Noncardiac genetic predisposition in sudden infant death syndrome.

PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls. METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis. RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS. CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.

Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome.

OBJECTIVE: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. STUDY DESIGN: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole-exome sequencing. Exome-wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole-exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinic's Medical Genome Facility, Rochester, Minnesota. RESULTS: Although no exome-wide significant (P < 2.5 × 10-6) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra-rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). CONCLUSIONS: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.

Systematic review and meta-analysis of appendiceal carcinoid tumors in children.

OBJECTIVE: The study's aim was to review the literature regarding past and current practices in managing incidental appendiceal carcinoid tumors and need for more procedures. METHOD: A search of MEDLINE, Embase, CINAHL, and Cochrane databases of systematic reviews was undertaken of the English language literature. The mesh terms used were "carcinoid" or "neuroendocrine," "tumour" or "tumor," "appendix," "appendicectomy," or "appendectomy," and "child," "pediatric," or "paediatric." Of the 369 articles found, 37 met the inclusion criteria. Our hospital records and pathology database identified 11 patients with confirmed histological diagnosis of appendicular carcinoids from January 1996 to December 2016. Those cases were also included in this study. RESULTS: A total of 958 cases were identified from the literature and our own experience. There were 566 females and 343 males giving us a ratio of 1.65:1. The frequency was 0.3% of appendicectomies. There was a 28-fold increase in the risk of having a positive lymph node if the tumor size was >2 cm compared with the risk of having a positive lymph node if the tumor size was ≤2 cm. There was no recurrence or mortality for those with criteria for secondary surgery, who were observed after appendicectomy compared to those that had secondary surgery. Mean follow-up was 58.6 months (4.8 years) with a range of 0-396 months (33 years). CONCLUSION: Appendicectomy alone is an adequate treatment for an appendicular carcinoid in children irrespective of size, position, lymph node, or mesenteric involvement. Post-appendicectomy investigations were found to be not helpful in this study.

Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS. METHODS: We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system. FINDINGS: Four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057). INTERPRETATION: Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths. FUNDING: UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

Cardiac Genetic Predisposition in Sudden Infant Death Syndrome.

BACKGROUND: Sudden infant death syndrome (SIDS) is a leading cause of postneonatal mortality. Genetic heart diseases (GHDs) underlie some cases of SIDS. OBJECTIVES: This study aimed to determine the spectrum and prevalence of GHD-associated mutations as a potential monogenic basis for SIDS. METHODS: A cohort of 419 unrelated SIDS cases (257 male; average age 2.7 ± 1.9 months) underwent whole exome sequencing and a targeted analysis of 90 GHD-susceptibility genes. The yield of "potentially informative," ultra-rare variants (minor allele frequency <0.00005) in GHD-associated genes was assessed. RESULTS: Overall, 53 of 419 (12.6%) SIDS cases had ≥1 "potentially informative," GHD-associated variant. The yield was 14.9% (21 of 141) for mixed-European ancestry cases and 11.5% (32 of 278) for European ancestry SIDS cases. Infants older than 4 months were more likely to host a "potentially informative" GHD-associated variant. There was significant overrepresentation of ultra-rare nonsynonymous variants in European SIDS cases (18 of 278 [6.5%]) versus European control subjects (30 of 973 [3.1%]; p = 0.013) when combining all 4 major cardiac channelopathy genes (KCNQ1, KCNH2, SCN5A, and RYR2). According to the American College of Medical Genetics guidelines, only 18 of 419 (4.3%) SIDS cases hosted a "pathogenic" or "likely pathogenic" variant. CONCLUSIONS: Less than 15% of more than 400 SIDS cases had a "potentially informative" variant in a GHD-susceptibility gene, predominantly in the 4- to 12-month age group. Only 4.3% of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families.

Embolism of brain tissue in intrapartum and early neonatal deaths: report of 9 cases.

We report the clinical features and pathological findings in 9 cases of intrapartum and early neonatal death associated with embolism of brain tissue to the pulmonary and systemic circulation following difficult delivery. All except 1 of the cases in this series were born at, or near to, term, were vertex presentations, and were normally grown. All followed instrumental delivery and in 5, at least one mode of assisted delivery had failed. Whilst some evidence of cranial trauma was present in 7 cases, only 3 had skull fractures and 7 showed intracranial hemorrhage, although this was described as minor in 3. Emboli of brain tissue were identified in the pulmonary circulation in all cases. Fragments of brain were also seen in vessels of other organs, in particular the heart, in 6 cases. Emboli were highlighted by immunostaining for glial fibrillary acid protein. Brain emboli should be sought in all post mortems of unexplained intrapartum or early neonatal death following difficult delivery, even in the absence of overt cranial trauma. Disseminated intravascular coagulation is a frequent association. Extensive sampling for histology, particularly of the lungs and coronary vessels, is essential if this condition is not to be missed.

Congenital vascular malformations: a series of five prenatally diagnosed cases.

In the literature there are single case reports of mediastinal/chest and limb combined vascular malformations (previously labeled "hemangiolymphangiomas"). A variable outcome in such prenatally diagnosed cases is reported. Presented here is the only series of patients reported with these macrocystic, predominantly lymphatic malformations. Prenatal ultrasound scan and post-mortem examination findings are described. In our experience the outcome has been poor and this highlights the dilemma faced by clinicians and parents when these lesions are diagnosed prenatally. We present a series of five, prenatally diagnosed vascular (combined vascular malformations and simple localized lymphatic malformations) malformations. Three cases had lower leg involvement with extension into the abdomen and two cases had lymphatic malformations of the chest wall with involvement of the upper limb(s). Management of a twin pregnancy, in which one twin was affected, is described. In two cases, termination of pregnancy was undertaken because of the extensive nature of the lesion. One case died in utero and one in the neonatal period. The fifth case is an 11-year-old boy, whose lower limb deformity illustrates the considerable morbidity associated with this condition.

Oral clindamycin and histologic chorioamnionitis in women with abnormal vaginal flora.

OBJECTIVE: Oral clindamycin reduced late miscarriage and preterm birth in asymptomatic women with bacterial vaginosis or intermediate flora. We investigated whether clindamycin reduced the incidence of histologic chorioamnionitis as a mechanism for these beneficial effects. METHODS: This was a subanalysis of 126 participants from a larger randomized controlled trial. We compared the incidence of histologic chorioamnionitis between the clindamycin and placebo groups. Histologic chorioamnionitis was diagnosed by the presence of polymorphonuclear leukocytes, separately in the amnion and chorion, decidua, fetal surface of the placenta, the walls of fetal chorionic vessels, umbilical cord, or in the subchorionic fibrin layer. Microbiologic cultures were done on swabs from the space between the chorion and amnion layers. RESULTS: Histopathologic results were available for 122 placentas, 62 (51%) and 60 (49%) in the clindamycin and placebo groups, respectively. There were no significant differences in inflammation between the groups in the decidua (41% compared with 43%), membranes (25% compared with 41%), fetal vessels (16% compared with 14%), or subchorionic fibrin (32% compared with 34%). Adjusting for gestational age, ethnic origin, or history of miscarriage did not alter the results. There were no significant differences in the outcomes of pregnancy between women with and without inflammation, either before or after adjustment for treatment group. CONCLUSION: Although oral clindamycin reduced late miscarriage and preterm birth in women with abnormal vaginal flora, this effect is unlikely to be mediated through a reduction in the incidence of histologic chorioamnionitis. The relatively small size of the groups, however, does not allow us to rule out a real effect, especially given the lower rate of membrane inflammation observed in the clindamycin group. LEVEL OF EVIDENCE: I.

Clinical features of molecular pathology of solid tumours in childhood.

The outlook for children with cancer has improved substantially over the past 20 years, with over three-quarters of children now surviving in the long term. Better use of existing cytotoxic drugs and supportive care have made large contributions, but some of the improvement in survival is due to a greater knowledge of childhood cancer at the cellular and molecular levels. As in leukaemias, several childhood solid tumours carry balanced chromosomal translocations, resulting in fusion genes that encode chimeric proteins with new oncogenic properties. Many of these fusion genes, and other genetic aberrations are tumour specific and are related to outcome. Tumour biology now plays an important part in identifying appropriate treatment through more accurate diagnoses and new risk stratifications based on molecular markers.

A newly recognized autosomal recessive syndrome with abnormal vertebral ossification, rib abnormalities, and nephrogenic rests.

We describe three cases of a severe malformation syndrome in siblings of both sexes. The characteristic features observed were absent intrauterine ossification of an apparently normal cartilaginous spinal column; rib abnormalities, with unossified segments and posterior gaps; thoracic hypoplasia; and multiple intralobar nephrogenic rests in the kidneys. This syndrome can be identified in early pregnancy by ultrasound scans due to the lack of ossification of the thoraco-lumbar spine and its association with increased nuchal translucency thickness. We suggest that this is a newly recognized autosomal recessive syndrome.

The critical role of perinatal pathology.

In spite of great advances in imaging and biochemistry, histological examination of tissues remains a vital part of the multidisciplinary approach to the prevention of the onset, morbidity and mortality of preterm birth. There has been increasing interest in the role of infection and inflammatory cytokines in causation both of early labour and the white matter damage in the brain of preterm infants. However, labour itself is associated with the build up of increased numbers of inflammatory cells in the uterine cervix and increased concentrations of inflammatory cytokines and positive microbiological cultures may reflect carriage or contamination. Confirmation of an infective aetiology in an individual case is best achieved by demonstration of a pathological inflammatory response in tissues, for example, by showing the presence of chorioamnionitis in the placenta. A proper understanding of the poor response to neonatal intensive care of some preterm babies often requires histological examination of the lungs after death, where unsuspected pneumonia, interstitial emphysema and/or pulmonary hypoplasia may help provide an explanation for the adverse outcome in individual cases. The pathophysiological mechanism of brain injury in preterm infants is undergoing re-evaluation, and the systemic study of brain tissue using the latest histological techniques may elucidate the importance of apoptosis in this situation and could point the way towards an effective preventative strategy. Paediatric pathology is also essential to explain many cases of sudden unexpected death in preterm infants, as demonstrated by the recent realisation that death may be caused by total parenteral nutrition fluid-associated myocardial necrosis, and acute cardiac tamponade.