Lessons learned from testing cardiac channelopathy and cardiomyopathy genes in individuals who died suddenly: A two-year prospective study in a large medical examiner's office with an in-house molecular genetics laboratory and genetic counseling services.

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.

Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths.

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: 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.

Sudden Unexpected Infant Death Certification in New York City: Intra-Agency Guideline Compliance and Variables that May Influence Death Certification.

INTRODUCTION: 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: 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: 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: 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.

Patient-reported Anxiety: A Possible Predictor of Pediatric Inflammatory Bowel Disease Health Care Use.

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 ≤1 versus ≥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.

Home Nasogastric Feeds: Feeding Status and Growth Outcomes in a Pediatric Population.

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.

Pulmonary capillary hemangiomatosis: a focus on the EIF2AK4 mutation in onset and pathogenesis.

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 2α 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 EIF2α 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.

Anxiety symptoms and disease severity in children and adolescents with Crohn disease.

OBJECTIVES: Children and adolescents diagnosed as having Crohn 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 article are 3-fold: to report the proportion of pediatric patients with CD whose self-reported anxiety symptoms are indicative of distress, to describe the constellation of anxiety symptoms, and to examine the relation between anxiety and disease symptoms. METHODS: Retrospective medical chart review was performed for 93 youths with CD (ages 9-18 years) who had completed the Screen for Child Anxiety Related Disorders during their gastroenterology visit. Medical records were reviewed for demographic and disease characteristics. the Harvey-Bradshaw Index (HBI) was used as a measure of CD activity. RESULTS: Thirty percent of the youths reported experiencing elevated anxiety symptoms (Screen for Child Anxiety Related Disorder score >20), and 50% had scored above the cutoff in 1 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 with youth with inactive disease (n = 78, P = 0.03). Greater school anxiety was significantly associated with decreased well-being (P = 0.003), more abdominal pain (P < 0.001), and the number of loose stools (P = 0.01). Having extraintestinal symptoms was significantly associated with higher somatic/panic anxiety (P = 0.01). CONCLUSIONS: Implementing a brief anxiety screen in tertiary pediatric settings may be one approach to identify young patients with CD in distress. Health care providers should consider periodic assessment of school anxiety among youth with CD.

Complementary and alternative medicine use at a single pediatric inflammatory bowel disease center.

The aim of this study was to determine the use of complementary and alternative medicine (CAM) in an inflammatory bowel disease population at a single pediatric center. The secondary aims were to determine predictors of CAM use and assess parental attitude to CAM use. A survey was developed that was distributed electronically and given out in the clinic. Two hundred thirty-five surveys were analyzed. Thirty-six percent of respondents reported that their children had used CAM, while 19.6% were current users. Sixty-three percent of respondents were "extremely" or "very supportive" of CAM and 57.6% would have been "extremely" or "very supportive" at the time of their children's diagnosis. The most commonly used CAM modalities were fish oil (48.8%), probiotics (22.5%), acupuncture/pressure (17.5%), aloe (16.3%), yoga/meditation (16.3%), chiropractic (12%), and herbal medicine (13.8%). Multivariate analysis revealed 2 independent factors predictive of subjects using CAM: use of biologics (odds ratio of 2.8; p = .008) and subjects' parent using CAM (odds ratio of 10.9; p ≤ .001). More than one third of children in this study and their parents have used CAM. Families are supportive of CAM both at the time of diagnosis and as an ongoing component of their child's treatment even if they were not past or current users of CAM. Predictors of CAM use were treatment with a biologic and having a parent who used CAM.

Percutaneous endoscopic gastrostomy tubes in pediatric bone marrow transplant patients.

BACKGROUND AND OBJECTIVES: Nourishing a child undergoing bone marrow transplant (BMT) is essential, but the optimal method to achieve this is not established. The objectives of the study were to investigate the incidence and risk factors for complications of gastrostomy tubes in patients with BMT. METHODS: A retrospective chart review was conducted of pediatric patients who received a percutaneous endoscopic gastrostomy (PEG) either for BMT or for other indications during a 3-year period. Occurrences of complications, absolute neutrophil count (ANC) at time of PEG placement, and ANC at time of complication were reviewed for both BMT and the comparison group. RESULTS: Of the 11 subjects in the BMT group, 4 (36%) had a major complication of infection related to PEG and 3 of those required PEG removal. Two of the 4 subjects who developed a major complication were moderately neutropenic at the time of PEG placement and all subjects were neutropenic at the time of complication. Of the 30 subjects in the comparison group, only 1 (2.8%) had a major complication with cellulitis. There were no statistically significant differences between the 2 groups before PEG placement for age, weight, albumin, or white blood cell count. The incidence of complication in BMT compared with the comparison group was significant (P=0.01). CONCLUSIONS: Our findings support that ANC should be considered before placement of PEG, significant neutropenia may be a contraindication for PEG placement in BMT patients, and other modalities for nutrition support might need to be considered.

Reoperative parathyroidectomy: location of missed glands based on a contemporary nomenclature system.

OBJECTIVES: To evaluate and categorize the locations of missed parathyroid glands found during reoperative parathyroidectomy and to determine any factors associated with these locations. DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Fifty-four patients who underwent reoperative parathyroidectomy for persistent or recurrent hyperparathyroidism from January 1, 2005, through January 1, 2009. MAIN OUTCOME MEASURES: Location of missed parathyroid glands and their association with continuous variables were analyzed using a Kruskal-Wallis test, and associations between gland location and categorical variables were evaluated using the Fisher exact test. RESULTS: Among 54 patients, 50 abnormal parathyroid glands were identified, resected, and classified as follows: 5 (10%) were type A (adherent to the posterior thyroid capsule); 11 (22%), type B (behind the thyroid in the tracheoesophageal groove); 7 (14%), type C (close to the clavicle in the prevertebral space); 3 (6%), type D (directly over the recurrent laryngeal nerve); 9 (18%), type E (easy to identify; near the inferior thyroid pole); 13 (26%), type F (fallen into the thymus); and 2 (4%), type G (gauche, within the thyroid gland). No demographic, biochemical, or pathological factors were significantly associated with gland location. Among the 43 patients followed up for 6 months, 40 (93%) had documented cures. CONCLUSIONS: Missed glands after parathyroidectomy for hyperparathyroidism can be found in standard locations in most cases. A standardized nomenclature system based on the regional anatomy and the embryology of the parathyroid glands can guide a systematic exploration for parathyroid adenomas that are not easily identified and facilitate communication about gland locations.

Outpatient minimally invasive parathyroidectomy is safe for elderly patients.

BACKGROUND: Elderly patients with primary hyperparathyroidism (PHPT) are often not referred for surgical intervention because of concern of comorbid conditions that may increase perioperative complications. Because PHPT is more common in the elderly, we sought to compare indications and complications of minimally invasive parathyroidectomy in patients 70 years of age and older (elderly) with their younger counterparts. STUDY DESIGN: A review was conducted of a prospectively collected database of all patients undergoing parathyroidectomy on our endocrine surgery service. Data collected included patient demographic, biochemical pathologic, and operative findings. Wilcoxon rank sum and chi-square tests were used for comparisons. RESULTS: Three hundred eighty-eight patients with PHPT recently underwent parathyroidectomy over a 3-year period (elderly, n=101; younger, n=287). The elderly cohort had significantly higher median preoperative creatinine (elderly, 2.0 mg/dL; younger,1.0 mg/dL; p=0.002) and parathyroid hormone (elderly, 145 pg/mL; younger, 123 pg/mL; p=0.026) levels. The elderly cohort also had more severe osteoporosis, with a significantly worse median bone mineral density T-score (elderly, -2.5; younger, -1.8; p<0.001). The rate of postoperative complications was similarly low in both groups (elderly, 5.9%; younger, 3.5%; p=0.38). CONCLUSIONS: Minimally invasive parathyroidectomy for PHPT can be performed as safely in elderly patients as in their younger counterparts. Elderly patients with PHPT are more likely to have osteoporosis and higher creatinine levels at the time of surgical referral. Additional study of the role of earlier intervention is warranted.

Posterior retroperitoneoscopic adrenalectomy: preferred technique for removal of benign tumors and isolated metastases.

OBJECTIVE: Posterior retroperitoneoscopic adrenalectomy (PRA) is a minimally invasive approach to removal of the adrenal gland. This anatomically direct approach, popularized by Walz, minimizes dissection and affords early access to the adrenal vein. We report the largest experience to date of PRA in the United States. METHODS: The prospective endocrine surgery database at a tertiary care center was used to capture all patients who underwent PRA between October 2005 and February 2008. All PRA procedures were performed using a 3-trocar technique with the patient in a prone jackknife position. RESULTS: Sixty-eight PRAs were performed in 62 patients; there were 6 conversions (3 video-assisted and 3 open). Indications for adrenalectomy were functional tumors in 43 patients (20 pheochromocytomas, 13 Cushing disease or syndrome, and 10 others), nonfunctional cortical adenomas in 4, and isolated adrenal metastases in 15. Mean tumor size was 3.4 cm. Complications occurred in 11 patients (16%), with no perioperative deaths. In 34 (55%) patients, there was a relative contraindication to an anterior approach. Additionally, 20 patients (38%) had a body mass index greater than 30. Median operating time was 121 minutes. CONCLUSION: PRA is safe, avoids intra-abdominal adjacent organ mobilization, is unaffected by the presence of intra-abdominal adhesions, and is possible in obese patients. PRA may be the preferred technique for removing benign adrenal tumors and isolated metastases.

Viability of cryopreserved parathyroid tissue: when is continued storage versus disposal indicated?

BACKGROUND: Parathyroid cryopreservation is used for potential autografting in patients who are rendered hypocalcemic following surgery. Cryopreservation employs multiple resources and carries a significant cost for processing and storage of tissue. Importantly, the length of time that parathyroid tissue remains functional after cryopreservation is not known. The goal of our study was to assess ex-vivo viability of parathyroid tissue in relation to the length of time in storage. We sought to define the appropriate time frame for tissue utilization and disposal to assist with long-term surgical planning. METHODS: From 1991 to 2006, 501 parathyroid specimens from 149 patients were cryopreserved at -80 degrees C according to standardized techniques. A single trained technician assessed viability, using a hemacytometer to count viable (clear cell) and nonviable (blue cell) tissue. Univariate analysis was performed to correlate length of preservation, diagnosis with viability. RESULTS: We evaluated 106 random parathyroid specimens. Samples were divided into two groups: those stored>24 months and those stored24 months (p<0.001). CONCLUSIONS: Viability of cryopreserved parathyroid cells is associated with duration of storage. Parathyroids preserved for greater than 24 months are unlikely to be viable. It seems reasonable to limit parathyroid cryopreservation to 24 months when frozen at -80 degrees C. Further studies are needed to optimize the process of cryopreservation to enhance cell viability.