Publications by authors named "Jennifer M Kalish"

52 Publications

The Prevalence of Difficult Airway in Children With Beckwith-Wiedemann Syndrome: A Retrospective Cohort Study.

Anesth Analg 2021 Apr 22. Epub 2021 Apr 22.

Division of Human Genetics.

Background: Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth disorder with an incidence of approximately 1 in 10,000 live births. The condition is characterized by lateralized overgrowth, abdominal wall defects, macroglossia, and predisposition to malignancy. Historically, children with BWS have been presumed to have difficult airways; however, most of the evidence to support this has been anecdotal and derived from case reports. Our study aimed to determine the prevalence of difficult airway in patients with BWS. We hypothesized that most patients with BWS would not have difficult airways.

Methods: We retrospectively reviewed the electronic medical records of patients enrolled in our institution's BWS registry. Patients with a molecular diagnosis of BWS who were anesthetized between January 2012 and July 2019 were included for analysis. The primary outcome was the presence of difficult airway, defined as difficult facemask ventilation, difficult intubation, or both. We defined difficult intubation as the need for 3 or more tracheal intubation attempts and the need for advanced airway techniques (nondirect laryngoscopy) to perform tracheal intubation or a Cormack and Lehane grade ≥3 during direct laryngoscopy. Secondary objectives were to define predictors of difficult intubation and difficult facemask ventilation, and the prevalence of adverse airway events. Generalized linear mixed-effect models were used to account for multiple anesthesia events per patient.

Results: Of 201 BWS patients enrolled in the registry, 60% (n = 122) had one or more documented anesthetics, for a total of 310 anesthetics. A preexisting airway was present in 22 anesthetics. The prevalence of difficult airway was 5.3% (95% confidence interval [CI], 3.0-9.3; 18 of 288) of the cases. The prevalence of difficult intubation was 5.2% (95% CI, 2.9-9.4; 12 of 226). The prevalence of difficult facemask ventilation was 2.9% (95% CI, 1.4-6.2; 12 of 277), and facemask ventilation was not attempted in 42 anesthetics. Age <1 year, macroglossia, lower weight, endocrine comorbidities, plastics/craniofacial surgery, tongue reduction surgery, and obstructive sleep apnea were associated with difficult airways in cases without a preexisting airway. About 83.8% (95% CI, 77.6-88.5) of the cases were intubated with a single attempt. Hypoxemia was the most common adverse event.

Conclusions: The prevalence of difficult tracheal intubation and difficult facemask ventilation in children with BWS was 5.2% and 2.9%, respectively. We identified factors associated with difficult airway, which included age <1 year, macroglossia, endocrine abnormalities, plastics/craniofacial surgery, tongue reduction surgery, and obstructive sleep apnea. Clinicians should anticipate difficult airways in patients with these factors.
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http://dx.doi.org/10.1213/ANE.0000000000005536DOI Listing
April 2021

Late Presentation of Wilms Tumor in a Patient with Hemihypertrophy after Normal Screening.

Urology 2021 Feb 11. Epub 2021 Feb 11.

Division of Urology, Hospital of the University of Pennsylvania, Perelman Center for Advanced Care, Philadelphia, PA; Division of Urology, Children's Hospital of Philadelphia, Philadelphia, PA.

An identifiable genetic malformation or predisposition syndrome is present in 18% of Wilms tumor cases. Given this, children with conditions associated with a greater than 1% risk of developing Wilms tumor are recommended to have regular surveillance imaging with renal ultrasound until age 7. Seven years is the recommended screening duration because 95% of cases will occur by this age. We present a case of a child with isolated hemihypertrophy, associated with 5% risk of Wilms tumor, who presented with a tumor after the recommended screening, at age 9, brining into question the age cutoffs currently used.
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http://dx.doi.org/10.1016/j.urology.2021.01.054DOI Listing
February 2021

Understanding Syndromic Leg Length Discrepancy.

J Pediatr 2021 Feb 9. Epub 2021 Feb 9.

Department of Human Genetics, Children's Hospital of Philadelphia; Departments of Pediatrics and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2021.01.076DOI Listing
February 2021

A dyadic approach to the delineation of diagnostic entities in clinical genomics.

Am J Hum Genet 2021 01;108(1):8-15

Molecular Medicine & Pathology and Pediatrics, McMaster University, Hamilton, ON L8S 3K9, Canada.

The delineation of disease entities is complex, yet recent advances in the molecular characterization of diseases provide opportunities to designate diseases in a biologically valid manner. Here, we have formalized an approach to the delineation of Mendelian genetic disorders that encompasses two distinct but inter-related concepts: (1) the gene that is mutated and (2) the phenotypic descriptor, preferably a recognizably distinct phenotype. We assert that only by a combinatorial or dyadic approach taking both of these attributes into account can a unitary, distinct genetic disorder be designated. We propose that all Mendelian disorders should be designated as "GENE-related phenotype descriptor" (e.g., "CFTR-related cystic fibrosis"). This approach to delineating and naming disorders reconciles the complexity of gene-to-phenotype relationships in a simple and clear manner yet communicates the complexity and nuance of these relationships.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820621PMC
January 2021

Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth.

Front Pediatr 2020 17;8:613260. Epub 2020 Dec 17.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.

Lateralized overgrowth (LO), or segmental overgrowth, is defined as an increase in growth of tissue (bone, muscle, connective tissue, vasculature, etc.) in any region of the body. Some overgrowth syndromes, characterized by both generalized and lateralized overgrowth, have been associated with an increased risk of tumor development. This may be due to the underlying genetic and epigenetic defects that lead to disrupted cell growth and proliferation pathways resulting in the overgrowth and tumor phenotypes. This chapter focuses on the four most common syndromes characterized by LO: Beckwith-Wiedemann spectrum (BWSp), -related overgrowth spectrum (PROS), Proteus syndrome (PS), and hamartoma tumor syndrome (PHTS). These syndromes demonstrate variable risks for tumor development in patients affected by LO, and we provide a comprehensive literature review of all common tumors reported in patients diagnosed with an LO-related disorder. This review summarizes the current data on tumor risk among these disorders and their associated tumor screening guidelines. Furthermore, this chapter highlights the importance of an accurate diagnosis when a patient presents with LO as similar phenotypes are associated with different tumor risks, thereby altering preventative screening protocols.
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http://dx.doi.org/10.3389/fped.2020.613260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773942PMC
December 2020

Derivation and investigation of the first human cell-based model of Beckwith-Wiedemann syndrome.

Epigenetics 2020 Dec 29:1-11. Epub 2020 Dec 29.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Genomic imprinting is a rare form of gene expression in mammals in which a small number of genes are expressed in a parent-of-origin-specific manner. The aetiology of human imprinting disorders is diverse and includes chromosomal abnormalities, mutations, and epigenetic dysregulation of imprinted genes. The most common human imprinting disorder is Beckwith-Wiedemann syndrome (BWS), frequently caused by uniparental isodisomy and DNA methylation alterations. Because these lesions cannot be easily engineered, induced pluripotent stem cells (iPSC) are a compelling alternative. Here, we describe the first iPSC model derived from patients with BWS. Due to the mosaic nature of BWS patients, both BWS and non-BWS iPSC lines were derived from the same patient's fibroblasts. Importantly, we determine that DNA methylation and gene expression patterns of the imprinted region in the iPSC lines reflect the parental cells and are stable over time. Additionally, we demonstrate that differential expression in insulin signalling, cell proliferation, and cell cycle pathways was seen in hepatocyte lineages derived from BWS lines compared to controls. Thus, this cell based-model can be used to investigate the role of imprinting in the pathogenesis of BWS in disease-relevant cell types.
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http://dx.doi.org/10.1080/15592294.2020.1861172DOI Listing
December 2020

Coexistence of paternally-inherited mutation and mosaic paternal uniparental disomy 11p hyperinsulinism.

Int J Pediatr Endocrinol 2020 10;2020:13. Epub 2020 Jul 10.

Prenatal Diagnostic Laboratory, Department of Obstetrics and Gynaecology, Tsan Yuk Hospital, Room 314, 3/F, 30 Hospital Road, Sai Ying Pun, Hong Kong.

Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome with variable clinical phenotype and complex molecular aetiology. It is mainly caused by dysregulation of the chromosome 11p15 imprinted region, which results in overgrowth in multiple tissues, often in a mosaic manner.

Case Presentation: A large-for-gestational-age infant without any other somatic features of BWS presented with medically refractory hyperinsulinism (HI) requiring 80% pancreatectomy. Next generation sequencing with congenital HI sequencing panel identified a pathogenic :c.1792C > T (p.Arg598Ter) variant of paternal origin, suggestive of focal HI. However, pancreatic histology revealed atypical findings of coalescing nests and trabeculae of adenomatosis scattered with islets with isolated enlarged, hyperchromatic nuclei scattered throughout the pancreas. Methylation analysis, SNP-based chromosomal microarray and short tandem repeat markers analysis revealed mosaic segmental paternal uniparental disomy (UPD) 11p15.5-p15.1 in the pancreatic tissue, but not the peripheral blood, suggestive of BWS/BW-spectrum HI.

Conclusions: This case highlights the importance of integrating the clinical presentation and subsequent clinical course, together with radiological, genetic and histological findings in the definitive diagnosis of this rare yet clinically important entity. In addition, this is the first report that demonstrated the level of paternal inherited c.1792 T pathogenic variant in the pancreatic tissue being directly correlated to the mosaic level of pUPD.
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http://dx.doi.org/10.1186/s13633-020-00083-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350603PMC
July 2020

Improved molecular detection of mosaicism in Beckwith-Wiedemann Syndrome.

J Med Genet 2021 Mar 19;58(3):178-184. Epub 2020 May 19.

Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

Background: Beckwith-Wiedemann Syndrome (BWS) is characterised by overgrowth and tumour predisposition. While multiple epigenetic and genetic mechanisms cause BWS, the majority are caused by methylation defects in imprinting control regions on chromosome 11p15.5. Disease-causing methylation defects are often mosaic within affected individuals. Phenotypic variability among individuals with chromosome 11p15.5 defects and tissue mosaicism led to the definition of the Beckwith-Wiedemann Spectrum (BWSp). Molecular diagnosis of BWSp requires use of multiple sensitive diagnostic techniques to reliably detect low-level aberrations.

Methods: Multimodal BWS diagnostic testing was performed on samples from 1057 individuals. Testing included use of a sensitive qRT-PCR-based quantitation method enabling identification of low-level mosaic disease, identification of CNVs within 11p15.5 via array comparative genomic hybridisation or qRT-PCR, and Sanger sequencing of .

Results: A molecular diagnosis was confirmed for 27.4% of individuals tested, of whom 43.4% had mosaic disease. The presence of a single cardinal feature was associated with a molecular diagnosis of BWSp in 20% of cases. Additionally, significant differences in the prevalence of mosaic disease among BWS molecular subtypes were identified. Finally, the diagnostic yield obtained by testing solid tissue samples from individuals with negative blood testing results shows improved molecular diagnosis.

Conclusion: This study highlights the prevalence of mosaic disease among individuals with BWSp and the increases in diagnostic yield obtained via testing both blood and solid tissue samples from affected individuals. Additionally, the results establish the presence of a molecular diagnosis in individuals with very subtle features of BWSp.
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http://dx.doi.org/10.1136/jmedgenet-2019-106498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959163PMC
March 2021

11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood.

Cancer 2020 Jul 22;126(13):3114-3121. Epub 2020 Apr 22.

Division of Clinical Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown.

Methods: Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients).

Results: Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration.

Conclusions: Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.
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http://dx.doi.org/10.1002/cncr.32907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383476PMC
July 2020

The Utility of Early Tongue Reduction Surgery for Macroglossia in Beckwith-Wiedemann Syndrome.

Plast Reconstr Surg 2020 04;145(4):803e-813e

From the Divisions of Human Genetics, Pulmonary Medicine, and Plastic and Reconstructive Surgery, Children's Hospital of Philadelphia; and the Departments of Pediatrics and Surgery, Perelman School of Medicine at the University of Pennsylvania.

Background: Macroglossia, a cardinal feature of the (epi)genetic disorder Beckwith-Wiedemann syndrome, is associated with obstructive sleep apnea, speech and/or feeding difficulties, and dental or jaw malalignment. These sequelae may be treated and/or prevented with tongue reduction surgery; the authors sought to determine whether certain Beckwith-Wiedemann syndrome patients may benefit from early surgical intervention before age 12 months.

Methods: The authors conducted a retrospective review of patients with Beckwith-Wiedemann syndrome who underwent tongue reduction from 2014 to 2019. The authors assessed primary outcomes of change in obstructive sleep apnea by polysomnography, respiratory support required, and feeding route before and after tongue reduction, and reviewed postoperative complications and the need for repeated tongue reduction.

Results: Of the 36 patients included, the median age at tongue reduction was 9.5 months (interquartile range, 3.8 to 22.8 months). For those with severe obstructive sleep apnea, there was a significant reduction in the obstructive apnea hypopnea index from 30.9 ± 21.8 per hour to 10.0 ± 18.3 per hour (p =0.019) and improvement in nadir oxyhemoglobin saturation from 72 ± 10 percent to 83 ± 6 percent (p =0.008). Although there was no significant change in overall supplemental feeding tube or respiratory support, there were specific patients who experienced clinically meaningful improvement. Of note, these positive outcomes applied equally to those who underwent surgery at a younger age (<12 months). To date, only one patient required a repeated tongue reduction.

Conclusion: Based on improved polysomnographic findings and rarity of surgical complications or repeated surgery, the authors' data support the safety and efficacy of this early intervention when clinical indications are present and an experienced multidisciplinary team is available for consultation.

Clinical Question/level Of Evidence: Therapeutic, IV.
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http://dx.doi.org/10.1097/PRS.0000000000006673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038320PMC
April 2020

Diagnosis and Management of Beckwith-Wiedemann Syndrome.

Front Pediatr 2019 21;7:562. Epub 2020 Jan 21.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.

Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder that presents with a wide spectrum of clinical features including overgrowth, abdominal wall defects, macroglossia, neonatal hypoglycemia, and predisposition to embryonal tumors. It is associated with genetic and epigenetic changes on the chromosome 11p15 region, which includes two imprinting control regions. Here we review strategies for diagnosing and managing BWS and delineate commonly used genetic tests to establish a molecular diagnosis of BWS. Recommended first-line testing assesses DNA methylation and copy number variation of the BWS region. Tissue mosaicism can occur in patients with BWS, posing a challenge for genetic testing, and a negative test result does not exclude a diagnosis of BWS. Further testing should analyze additional tissue samples or employ techniques with higher diagnostic yield. Identifying the BWS molecular subtype is valuable for coordinating patient care because of the (epi)genotype-phenotype correlations, including different risks and types of embryonal tumors.
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http://dx.doi.org/10.3389/fped.2019.00562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990127PMC
January 2020

Tatton-Brown-Rahman syndrome: Six individuals with novel features.

Am J Med Genet A 2020 04 21;182(4):673-680. Epub 2020 Jan 21.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

Tatton-Brown Rahman syndrome (TBRS) is an overgrowth-intellectual disability syndrome caused by heterozygous variants in DNMT3A. Seventy-eight individuals have been reported with a consistent phenotype of somatic overgrowth, mild to moderate intellectual disability, and similar dysmorphisms. We present six individuals with TBRS, including the youngest individual thus far reported, first individual to be diagnosed with tumor testing and two individuals with variants at the Arg882 domain, bringing the total number of reported cases to 82. Patients reported herein have additional clinical features not previously reported in TBRS. One patient had congenital diaphragmatic hernia. One patient carrying the recurrent p.Arg882His DNMT3A variant, who was previously reported as having a phenotype due to a truncating variant in the CLTC gene, developed a ganglioneuroblastoma at 18 months and T-cell lymphoblastic lymphoma at 6 years of age. Four patients manifested symptoms suggestive of autonomic dysfunction, including central sleep apnea, postural orthostatic hypotension, and episodic vasomotor instability in the extremities. We discuss the molecular and clinical findings in our patients with TBRS in context of existing literature.
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http://dx.doi.org/10.1002/ajmg.a.61475DOI Listing
April 2020

Novel variants in CDH2 are associated with a new syndrome including Peters anomaly.

Clin Genet 2020 03 10;97(3):502-508. Epub 2019 Nov 10.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.

Peters anomaly (PA) is a congenital corneal opacity associated with corneo-lenticular attachments. PA can be isolated or part of a syndrome with most cases remaining genetically unsolved. Exome sequencing of a trio with syndromic PA and 145 additional unexplained probands with developmental ocular conditions identified a de novo splicing and three novel missense heterozygous CDH2 variants affecting the extracellular cadherin domains in four individuals with PA. Syndromic anomalies were seen in three individuals and included left-sided cardiac lesions, dysmorphic facial features, and decreasing height percentiles; brain magnetic resonance imaging identified agenesis of the corpus callosum and hypoplasia of the inferior cerebellar vermis. CDH2 encodes for N-cadherin, a transmembrane protein that mediates cell-cell adhesion in multiple tissues. Immunostaining in mouse embryonic eyes confirmed N-cadherin is present in the lens stalk at the time of separation from the future cornea and in the developing lens and corneal endothelium at later stages, supporting a possible role in PA. Previous studies in animal models have noted the importance of Cdh2/cdh2 in the development of the eye, heart, brain, and skeletal structures, also consistent with the patient features presented here. Examination of CDH2 in additional patients with PA is indicated to confirm this association.
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http://dx.doi.org/10.1111/cge.13660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028510PMC
March 2020

Reply.

J Pediatr 2020 01 11;216:249-250. Epub 2019 Oct 11.

Division of Human Genetics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pediatrics, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania; Department of Genetics, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1016/j.jpeds.2019.09.021DOI Listing
January 2020

The effectiveness of Wilms tumor screening in Beckwith-Wiedemann spectrum.

J Cancer Res Clin Oncol 2019 Dec 4;145(12):3115-3123. Epub 2019 Oct 4.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, USA.

Purpose: It is well documented that patients with Beckwith-Wiedemann spectrum (BWS) have a significantly higher risk of developing Wilms tumor (WT) than the general population. There has been little research on the timing of WT diagnosis in BWS in regard to optimizing suggested screening protocols.

Methods: A literature search was performed to identify all reports of patients with BWS and WT. These data were combined with unpublished data from patients in the authors' cohorts. Age at WT diagnosis was compared against data collected through the NIH Surveillance, Epidemiology, and End Results Program (SEER) registry.

Results: Patients with BWS had a significantly higher incidence of WT diagnoses between age 12 and 84 months compared to patients in the SEER registry. Patients with BWS and WT diagnosed through screening had significantly lower stages at diagnosis compared to patients with BWS that were not screened.

Conclusions: Screening until age 7 years is effective in detecting close to 95% of all WT in patients with BWS.
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http://dx.doi.org/10.1007/s00432-019-03038-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876630PMC
December 2019

Characterization of the Beckwith-Wiedemann spectrum: Diagnosis and management.

Am J Med Genet C Semin Med Genet 2019 12 30;181(4):693-708. Epub 2019 Aug 30.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Beckwith-Wiedemann syndrome (BWS) is the most common epigenetic overgrowth and cancer predisposition disorder. Due to both varying molecular defects involving chromosome 11p15 and tissue mosaicism, patients can present with a variety of clinical features, leading to the newly defined Beckwith-Wiedemann spectrum (BWSp). The BWSp can be further divided into three subsets of patients: those presenting with classic features, those presenting with isolated lateralized overgrowth (ILO) and those not fitting into the previous two categories, termed atypical BWSp. Previous reports of patients with BWS have focused on those with the more recognizable, classic features, and limited information is available on those who fit into the atypical and ILO categories. Here, we present the first cohort of patients recruited across the entire BWSp, describe clinical features and molecular diagnostic characteristics, and provide insight into practical diagnosis and management recommendations that we have gained from this cohort.
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http://dx.doi.org/10.1002/ajmg.c.31740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959855PMC
December 2019

Development of the Serum α-Fetoprotein Reference Range in Patients with Beckwith-Wiedemann Spectrum.

J Pediatr 2019 09 22;212:195-200.e2. Epub 2019 Jun 22.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address:

Objective: To establish reference ranges for serum α-fetoprotein (AFP) at various ages in patients with Beckwith-Wiedemann spectrum (BWSp), to better predict the risk for hepatoblastoma in this population.

Study Design: A retrospective analysis of AFP measurements collected from patients with BWSp was performed. Factors including sex, prematurity, molecular diagnosis of patients, and performing laboratory were evaluated for significant differences. In total, 1372 AFP values were collected from 147 patients and the predictive AFP values at various ages were calculated to establish reference ranges. Mixed-effects polynomial regression models were used to study various potential factors affecting log(AFP) values.

Results: Overall, predicted AFP values declined to normal range for age (<10 ng/mL) by 14 months old. Patient sex and performing laboratory were found not to influence values. A significant difference was demonstrated between premature and nonpremature patients, and separate reference values were established. Significant differences in the predicted AFP value were not broadly apparent between molecular subtypes; however, interpretation was limited due to the small sample size of some of these subtypes.

Conclusions: Predictive AFP values were created for premature and nonpremature patients with BWSp to aid with interpretation and monitoring of the risk for hepatoblastoma. Further analysis is needed to determine whether AFP values differ within the less common molecular subtypes of patients with BWSsp.
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http://dx.doi.org/10.1016/j.jpeds.2019.05.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707865PMC
September 2019

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

Genet Med 2019 11 31;21(11):2644-2649. Epub 2019 May 31.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Purpose: Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management.

Methods: Three male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed.

Results: SNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism.

Conclusion: SNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.
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http://dx.doi.org/10.1038/s41436-019-0551-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848850PMC
November 2019

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

Epigenetics 2019 09 30;14(9):850-876. Epub 2019 May 30.

a Division of Animal Sciences, University of Missouri , Columbia , MO , USA.

The use of assisted reproductive technologies (ART) can induce a congenital overgrowth condition in humans and ruminants, namely Beckwith-Wiedemann syndrome (BWS) and large offspring syndrome (LOS), respectively. Shared phenotypes and epigenotypes have been found between BWS and LOS. We have observed global misregulation of transcripts in bovine foetuses with LOS. microRNAs (miRNAs) are important post-transcriptional gene expression regulators. We hypothesize that there is miRNA misregulation in LOS and that this misregulation is shared with BWS. In this study, small RNA sequencing was conducted to investigate miRNA expression profiles in bovine and human samples. We detected 407 abundant known miRNAs and predicted 196 putative miRNAs from the bovine sequencing results and identified 505 abundant miRNAs in human tongue. Differentially expressed miRNAs (DE-miRNAs) were identified between control and LOS groups in all tissues analysed as well as between BWS and control human samples. DE-miRNAs were detected from several miRNA clusters including DLK1-DIO3 genomic imprinted cluster in LOS and BWS. DNA hypermethylation was associated with downregulation of miRNAs in the DLK1-DIO3. mRNA targets of the DE-miRNAs were predicted and signalling pathways associated with control of organ size (including the Hippo signalling pathway), cell proliferation, apoptosis, cell survival, cell cycle, and cell adhesion were found to be enriched with these genes. Yes associated protein 1 (YAP1) is the core effector of the Hippo signalling pathway, and increased level of active (non-phosphorylated) YAP1 protein was detected in skeletal muscle of LOS foetuses. Overall, our data provide evidence of miRNA misregulation in LOS and BWS.
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http://dx.doi.org/10.1080/15592294.2019.1615357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691986PMC
September 2019

Diagnosis and management of the phenotypic spectrum of twins with Beckwith-Wiedemann syndrome.

Am J Med Genet A 2019 07 8;179(7):1139-1147. Epub 2019 May 8.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum. There is an increased prevalence of monozygotic twinning in BWS. Given the epigenetic nature and phenotypic spectrum that defines BWS, twins are often discordant for clinical features, and clinicians are faced with the challenge of diagnosing and managing these twins. We present a cohort of multiple pregnancies in which one or more child from each pregnancy was diagnosed with BWS. We conducted a chart review of monochorionic and dichorionic gestations. Clinical scores for monochorionic twins demonstrated phenotypic discordance between the proband and twin. Based on linear regression analysis, a higher clinical score in the proband correlated with larger phenotypic discordance between twin siblings. Despite phenotypic discordance, however, we observed a consistent additive clinical score for a pregnancy (proband's plus twin's scores from a pregnancy). This idea of a finite degree of affectedness for a pregnancy implies a finite number of epigenetically affected cells. This further corroborates the idea that timing of monozygotic monochorionic twinning correlates with the disruption of establishment and/or maintenance of imprinting. The difference in clinical score between a proband and their twin may be due to diffused mosaicism, whereby there is an asymmetric distribution of affected cells among the multiple fetuses in a monozygotic monochorionic pregnancy, leading to a spectrum of variably affected phenotypes. Based on these findings, we recommend an algorithm for a conservative approach to clinically evaluate all children in a monozygotic multiple gestation affected by BWS.
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http://dx.doi.org/10.1002/ajmg.a.61164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959854PMC
July 2019

Obstructive Sleep Apnea in Children With Beckwith-Wiedemann Syndrome.

J Clin Sleep Med 2019 03 15;15(3):375-381. Epub 2019 Mar 15.

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Study Objectives: Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder that includes a spectrum of clinical findings including macroglossia, especially in those with loss of methylation at the imprinting control region (IC2 LOM) on chromosome 11. Children with BWS can have very severe obstructive sleep apnea (OSA), but the prevalence of OSA in this population is poorly understood, as is the relationship between OSA and the BWS genotype/phenotype. We hypothesized that there would be a high prevalence of OSA in children with BWS, and that OSA would be more severe in children with IC2 LOM.

Methods: Medical records from children evaluated from March 2015 through January 2018 were reviewed for results from polysomnography, genetic testing, and clinical assessment.

Results: A total of 26 children with BWS not previously treated for OSA underwent polysomnography, genetic testing, and clinical assessment. Median (range) age was 5 months (3 days to 33 months). Most children, 20 (76.9%), had an obstructive apnea-hypopnea index (OAHI) > 2 events/h. Median (range) OAHI was 4.4 events/h (0 to 56.1 events/h). OAHI was significantly greater in participants younger than 6 months compared with those older than 6 months ( = .008). Those with IC2 LOM did not have a greater OAHI ( = .61) than those with other genetic causes of BWS, but OAHI had a strong positive correlation with BWS clinical score (Spearman rho = .54, = .004).

Conclusions: There is a high prevalence of OSA in children with BWS with macroglossia. Younger children with BWS and those with more phenotypic features may be at greatest risk of OSA.
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http://dx.doi.org/10.5664/jcsm.7656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411187PMC
March 2019

Pediatric chondrodermatitis nodularis helicis (CNH) in a child with Beckwith-Wiedemann syndrome (BWS).

Pediatr Dermatol 2019 May 17;36(3):388-390. Epub 2019 Feb 17.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Chondrodermatitis nodularis helicis is an idiopathic degenerative process that presents as a painful nodule, papule, or ulcer on the helix or antihelix. It predominantly affects adults and is thought to be associated with trauma to the ear. We describe a case of pediatric chondrodermatitis nodularis helicis occurring in a child with a history of Beckwith-Wiedemann syndrome that was successfully treated with an excisional biopsy and relief from a recurrent source of pressure on the ear.
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http://dx.doi.org/10.1111/pde.13765DOI Listing
May 2019

Molecular diagnosis of somatic overgrowth conditions: A single-center experience.

Mol Genet Genomic Med 2019 03 13;7(3):e536. Epub 2019 Feb 13.

Genetic Diagnostic Laboratory, Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Somatic overgrowth conditions, including Proteus syndrome, Sturge-Weber syndrome, and PIK3CA-related overgrowth spectrum, are caused by post-zygotic pathogenic variants, result in segmental mosaicism, and give rise to neural, cutaneous and/or lipomatous overgrowth. These variants occur in growth-promoting pathways leading to cellular proliferation and expansion of tissues that arise from the affected cellular lineage.

Methods: We report on 80 serial patients evaluated for somatic overgrowth conditions in a diagnostic laboratory setting, including three prenatal patients. In total, 166 tissues from these 80 patients were subjected to targeted sequencing of an 8-gene panel capturing 10.2 kb of sequence containing known pathogenic variants associated with somatic overgrowth conditions. Deep next-generation sequencing was performed with the IonTorrent PGM platform at an average depth typically >5,000×.

Results: Likely pathogenic or pathogenic variants were identified in 36 individuals and variants of unknown significance in four. The overall molecular diagnostic yield was 45% but was highly influenced by both submitted tissue type and phenotype. In the prenatal setting, two patients had pathogenic variants identified in cultured amniocytes but in a third patient, the pathogenic variant was only present in post-natal tissues. Finally, expanding the test to include full gene sequencing of PIK3CA in contrast to targeted sequencing identified likely pathogenic variants in 3 of 7 patients that tested negative on the original panel.

Conclusion: Next-generation sequencing has enabled sensitive detection of somatic pathogenic variants associated with overgrowth conditions. However, as the pathogenic variant allele frequency varies by tissue type within an individual, submission of affected tissue(s) greatly increases the chances of a molecular diagnosis.
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http://dx.doi.org/10.1002/mgg3.536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418364PMC
March 2019

Hyperinsulinemic hypoglycemia in seven patients with de novo NSD1 mutations.

Am J Med Genet A 2019 04 4;179(4):542-551. Epub 2019 Feb 4.

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features and intellectual disability caused by haploinsufficiency of the NSD1 gene. Genotype-phenotype correlations have been observed, with major anomalies seen more frequently in patients with 5q35 deletions than those with point mutations in NSD1. Though endocrine features have rarely been described, transient hyperinsulinemic hypoglycemia (HI) of the neonatal period has been reported as an uncommon presentation of Sotos syndrome. Eight cases of 5q35 deletions and one patient with an intragenic NSD1 mutation with transient HI have been reported. Here, we describe seven individuals with HI caused by NSD1 gene mutations with three having persistent hyperinsulinemic hypoglycemia. These patients with persistent HI and Sotos syndrome caused by NSD1 mutations, further dispel the hypothesis that HI is due to the deletion of other genes in the deleted 5q35 region. These patients emphasize that NSD1 haploinsufficiency is sufficient to cause HI, and suggest that Sotos syndrome should be considered in patients presenting with neonatal HI. Lastly, these patients help extend the phenotypic spectrum of Sotos syndrome to include HI as a significant feature.
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http://dx.doi.org/10.1002/ajmg.a.61062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454923PMC
April 2019

Beckwith-Wiedemann syndrome in diverse populations.

Am J Med Genet A 2019 04 4;179(4):525-533. Epub 2019 Feb 4.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Beckwith-Wiedemann syndrome (BWS) is the most common epigenetic overgrowth disorder and presents with patients affected by a variety of clinical features. Although genotype-phenotype correlations have been demonstrated in BWS and although BWS has been reported to occur equally among racial and ethnic backgrounds, no study to date has evaluated the frequency of findings in different backgrounds. In this study, we evaluated the incidence of clinical features and molecular diagnoses among patients with BWS in Caucasian, Mixed, and non-Caucasian groups. These results suggest that clinical features and molecular diagnoses differ between race/ethnicity groups and raise the possibility of race and ethnicity effects on genotype-phenotype correlations in BWS.
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http://dx.doi.org/10.1002/ajmg.a.61053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454922PMC
April 2019

Longitudinal Monitoring of Alpha-Fetoprotein by Dried Blood Spot for Hepatoblastoma Screening in Beckwith⁻Wiedemann Syndrome.

Cancers (Basel) 2019 Jan 14;11(1). Epub 2019 Jan 14.

Department of Pediatrics and Public Health and Pediatric Sciences, University of Torino, 10126 Torino, Italy.

Background: Hepatoblastoma screening in the Beckwith⁻Wiedemann spectrum (BWSp) is currently based on measuring a specific serum marker alpha-fetoprotein (αFP) every three months until the fourth birthday. Frequent blood draws can be a burden for patients and their families.

Methods: We have developed a less invasive alternative testing method based on measuring αFPs from dried blood spots (DBS). The method was validated with 259 simultaneous plasma and DBS αFP measurements in 171 children (132 controls and 39 patients with BWSp).

Results: The DBS and plasma measurements overlapped across the wide range of αFP concentrations independent of patient age ( < 0.0001), demonstrating the utility of this method for longitudinal monitoring. Occasional differences between measurements by the two techniques fell within standard laboratory error and would not alter clinical management.

Conclusions: This novel method shows consistent overlap with the traditional blood draws, thereby demonstrating its utility for hepatoblastoma screening in this setting and alleviating the burden of frequent blood draws. This also may help increase patient compliance and reduce costs of health care screening. The DBS-based method for the measurement of cancer biomarkers may also be applied to several other chronic diseases with increased risks of αFP-producing liver tumors.
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http://dx.doi.org/10.3390/cancers11010086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356556PMC
January 2019

Allele-specific RNA imaging shows that allelic imbalances can arise in tissues through transcriptional bursting.

PLoS Genet 2019 01 9;15(1):e1007874. Epub 2019 Jan 9.

Department of Bioengineering, University of Pennsylvania, Skirkanich Hall, Philadelphia, Pennsylvania, United States of America.

Extensive cell-to-cell variation exists even among putatively identical cells, and there is great interest in understanding how the properties of transcription relate to this heterogeneity. Differential expression from the two gene copies in diploid cells could potentially contribute, yet our ability to measure from which gene copy individual RNAs originated remains limited, particularly in the context of tissues. Here, we demonstrate quantitative, single molecule allele-specific RNA FISH adapted for use on tissue sections, allowing us to determine the chromosome of origin of individual RNA molecules in formaldehyde-fixed tissues. We used this method to visualize the allele-specific expression of Xist and multiple autosomal genes in mouse kidney. By combining these data with mathematical modeling, we evaluated models for allele-specific heterogeneity, in particular demonstrating that apparent expression from only one of the alleles in single cells can arise as a consequence of low-level mRNA abundance and transcriptional bursting.
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http://dx.doi.org/10.1371/journal.pgen.1007874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342324PMC
January 2019

Defining an optimal time window to screen for hepatoblastoma in children with Beckwith-Wiedemann syndrome.

Pediatr Blood Cancer 2019 01 30;66(1):e27492. Epub 2018 Sep 30.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Patients with Beckwith-Wiedemann spectrum (BWSp) undergo quarterly alpha-fetoprotein measurement for hepatoblastoma (HB) screening up to 4 years of age, paralleling the epidemiology of nonsyndromic HB. However, specific data on the timing of HB development in BWSp are lacking. Here we compare the timing of presentation of HBs in BWSp with a control cohort of consecutive HB cases, demonstrating that halving screening duration of screening procedures in BWSp likely will not impact its effectiveness.
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http://dx.doi.org/10.1002/pbc.27492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955797PMC
January 2019

Nonreentrant atrial tachycardia occurs independently of hypertrophic cardiomyopathy in RASopathy patients.

Am J Med Genet A 2018 08 28;176(8):1711-1722. Epub 2018 Jul 28.

Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts.

Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT.
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http://dx.doi.org/10.1002/ajmg.a.38854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107379PMC
August 2018