spectrum (BWSp).

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 CTNNB1 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.

Investigation of a pervasive immune, cardiac, and behavioral phenotype in Beckwith-Wiedemann syndrome: A case report.

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by genetic and epigenetic changes in the chromosome 11p15 region. The syndrome is characterized by a wide range of features including macrosomia, lateralized overgrowth, abdominal wall defects, and hypoglycemia. BWS presentation is variable across the entire patient population, but certain areas including immunology, cardiology, and behavioral differences are not well characterized. We present a case of a male patient with BWS due to the most common cause of BWS, loss of methylation at imprinting center 2 with a variable phenotype, including classical features (macrosomia, macroglossia, omphalocele, placentomegaly and mild lateralized overgrowth) in addition to uncommon features (immune deficiency, developmental delays, and pulmonary stenosis) not typically seen in BWS. This study defines a patient's clinical presentation and course and highlights the need to consider atypical organ systems in BWS as either an expansion of the phenotype or co-existing conditions to develop personalized care models.

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.

The counterpart congenital overgrowth syndromes Beckwith-Wiedemann Syndrome in human and large offspring syndrome in bovine involve alterations in DNA methylation, transcription, and chromatin configuration.

Beckwith-Wiedemann Syndrome (BWS, OMIM #130650) is a congenital epigenetic disorder in humans which affects approximately 1 in 10,340 children. The incidence is likely an underestimation as the condition is usually recognized based on observable phenotypes at birth. BWS children have up to a 28% risk of developing tumors and currently, only 80% of patients can be corroborated molecularly (epimutations/variants). It is unknown how the subtypes of this condition are molecularly similar/dissimilar globally, therefore there is a need to deeply characterize the syndrome at the molecular level. Here we characterize the methylome, transcriptome and chromatin configuration of 18 BWS individuals together with the animal model of the condition, the bovine large offspring syndrome (LOS). Sex specific comparisons are performed for a subset of the BWS patients and LOS. Given that this epigenetic overgrowth syndrome has been characterized as a loss-of-imprinting condition, parental allele-specific comparisons were performed using the bovine animal model. In general, the differentially methylated regions (DMRs) detected in BWS and LOS showed significant enrichment for CTCF binding sites. Altered chromosome compartments in BWS and LOS were positively correlated with gene expression changes, and the promoters of differentially expressed genes showed significant enrichment for DMRs, differential topologically associating domains, and differential A/B compartments in some comparisons of BWS subtypes and LOS. We show shared regions of dysregulation between BWS and LOS, including several HOX gene clusters, and also demonstrate that altered DNA methylation differs between the clinically epigenetically identified BWS patients and those identified as having DNA variants (i.e. CDKN1C microdeletion). Lastly, we highlight additional genes and genomic regions that have the potential to serve as targets for biomarker development to improve current molecular methodologies. In summary, our results suggest that genome-wide alternation of chromosome architecture, which is partially caused by DNA methylation changes, also contribute to the development of BWS and LOS.

Clinical Effectiveness of Telemedicine-Based Pediatric Genetics Care.

BACKGROUND AND OBJECTIVES: Telemedicine may increase access to medical genetics care. However, in the pediatric setting, how telemedicine may affect the diagnostic rate is unknown, partially because of the perceived importance of the dysmorphology physical examination. We studied the clinical effectiveness of telemedicine for patients with suspected or confirmed genetic conditions. METHODS: We conducted a retrospective cohort study of outpatient encounters before and after the widespread implementation of telemedicine (N = 5854). Visit types, diagnoses, patient demographic characteristics, and laboratory data were acquired from the electronic health record. Patient satisfaction was assessed through survey responses. New molecular diagnosis was the primary end point. RESULTS: Patients seen by telemedicine were more likely to report non-Hispanic White ancestry, prefer to speak English, live in zip codes with higher median incomes, and have commercial insurance (all P < .01). Genetic testing was recommended for more patients evaluated by telemedicine than in person (79.5% vs 70.9%; P < .001). Patients seen in person were more likely to have a sample collected, resulting in similar test completion rates (telemedicine, 51.2%; in person, 55.1%; P = .09). There was no significant difference in molecular diagnosis rate between visit modalities (telemedicine, 13.8%; in person, 12.4%; P = .40). CONCLUSIONS: Telemedicine and traditional in-person evaluation resulted in similar molecular diagnosis rates. However, improved methodologies for remote sample collection may be required. This study reveals the feasibility of telemedicine in a large academic medical genetics practice and is applicable to other pediatric specialties with perceived importance of physical examination.

Molecular networks of hepatoblastoma predisposition and oncogenesis in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann Syndrome (BWS) is the most common human overgrowth disorder caused by structural and epigenetic changes to chromosome 11p15. Patients with BWS are predisposed to developing hepatoblastoma (HB). To better understand the mechanism of HB oncogenesis in this cancer predisposition background, we performed the first multi-dimensional study of HB samples collected from patients diagnosed with BWS. This multi-omic investigation of seven BWS HB and five matched nontumor BWS liver samples from 7 unique patients included examination of whole exome sequences, messenger RNA/microRNA expression, and methylation levels to elucidate the genomic, transcriptomic, and epigenomic landscape of BWS-associated HB. We compared the transcriptional profiles of the BWS samples, both HB and nontumor, to that of control livers. Genes differentially expressed across BWS tissues were identified as BWS HB predisposition factors; this gene group included cell cycle regulators, chromatin organizers, and WNT, mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/AKT members. We also compared transcriptional changes associated with non-syndromic HB carrying BWS-like 11p15 alterations compared to those without, as well as to BWS HB. Through this analysis, we identified factors specific to 11p15-altered HB oncogenesis, termed the BWS oncogenesis network. We propose that 11p15 alterations drive HB oncogenesis by initially dysregulating cell-cycle regulators and chromatin organizers, including histone deacetylase 1 (HDAC1), ATP-dependent helicase X, and F-Box and WD repeat domain containing 7. Furthermore, we found oncogenic factors such as dickkopf WNT signaling pathway inhibitor 1 and 4, WNT16, forkhead box O3 (FOXO3), and MAPK10 are differentially expressed in 11p15-altered HB in both the BWS and non-syndromic backgrounds. These genes warrant further investigation as diagnostic or therapeutic targets.

Results From the WAGR Syndrome Patient Registry: Characterization of WAGR Spectrum and Recommendations for Care Management.

WAGR syndrome is a rare genetic disorder characterized by Wilms tumor, Aniridia, Genitourinary anomalies, and Range of developmental delays. In addition to the classic features, patients affected by WAGR syndrome can develop obesity and kidney failure, and a wide variety of non-classical manifestations have also been described. This suggests that a broader phenotypic spectrum beyond the classic syndrome exists and here we demonstrate that spectrum using data from the WAGR Syndrome Patient Registry. In the present study, we collected information from 91 individuals enrolled in the registry to explore self-reported health issues in this patient population. A wide variety of common clinical issues not classically associated with the disorder were found, prompting the redefinition from WAGR syndrome to WAGR spectrum disorder to incorporate the phenotypic variations that occur. A comprehensive care management approach is needed to address the wide range of clinical issues and we propose a care model for patients affected by WAGR spectrum disorder. Further research is needed to solidify the breath of the phenotype and confirm the observations in this study to advance individualized patient care in this population.

Characteristics Associated with Tumor Development in Individuals Diagnosed with Beckwith-Wiedemann Spectrum: Novel Tumor-(epi)Genotype-Phenotype Associations in the BWSp Population.

Beckwith-Wiedemann Spectrum (BWSp) is the most common epigenetic childhood cancer predisposition disorder. BWSp is caused by (epi)genetic changes affecting the BWS critical region on chromosome 11p15. Clinically, BWSp represents complex molecular and phenotypic heterogeneity resulting in a range of presentations from Classic BWS to milder features. The previously reported tumor risk based on Classic BWS cohorts is 8-10% and routine tumor screening has been recommended. This work investigated the tumor risk and correlation with phenotype within a cohort of patients from Classic BWS to BWSp using a mixed-methods approach to explore phenotype and epigenotype profiles associated with tumor development through statistical analyses with post-hoc retrospective case series review. We demonstrated that tumor risk across BWSp differs from Classic BWS and that certain phenotypic features are associated with specific epigenetic causes; nephromegaly and/or hyperinsulinism appear associated with cancer in some patients. We also demonstrated that prenatal and perinatal factors that are not currently part of the BWSp classification may factor into tumor risk. Additionally, blood testing results are not necessarily synonymous with tissue testing results. Together, it appears that the current understanding from Classic BWS of (epi)genetics and phenotype correlations with tumors is not represented in the BWSp. Further study is needed in this complex population.