Sudden Death in a Child With Ocular Lesions.

This case report describes a patient treated for ocular lesions who died suddenly at age 8 years and was diagnosed postmortem with Carney complex.

Multiomic Analysis of Neuroinflammation and Occult Infection in Sudden Infant Death Syndrome.

Importance: Antemortem infection is a risk factor for sudden infant death syndrome (SIDS)-the leading postneonatal cause of infant mortality in the developed world. Manifestations of infection and inflammation are not always apparent in clinical settings or by standard autopsy; thus, enhanced resolution approaches are needed. Objective: To ascertain whether a subset of SIDS cases is associated with neuroinflammation and occult infection. Design, Setting, and Participants: In this case-control study, postmortem fluids from SIDS cases and controls collected between July 2011 and November 2018 were screened for elevated inflammatory markers, specifically cerebrospinal fluid (CSF) neopterin and CSF and serum cytokines. CSF, liver, and brain tissue from SIDS cases with elevated CSF neopterin were subjected to metagenomic next-generation sequencing (mNGS) to probe for infectious pathogens. Brainstem tissue from a subset of these cases was analyzed by single-nucleus RNA sequencing (snRNAseq) to measure cell type-specific gene expression associated with neuroinflammation and infection. All tissue and fluid analyses were performed from April 2019 to January 2023 in a pathology research laboratory. Included was autopsy material from infants dying of SIDS and age-matched controls dying of known causes. Exposures: There were no interventions or exposures. Main Outcomes and Measures: CSF neopterin levels were measured by high-performance liquid chromatography. Cytokines were measured by multiplex fluorometric assay. mNGS was performed on liver, CSF, brain, and brainstem tissue. snRNAseq was performed on brainstem tissue. Results: A cohort of 71 SIDS cases (mean [SD] age, 55.2 [11.4] postconceptional weeks; 42 male [59.2%]) and 20 controls (mean [SD] age, 63.2 [16.9] postconceptional weeks; 11 male [55.0%]) had CSF and/or serum available. CSF neopterin was screened in 64 SIDS cases and 15 controls, with no exclusions. Tissues from 6 SIDS cases were further analyzed. For CSF neopterin measures, SIDS samples were from infants with mean (SD) age of 54.5 (11.3) postconceptional weeks (38 male [59.4%]) and control samples were from infants with mean (SD) age of 61.5 (17.4) postconceptional weeks (7 male [46.7%]). A total of 6 SIDS cases (9.3%) with high CSF neopterin were identified, suggestive of neuroinflammation. mNGS detected human parechovirus 3 (HPeV3) in tissue and CSF from 1 of these 6 cases. snRNAseq of HPeV3-positive brainstem tissue (medulla) revealed dramatic enrichment of transcripts for genes with predominately inflammatory functions compared with 3 age-matched SIDS cases with normal CSF neopterin levels. Conclusions and Relevance: Next-generation molecular tools in autopsy tissue provide novel insight into pathogens that go unrecognized by normal autopsy methodology, including in infants dying suddenly and unexpectedly.

Seizures and Sudden Death Beyond SUDEP.

Many physicians and researchers are familiar with the tragic phenomenon known as sudden infant death syndrome (SIDS), the leading cause of postneonatal mortality in high-resource countries. A less familiar category of unexplained deaths is the problem of sudden unexplained death in childhood (SUDC), a more rare and unusual presentation of sudden death in children who are no longer infants and whose reasons for death defy explanation. A substantial body of research in SUDC now supports the possibility of an overlap with epilepsy and associated sudden death in that context (SUDEP). Stemming from the first contemporary reports of SUDC, we have learned that a disproportionate number of these children have personal and/or family histories of febrile seizures,1 in many cases, inherited in an autosomal dominant manner.2 Their febrile seizures can be associated with abnormalities in their temporal lobes,3,4 including bilamination of the dentate gyrus and other findings conventionally associated with temporal lobe epilepsy, implicating potential epilepsy-related mechanisms.5 Further evaluation of this emerging epilepsy-related phenotype has led to the identification of genetic variants in SCN1A and other epilepsy-associated genes,6,7 moving SUDC away from being considered an unexplained phenomenon to one where the working hypothesis includes a role for genetic predisposition and epilepsy-like mechanisms in the deaths, even without an established history of epilepsy. Nonetheless, because the terminal events of these seemingly healthy children are unexpected and unobserved, the clinical manifestations of whatever underlying vulnerabilities exist-generally discovered posthumously-remain a matter of speculation.

Sudden Unexplained Death in Childhood: Current Understanding.

ABSTRACT: Sudden unexplained death in childhood is a term that encompasses apparently natural deaths in children aged older than 1 year with no discernible cause despite a thorough assessment. Definitive underlying causes vary but most cases remain largely unexplained. Research has furthered the view that sudden unexplained death in childhood is not an accident, but rather a sentinel medical event for which a thorough postmortem investigation is indicated. Emerging evidence in genetics, neurology, and neuropathology point to heterogeneous causes that in some cases share features of recognized diseases.

The fundamental need for unifying phenotypes in sudden unexpected pediatric deaths.

A definitive, authoritative approach to evaluate the causes of unexpected, and ultimately unexplained, pediatric deaths remains elusive, relegating final conclusions to diagnoses of exclusion in the vast majority of cases. Research into unexplained pediatric deaths has focused primarily on sudden infant deaths (under 1 year of age) and led to the identification of several potential, albeit incompletely understood, contributory factors: nonspecific pathology findings, associations with sleep position and environment that may not be uniformly relevant, and the elucidation of a role for serotonin that is practically difficult to estimate in any individual case. Any assessment of progress in this field must also acknowledge the failure of current approaches to substantially decrease mortality rates in decades. Furthermore, potential commonalities with pediatric deaths across a broader age spectrum have not been widely considered. Recent epilepsy-related observations and genetic findings, identified post-mortem in both infants and children who died suddenly and unexpectedly, suggest a role for more intense and specific phenotyping efforts as well as an expanded role for genetic and genomic evaluation. We therefore present a new approach to reframe the phenotype in sudden unexplained deaths in the pediatric age range, collapsing many distinctions based on arbitrary factors (such as age) that have previously guided research in this area, and discuss its implications for the future of postmortem investigation.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part I. Tissue-based evidence for serotonin receptor signaling abnormalities in cardiorespiratory- and arousal-related circuits.

The sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality in the United States, is typically associated with a sleep period. Previously, we showed evidence of serotonergic abnormalities in the medulla (e.g. altered serotonin (5-HT)1A receptor binding), in SIDS cases. In rodents, 5-HT2A/C receptor signaling contributes to arousal and autoresuscitation, protecting brain oxygen status during sleep. Nonetheless, the role of 5-HT2A/C receptors in the pathophysiology of SIDS is unclear. We hypothesize that in SIDS, 5-HT2A/C receptor binding is altered in medullary nuclei that are key for arousal and autoresuscitation. Here, we report altered 5-HT2A/C binding in several key medullary nuclei in SIDS cases (n = 58) compared to controls (n = 12). In some nuclei the reduced 5-HT2A/C and 5-HT1A binding overlapped, suggesting abnormal 5-HT receptor interactions. The data presented here (Part 1) suggest that a subset of SIDS is due in part to abnormal 5-HT2A/C and 5-HT1A signaling across multiple medullary nuclei vital for arousal and autoresuscitation. In Part II to follow, we highlight 8 medullary subnetworks with altered 5-HT receptor binding in SIDS. We propose the existence of an integrative brainstem network that fails to facilitate arousal and/or autoresuscitation in SIDS cases.

Copy Number Variation and Structural Genomic Findings in 116 Cases of Sudden Unexplained Death between 1 and 28 Months of Age.

In sudden unexplained death in pediatrics (SUDP) the cause of death is unknown despite an autopsy and investigation. The role of copy number variations (CNVs) in SUDP has not been well-studied. Chromosomal microarray (CMA) data are generated for 116 SUDP cases with age at death between 1 and 28 months. CNVs are classified using the American College of Medical Genetics and Genomics guidelines and CNVs in our cohort are compared to an autism spectrum disorder (ASD) cohort, and to a control cohort. Pathogenic CNVs are identified in 5 of 116 cases (4.3%). Variants of uncertain significance (VUS) favoring pathogenic CNVs are identified in 9 cases (7.8%). Several CNVs are associated with neurodevelopmental phenotypes including seizures, ASD, developmental delay, and schizophrenia. The structural variant 47,XXY is identified in two cases (2/69 boys, 2.9%) not previously diagnosed with Klinefelter syndrome. Pathogenicity scores for deletions are significantly elevated in the SUDP cohort versus controls (p = 0.007) and are not significantly different from the ASD cohort. The finding of pathogenic or VUS favoring pathogenic CNVs, or structural variants, in 12.1% of cases, combined with the observation of higher pathogenicity scores for deletions in SUDP versus controls, suggests that CMA should be included in the genetic evaluation of SUDP.

Genetic Determinants of Sudden Unexpected Death in Pediatrics.

PURPOSE: This study aimed to evaluate genetic contributions to sudden unexpected death in pediatrics (SUDP). METHODS: We phenotyped and performed exome sequencing for 352 SUDP cases. We analyzed variants in 294 "SUDP genes" with mechanisms plausibly related to sudden death. In a subset of 73 cases with parental data (trios), we performed exome-wide analyses and conducted cohort-wide burden analyses. RESULTS: In total, we identified likely contributory variants in 37 of 352 probands (11%). Analysis of SUDP genes identified pathogenic/likely pathogenic variants in 12 of 352 cases (SCN1A, DEPDC5 [2], GABRG2, SCN5A [2], TTN [2], MYBPC3, PLN, TNNI3, and PDHA1) and variants of unknown significance-favor-pathogenic in 17 of 352 cases. Exome-wide analyses of the 73 cases with family data additionally identified 4 de novo pathogenic/likely pathogenic variants (SCN1A [2], ANKRD1, and BRPF1) and 4 de novo variants of unknown significance-favor-pathogenic. Comparing cases with controls, we demonstrated an excess burden of rare damaging SUDP gene variants (odds ratio, 2.94; 95% confidence interval, 2.37-4.21) and of exome-wide de novo variants in the subset of 73 with trio data (odds ratio, 3.13; 95% confidence interval, 1.91-5.16). CONCLUSION: We provide strong evidence for a role of genetic factors in SUDP, involving both candidate genes and novel genes for SUDP and expanding phenotypes of disease genes not previously associated with sudden death.

The parental role before and after SIDS.

Role confusion is a prominent constituent symptom of Prolonged Grief Disorder in parents after their infants die from sudden infant death syndrome (SIDS). We interviewed 31 parents of SIDS infants 2-5 years post-loss examining the parental role before death, at the time of loss, and in bereavement. Thematic analysis found disruption of the role and re-imagined responsibilities for their child's physical security, emotional security, and meaning. Tasks within these domains changed from concrete and apparent to representational and self-generated. Parents in bereavement locate ongoing, imperative parental responsibilities, particularly asserting their child's meaningful place in the world and in their family.

Parents as Advocates for Pediatric Palliative Care.

Caring for a child with a serious or life-limiting illness presents many challenges for families and health care providers. Through that experience (and, many times, as it ends), parents are compelled to find and make meaning from their ultimate loss and the many losses along the way. In this Advocacy Case Study, we describe the experiences that led a bereaved mother to seek to harness the insights from her own family's loss to help support other families facing the challenges and complexities of a child's serious illness. Her family initially established a family foundation to advocate for palliative care. She later partnered with her family's general pediatrician and the American Academy of Pediatrics to educate providers and bring parent voices to health care provider discussions. This work eventually led to the development of the Courageous Parents Network, a nonprofit focused on making these parent and provider voices widely available to families and providers through a Web-based collection of videos, blogs, podcasts, and printable guides. Through these insights, the organization addresses feelings of isolation, anxiety, and grief. In addition, these voices illustrate the power and benefits of the growing acceptance of pediatric palliative care practices. Important lessons learned through these efforts include: (1) the power of stories for validation, healing, and understanding; (2) opportunity to extend the reach of pediatric palliative care through provider education and skill-building; (3) critical importance of the parent-provider advocacy collaboration; and (4) necessity of market testing and continuous improvement.

Genetic Factors Underlying Sudden Infant Death Syndrome.

Sudden Infant Death syndrome (SIDS) is a diagnosis of exclusion. Decades of research have made steady gains in understanding plausible mechanisms of terminal events. Current evidence suggests SIDS includes heterogeneous biological conditions, such as metabolic, cardiac, neurologic, respiratory, and infectious conditions. Here we review genetic studies that address each of these areas in SIDS cases and cohorts, providing a broad view of the genetic underpinnings of this devastating phenomenon. The current literature has established a role for monogenic genetic causes of SIDS mortality in a subset of cases. To expand upon our current knowledge of disease-causing genetic variants in SIDS cohorts and their mechanisms, future genetic studies may employ functional assessments of implicated variants, broader genetic tests, and the inclusion of parental genetic data and family history information.

Medullary Serotonergic Binding Deficits and Hippocampal Abnormalities in Sudden Infant Death Syndrome: One or Two Entities?

Sudden infant death syndrome (SIDS) is understood as a syndrome that presents with the common phenotype of sudden death but involves heterogenous biological causes. Many pathological findings have been consistently reported in SIDS, notably in areas of the brain known to play a role in autonomic control and arousal. Our laboratory has reported abnormalities in SIDS cases in medullary serotonin (5-HT) receptor 1A and within the dentate gyrus of the hippocampus. Unknown, however, is whether the medullary and hippocampal abnormalities coexist in the same SIDS cases, supporting a biological relationship of one abnormality with the other. In this study, we begin with an analysis of medullary 5-HT1A binding, as determined by receptor ligand autoradiography, in a combined cohort of published and unpublished SIDS (n = 86) and control (n = 22) cases. We report 5-HT1A binding abnormalities consistent with previously reported data, including lower age-adjusted mean binding in SIDS and age vs. diagnosis interactions. Utilizing this combined cohort of cases, we identified 41 SIDS cases with overlapping medullary 5-HT1A binding data and hippocampal assessment and statistically addressed the relationship between abnormalities at each site. Within this SIDS analytic cohort, we defined abnormal (low) medullary 5-HT1A binding as within the lowest quartile of binding adjusted for age and we examined three specific hippocampal findings previously identified as significantly more prevalent in SIDS compared to controls (granular cell bilamination, clusters of immature cells in the subgranular layer, and single ectopic cells in the molecular layer of the dentate gyrus). Our data did not find a strong statistical relationship between low medullary 5-HT1A binding and the presence of any of the hippocampal abnormalities examined. It did, however, identify a subset of SIDS (~25%) with both low medullary 5-HT1A binding and hippocampal abnormalities. The subset of SIDS cases with both low medullary 5-HT1A binding and single ectopic cells in the molecular layer was associated with prenatal smoking (p = 0.02), suggesting a role for the exposure in development of the two abnormalities. Overall, our data present novel information on the relationship between neuropathogical abnormalities in SIDS and support the heterogenous nature and overall complexity of SIDS pathogenesis.

A de novo BRPF1 variant in a case of Sudden Unexplained Death in Childhood.

Sudden Unexplained Death in Childhood (SUDC), the death of a child that remains unexplained after a complete autopsy and investigation, is a rare and poorly understood entity. This case report describes a 3-year-old boy with history of language delay and ptosis, who died suddenly in his sleep without known cause. A pathogenic de novo frameshift mutation in BRPF1, a gene which has been associated with the syndrome of Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP), was identified during a post-mortem evaluation. The finding of a pathogenic variant in BRPF1, which has not previously been associated with sudden death, in an SUDC case has implications for this child's family and contributes to the broader field of SUDC research. This case demonstrates the utility of post-mortem genetic testing in SUDC.

The role of sodium channels in sudden unexpected death in pediatrics.

BACKGROUND: Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes. METHODS: To address this hypothesis, we evaluated whole-exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP-associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long-standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data. CONCLUSION: We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia- and epilepsy-associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel-related variants to SUDP.

Transitional objects of grief.

BACKGROUND: Transitional objects provide security and symbolic connection with valued others when separated from them. Bereaved parents often keep, cherish and visit saved objects of their deceased child. This research examined the hypothesis that these objects behave as transitional objects of grief in bereaved mothers during three years following their infants' deaths from Sudden Infant Death Syndrome. METHODS: Questionnaires were administered asking about the presence of kept objects and momentos from their deceased infant, and the frequency, location and emotions experienced during visits to them. Diagnostic criteria for Prolonged Grief Disorder (PGD) were assessed using the Parental Bereavement Questionnaire. RESULTS: 98.6% of the mothers reported having transitional objects of grief, and most visited them more frequently than once per week regardless of PGD status. Mothers with PGD reported significantly more distress when visiting the objects, especially those visiting them privately. Mothers with PGD who felt comforted by the objects had lower risk for finding life meaningless or finding discussion about the infant intolerable. CONCLUSIONS: Transitional objects of grief are common and associated with key aspects of grief. There is a need to understand the potential therapeutic uses of transitional objects in promoting bereavement adjustment.

Inconsistent classification of unexplained sudden deaths in infants and children hinders surveillance, prevention and research: recommendations from The 3rd International Congress on Sudden Infant and Child Death.

This report details the proceedings and conclusions from the 3rd International Congress on Unexplained Deaths in Infants and Children, held November 26-27, 2018 at the Radcliffe Institute at Harvard University. The Congress was motivated by the increasing rejection of the diagnosis Sudden Infant Death Syndrome (SIDS) in the medical examiner community, leading to falsely depressed reported SIDS rates and undermining the validity and reliability of the diagnosis, which remains a leading cause of infant and child mortality. We describe the diagnostic shift away from SIDS and the practical issues contributing to it. The Congress was attended by major figures and opinion leaders in this area from countries significantly engaged in this problem. Four categories (International Classification of Diseases (ICD)-11 categories of MH11, MH12, MH14, PB00-PB0Z) were recommended for classification, and explicit definitions and guidance were provided for death certifiers. SIDS was reframed as unexplained sudden death in infancy or SIDS/MH11 to emphasize that either term signifies the lack of explanation following a rigorous investigation. A distinct category for children over the age of 1 was recommended (MH12). Definitions and exclusions were provided for the alternative categories of accidental asphyxia and undetermined. As recommended, unexplained sudden death in infancy or SIDS on a death certificate will code a unique, trackable entity, accurately reflecting the inability to determine a definitive explanation, while satisfying surveillance needs and reliable identification for research efforts. The conclusions will be submitted to the World Health Organization for inclusion in the upcoming ICD-11.

Maternal Smoking Before and During Pregnancy and the Risk of Sudden Unexpected Infant Death.

OBJECTIVES: Maternal smoking during pregnancy is an established risk factor for sudden unexpected infant death (SUID). Here, we aim to investigate the effects of maternal prepregnancy smoking, reduction during pregnancy, and smoking during pregnancy on SUID rates. METHODS: We analyzed the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set (2007-2011: 20 685 463 births and 19 127 SUIDs). SUID was defined as deaths at <1 year of age with International Classification of Diseases, 10th Revision codes R95 (sudden infant death syndrome), R99 (ill-defined or unknown cause), or W75 (accidental suffocation or strangulation in bed). RESULTS: SUID risk more than doubled (adjusted odds ratio [aOR] = 2.44; 95% confidence interval [CI] 2.31-2.57) with any maternal smoking during pregnancy and increased twofold between no smoking and smoking 1 cigarette daily throughout pregnancy. For 1 to 20 cigarettes per day, the probability of SUID increased linearly, with each additional cigarette smoked per day increasing the odds by 0.07 from 1 to 20 cigarettes; beyond 20 cigarettes, the relationship plateaued. Mothers who quit or reduced their smoking decreased their odds compared with those who continued smoking (reduced: aOR = 0.88, 95% CI 0.79-0.98; quit: aOR = 0.77, 95% CI 0.67-0.87). If we assume causality, 22% of SUIDs in the United States can be directly attributed to maternal smoking during pregnancy. CONCLUSIONS: These data support the need for smoking cessation before pregnancy. If no women smoked in pregnancy, SUID rates in the United States could be reduced substantially.