Faculty Bibliography

This is a comprehensive review and analysis of 254 cases tested consecutively in the in-house College of American Pathologist-accredited molecular genetics laboratory within the New York City Office of Chief Medical Examiner between October 2015 and February 2018, using a multigene cardiac panel composed of 95 genes associated with cardiac channelopathy and cardiomyopathy. Demographics, autopsy findings, medical history, and postmortem genetic testing results were collected for each case. The majority of decedents were adults (>25 years old, 52.7%), followed by infants (<12 months, 25.6%), young adults (19-25 years old, 11.4%), and children (1-18 years old, 10.2%). There were more males (64.2%) than females (35.8%). The racial/ethnic composition of decedents was 40.2% Black, 29.9% Hispanic, 22.4% White, 5.1% Asian/Pacific Islander, and 2.8% mixed/unspecified. Overall, 45.7% of decedents had a negative autopsy, and the remaining had one to four cardiac findings (cardiac hypertrophy, dilation, atherosclerosis, and fatty change). Twenty-seven pathogenic/likely pathogenic variants (P/LP) and 99 variants of uncertain significance (VUS) were identified in 10.6% and 39% of decedents respectively. P/LP and VUS were found in 51 cardiac genes of the total 95 genes, where MYBPC3, TTN (predicted truncating variants), KCNH2, RYR2 and DSP genes had more than two P/LP variants identified. Among the 73 decedents who were suspected of having cardiac arrhythmia or cardiomyopathy, 20.3% had P/LP variants and 47.9% had VUS; among 23 decedents who had hypertensive cardiovascular diseases and 20 decedents with a history of substance use, 13% and 30% had P/LP variants, respectively. There were 26 referrals from medical examiners for genetic counseling and the outcomes are discussed. The study demonstrates characteristics of the diverse population typically seen by medical examiners in an urban center and our results support a broader implementation of molecular testing in sudden death.

BACKGROUND:Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office. METHODS AND RESULTS/RESULTS:The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years). Eighty-nine cardiac disease genes were evaluated. Using a high-resolution variant interpretation workflow, we classified 17 variants as pathogenic or likely pathogenic (2 of which were incidental findings and excluded in testing yield analysis), 46 novel variants of uncertain significance, and 130 variants of uncertain significance. Nine pathogenic or likely pathogenic variants in ClinVar were reclassified to likely benign and excluded in testing yield analysis. The yields of positive cases by ethnicity and age were 21.4% in mixed ethnicities, 10.2% Whites, 4.5% Asians, 3.1% Hispanics, and 2% Blacks; 7.7% children, 7.3% in adults, 5.4% young adults, and 2.8% infants. The percentages of uncertain cases with variants of uncertain significance by ethnicity were 45.5% in Asians, 45.3% Hispanics, 44.20% Blacks, 36.7% Whites, and 14.3% in mixed ethnicities. CONCLUSIONS:High-resolution variant interpretation provides diagnostic accuracy and healthcare efficiency. Under-represented populations warrant greater inclusion in future studies.

Introduction/UNASSIGNED:Differences in certification of similar sudden infant deaths exists among forensic pathologists. This study sought to measure adherence to intra-agency guidelines for infant death certification in one jurisdiction and describe variables that may be associated with the differentiation of sudden infant death syndrome (SIDS), asphyxia, and undetermined death certifications. Methods/UNASSIGNED:A retrospective study of deaths at the New York City Office of Chief Medical Examiner identified 427 sudden infant deaths with investigation and autopsy whose cause of death was ruled SIDS, asphyxia, or undetermined. Cases were reviewed for number and types of risk factors for asphyxia, demonstrable evidence of asphyxia, potential competing causes of death, and a doll reenactment. Descriptive and statistical analysis was performed. Results/UNASSIGNED:Of 427 deaths, the causes of 100 deaths (23.4%) were ruled asphyxia; 43 (10.0%) SIDS; and 284 (66.5%) undetermined. Forensic pathologists conformed to agency guidelines in 406 deaths (95.1%). Three or more risk factors for asphyxia were found in 328 deaths (76.8%). Demonstrable evidence of asphyxia (40.7%) was most associated with a certification of asphyxia. A potential competing cause of death (20%) was most associated with undetermined. A doll reenactment had little association with certification type. Discussion/UNASSIGNED:Guidelines in one agency were effective at limiting incorrect SIDS diagnoses. The interpretation of risk factors can be subjective. Diagnostic overlap occurred in deaths certified differently as SIDS, asphyxia, and undetermined, despite similar findings. Elimination of SIDS as a certification option and better guidelines that help differentiate asphyxia and undetermined deaths are recommended for improved infant death certification.

BACKGROUND: Anxiety is linked with adverse health-related outcomes and increased health-seeking behaviors among patients with chronic illness. Yet, this relationship has received little attention in pediatric inflammatory bowel disease. The aim of this study was to examine whether anxiety symptoms predicted youth at increased risk for repeated disease relapse and greater gastrointestinal health care use over the subsequent 12 months. METHODS: Eighty-six pediatric patients aged 11 to 18 years (M = 14.7, SD = 2.0), and their caregivers completed a validated anxiety questionnaire during a gastrointestinal specialty appointment (baseline). Medical records were reviewed for the subsequent year to record the number of disease relapses and gastrointestinal health care services and generate disease activity scores at baseline and 12 months. Analysis of variance was used to examine anxiety levels between those who experienced /=2 disease relapses. Poisson regressions were used to model the relationship between child- and caregiver-reported anxiety and health care use, controlling for disease activity. RESULTS: The sample was predominantly white (81%) and male (56%). Patients with higher anxiety at baseline (M = 19.6; SD = 13.7) had more frequent (>/=2) disease relapses compared with those with lower anxiety at baseline (M = 12.6; SD = 10.3). Higher anxiety, irrespective of reporter, also predicted greater total gastrointestinal health care use (P < 0.01). This included hospital-based interventions (P < 0.01), but not office encounters or outpatient endoscopic procedures. Findings remained significant after controlling for disease severity (P < 0.05). CONCLUSIONS: Assessment of anxiety may be one mechanism by which to identify those youth who are most vulnerable for disease exacerbation and costly interventions in the near future.

Background: Home enteral nutrition (HEN) is a safe method for providing nutrition to children with chronic diseases. Advantages of HEN include shorter hospitalizations, lower cost, and decreased risk of malnutrition-associated complications. Follow-up after hospital discharge on HEN is limited. The purpose of this study was to look at children discharged on nasogastric (NG) feeds to assess follow-up feeding status and impact on growth. Methods: A retrospective chart review was conducted of pediatric patients discharged from Mount Sinai Medical Center on NG feeds between January 2010 and March 2013. Results: A total of 87 patients were included. Average age was 1.2 years. The most common diagnoses were congenital heart disease (47%), metabolic disease (17%), neurologic impairment (10%), liver disease (9%), prematurity (8%), and inflammatory bowel disease (6%). At most recent follow-up, 44 (50.6%) were on full oral feeds, 8 (9.2%) were still on NG feeds, 9 (10.3%) had a gastrostomy tube placed, 9 (10.3%) were deceased, and 17 (19.5%) had transferred care or were lost to follow-up. Average time to discontinuation of NG feeds was 4.8 months. Change in body mass index from hospital discharge to follow-up visit 6 to 12 weeks after discharge was statistically significant, from a mean (SD) of 13.78 (2.82) to 14.58 (2.1) (P = .02). Change in weight z score was significant for neurologic impairment (-1.35 to -0.04; P = .03). Height z score change was significant for prematurity (-3.84 to -3.34; P = .02). There was no significant change in height or weight z scores for the other diagnoses. Conclusions: NG feeds can help to improve short-term growth after hospital discharge in children with chronic illnesses.

Cantu syndrome is characterized by hypertrichosis, distinct facial features, cardiovascular abnormalities and a wide variety of phenotypes in many other organs and systems. This study is to illustrate clinical characters of Cantu syn-drome in cardiovascular system and to investigate etiology of this disease. Methods: Cantu syndrome cases were searched from PubMed. Clinical data were collected from previous reports. Descriptive analysis was conducted to study clinical char-acters of Cantu syndrome patients especially in cardiovascular system. Fisher’s exact test was used to examine if age of parents played a role in disease occurrence. Results: 60 Cantu syndrome patients were studied. 56/60 (93%) had congen-ital heart disease and/or cardiac diseases, including patent ductus arteriosus, atrial septal defect, coarctation of the aorta, bicuspid aortic valve, aortic stenosis, pulmonary stenosis, aortopulmonary collateral artery, partial anomalous pulmonary venous return, cardiomegaly, hypertrophic/dilated/noncompaction cardiomyopathy, pericardial effusion or heart failure. 10/60 (16.7%) patients developed transient or persistent pulmonary hypertension. Most of the cases were sporadic. More patients were born to father at age>35 when compared with normal population and the result was statistically significant. 3 (5%) patients died in infancy or in childhood while 57 patients were alive during last follow up. More than half of the pa-tients were seen in 0-10 age group. Conclusions: The disease presented a wide variety of clinical presentations and different severity. Besides hypertrichosis and osteochondrodysplasia, there was high penetrance of cardiovascular phenotypes. Some of the clinical manifestations resolved spontaneously. Patients were more frequently observed in 0-10 age group in the clinic. Advanced father’s age played a role in disease occurrence

Inflammatory bowel disease (IBD) is considered as genetic disease due to observation of familial clustering of cases, genetic anticipation between generations and phenotypic concordance of some clinical features within families. Current knowledge of genes/loci associated IBD was largely developed by genome wide association studies which is common disease-common variant analysis strategy. With heterogeneity character and disease incidence of 4.75/100,000/year for Crohn’s disease and 2.06/100,000/year for ulcerative colitis in pediatric population, targeted resequencing and whole exome sequencing for the identification of rare pathogenic variants in known or novel genes are becoming more applicable for IBD genetic studies. According to chromosomal locus of genetic susceptibility, IBD was classified into 28 subtypes. According to functions and pathogenesis, genes involved in IBD can be classified into three groups including inflammation, immune regulation, and cel-lular adhesion/epithelial barrier integration. Genes regulate cell cycle, dysplasia or adhesion may be associated with cancer development in patients with long-standing IBD. Identification of casual genes/variants will be significant for diagnosis, treatment, prevention, cancer surveillance and improved health care for IBD patients

OBJECTIVES:: Children and adolescents diagnosed with Crohn's disease (CD), a type of inflammatory bowel disease (IBD), have increased vulnerability for anxiety symptoms that may be related to disease-related processes. The aims of this paper are threefold: 1) to report the proportion of pediatric CD patients whose self-reported anxiety symptoms are indicative of distress; 2) to describe the constellation of anxiety symptoms; and 3) to examine the relationship between anxiety and disease symptoms. METHODS:: Retrospective medical chart review was performed for 93 youths with CD (ages 9-18) who had completed the Screen for Child Anxiety Related Disorders (SCARED) during their gastroenterology visit. Medical records were reviewed for demographic and disease characteristics. Harvey Bradshaw Index (HBI) was used as a measure of CD activity. RESULTS:: Thirty percent of the youths reported experiencing elevated anxiety symptoms (SCARED score >20) and 50% had scored above cutoff in one or more anxiety domains, with school anxiety, general anxiety, and separation anxiety symptoms reported most frequently. Youth rated with moderate/severe disease activity on the HBI (n = 4) self-reported more anxiety symptoms compared to youth with inactive disease (n = 78; p = .03). Greater school anxiety was significantly associated with decreased well-being (p = .003), more abdominal pain (p < .001), and the number of loose stools (p = .01). Having extraintestinal symptoms was significantly associated with higher somatic/panic anxiety (p = .01). CONCLUSIONS:: Implementing a brief anxiety screen in tertiary pediatric settings may be one approach to identify young patients with CD in distress. Health providers should consider periodic assessment of school anxiety among youth with CD.

Pulmonary capillary hemangiomatosis (PCH) is a pulmonary vascular disease that mainly affects small capillaries in the lung, and is often misdiagnosed as pulmonary arterial hypertension or pulmonary veno-occlusive disease due to similarities in their clinical presentations, prognosis, and management. In patients who are symptomatic, there is a high mortality rate with median survival of 3 years after diagnosis. Both idiopathic and familial PCH cases are being reported, indicating there is genetic component in disease etiology. Mutations in the eukaryotic translation initiation factor 2alpha kinase 4 (EIF2AK4) gene were identified in familial and idiopathic PCH cases, suggesting EIF2AK4 is a genetic risk factor for PCH. EIF2AK4 mutations were identified in 100% (6/6) of autosomal recessively inherited familial PCH and 20% (2/10) of sporadic PCH cases. EIF2AK4 is a member of serine/threonine kinases. It downregulates protein synthesis in response to a variety of cellular stress such as hypoxia, viral infection, and amino acid deprivation. Bone morphogenetic protein receptor 2 (BMPR2) is a major genetic risk factor in pulmonary arterial hypertension and EIF2AK4 potentially connects with BMPR2 to cause PCH. L-Arginine is substrate of nitric oxide synthase, and L-arginine is depleted during the production of nitric oxide, which may activate EIF2AK4 to inhibit protein synthesis and negatively regulate vasculogenesis. Mammalian target of rapamycin and EIF2alpha kinase are two major pathways for translational regulation. Mutant EIF2AK4 could promote proliferation of small pulmonary arteries by crosstalk with mammalian targets of the rapamycin signaling pathway. EIF2AK4 may regulate angiogenesis by modulating the immune system in PCH pathogenesis. The mechanisms of abnormal capillary angiogenesis are suggested to be similar to that of tumor vascularization. Specific therapies were developed according to pathogenesis and are proved to be effective in reported cases. Targeting the EIF2AK4 pathway may provide a novel therapy for PCH.