Prevalence, Predictive Factors, and Clinical Manifestations of Fungal Esophagitis in Children.

OBJECTIVES: Fungal esophagitis (FE) is the most common cause of esophageal infection and its prevalence in immunocompetent adults is rising. However, there is minimal data on FE in children without human immunodeficiency virus. Therefore, the objective of this study was to determine the prevalence, symptoms, endoscopic appearances, and predictive factors of FE in children, regardless of immune status. METHODS: A 2010-2020 retrospective case-control study was conducted on 1823 children presenting to Sydney Children's Hospital for elective endoscopy with esophageal biopsy. Histopathology reports were reviewed to identify FE cases and determine prevalence rates. Thirty-two patients with FE were age- and sex-matched (1:2) to 64 controls. Significant symptoms and risk factors of FE were identified via univariate and multivariate logistic regression analysis. RESULTS: The prevalence of FE in children was 1.76%. Common symptoms included dysphagia (25%), heartburn (25%), poor oral intake (21.9%), vomiting (18.8%), cough (15.6%), nausea (12.5%), and weight loss (9.4%). No significant differences in symptoms were found between cases and controls. On endoscopy, although white plaques were associated with FE ( P < 0.001), visually normal findings were reported in 28.1% of cases. Topical swallowed corticosteroids were a significant independent risk factor for FE (adjusted odds ratio = 10.740, 95% confidence interval: 1.213-95.101, P = 0.033). CONCLUSIONS: The prevalence of FE in this pediatric cohort reflects rates among immunocompetent adults. Given that many of these children presented with a wide range of gastrointestinal symptoms, esophageal biopsy is required to accurately diagnose FE. Pediatricians should consider the risk of FE when prescribing topical swallowed corticosteroids.

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Autopsy findings of co-sleeping-associated sudden unexpected deaths in infancy: relationship between pathological features and asphyxial mode of death.

AIM: Co-sleeping is associated with increased risk of sudden unexpected death in infancy (SUDI)/sudden infant death syndrome (SIDS). The aim of this study is to examine autopsy findings from a single U.K. specialist centre to determine the relationship between co-sleeping and cause of death. METHODS: Retrospective analysis of >1500 paediatric autopsies carried out by paediatric pathologists over a 10-year period. SUDI was defined as sudden unexpected death of an infant aged 7-365 days; deaths were categorised into explained SUDI (cause of death was determined) and unexplained SUDI (equivalent to SIDS). RESULTS: There were 546 SUDI; sleeping arrangements were specifically recorded in 314; of these, 174 (55%) were co-sleeping-associated deaths. Almost two thirds (59%) of unexplained SUDI were co-sleeping compared to 44% explained SUDI (95% confidence interval (CI) 1.0-27.2%, P=0.03); however, this difference remained statistically significant only for the first 5 months of life (95% CI 3.5-33.2%, P=0.01). In unexplained SUDI aged < 6 months, there were no significant differences between co-sleeping and non-co-sleeping deaths with respect to ante-mortem symptoms, intrathoracic petechiae, macroscopic lung appearances, pulmonary haemosiderin-laden macrophages, and isolation of specific bacterial pathogens; however, fresh intra-alveolar haemorrhage was reported more commonly in co-sleeping (54%) than in those that were not (38%; 95% CI 1.4-30.5%, P=0.03). CONCLUSIONS: Co-sleeping is associated with unexplained SUDI/SIDS in infants aged < 6 months, suggesting that co-sleeping is related to the pathogenesis of death in younger infants. The finding that intra-alveolar haemorrhage is more common in co-sleeping suggests that a minority of co-sleeping-associated deaths may be related to an asphyxial process.

Clinicopathological features of fatal cardiomyopathy in childhood: an autopsy series.

AIM: Cardiomyopathy, a group of primary myocardial disorders, is an uncommon, but important, cause of death in childhood. This study examines the demographic, clinical and pathological features of fatal cardiomyopathy in childhood with particular reference to its classification and autopsy findings. METHOD: The method of this study was a retrospective structured review of all paediatric autopsies performed at a single specialist centre from 1995 to 2009 inclusive, in order to determine the demographic, clinical and pathological features of fatal cardiomyopathy. RESULTS: From a total of 2229 autopsies performed at the centre during the study period on live-born infants and children, 34 confirmed cases of cardiomyopathy were identified (1.5%). More than half (59%) of these cases occurred in infants (less than 1 year of age). Heart weight of cardiomyopathy cases was significantly greater than those with normal hearts (P < 0.001), and 77% had heart weights above the 95th percentile of the normal expected range for age, including all of those over 1 year age. Of cardiomyopathy cases, 50% were primary dilated cardiomyopathy and 27% were primary hypertrophic cardiomyopathy. Twelve of 34 cases (35%) presented as sudden unexpected death, the diagnosis of cardiomyopathy being only made at autopsy. CONCLUSION: Cardiomyopathy is an uncommon cause of death in infancy and childhood. It can present as sudden unexpected death and encompasses a range of aetiologies. Heart weight above the 95th percentile at autopsy is present in most cases but heart weight may be within the normal range in infants.

Postmortem tandem mass spectrometry profiling for detection of infection in unexpected infant death.

Numerous hypotheses have been suggested to explain the cause of sudden unexpected infant death, including infection. As part of the autopsy, routine ancillary investigations are performed, including blood/bile tandem mass spectrometry (TMS) primarily for detection of metabolic disease. The aim of this study was to evaluate and assess TMS derived acylcarnitine profiles to determine whether infectious deaths were associated with characteristic profiles. As part of a retrospective study including >2,500 pediatric autopsies at a single specialist centre over a 14 year period, acylcarnitine profiles were reviewed. Using multiple linear regression, standardised residuals were prepared and findings compared between different cause of death groups, including unexplained, focal infection, microbiological infection and accidental injuries. 415 blood samples from SUDI autopsies were identified. Statistically significant differences in TMS profiles were identified between those dying of infection and the unexplained SUDI group, including changes in free carnitine, short chain acylcarnitines and octanoylcarnitine. Cases with microbiological infection diagnosed only from postmortem cultures did not show any significant difference from the unexplained group. Postmortem TMS profiling identifies SUDI deaths which are associated with histological evidence of infection, and an acylcarnitine profile suggesting perturbation of oxidative metabolism. Such findings raise the possibility that more comprehensive TMS profiling may offer additional diagnostic clues beyond screening for metabolic disorders, and may contribute to determination of mode of death.

Postmortem MRI of bladder agenesis.

We report a 35-week preterm neonate with bladder agenesis and bilateral dysplastic kidneys. A suprapubic catheter was inadvertently inserted into one of the larger inferior cysts of the left dysplastic kidney. A postmortem MRI scan was performed with the findings being confirmed on autopsy. We are unaware of another postmortem MRI study demonstrating bladder agenesis.

Parents' experiences of postmortem tumor donation for high-grade gliomas: benefits and suggested improvements.

BACKGROUND: Pediatric high-grade glioma is a devastating diagnosis. There has been no improvement in outcomes for several decades, with few children surviving 2 years postdiagnosis. Research progress has been hampered by a lack of tumor samples, which can be used to develop and test novel therapies. Postmortem tumor donations are therefore a valuable opportunity to collect tissue. In this study, we explored Australian parents' experiences of donating their child's tumor for research after their child had died. METHODS: We collected qualitative data from 11 bereaved parents who consented to donate samples of their child's high-grade glioma for research postmortem. We asked parents about their perceived benefits/burdens of the autopsy, recommendations for improving consent discussions, and decision regret. RESULTS: Parents hoped that their donation would help to find a cure for future children with high-grade glioma. They described feeling comforted knowing that their child's suffering may help others. Some parents also felt that the donation would help them better understand their child's tumor. Although some parents described discomfort about procedures leading up to the autopsy, parents reported minimal regret regarding their decision to donate their child's tumor. Parents provided recommendations to improve consent discussions, such as providing more information about the autopsy logistics and why the donation was needed. CONCLUSION: Parents consented to autopsy for altruistic reasons, although donation may also assist parents in their grieving. There is a strong need to improve access to tumor donations for any family who wishes to donate.

Disseminated langerhans cell histiocytosis-related sudden unexpected death in infancy.

Sudden unexpected death in infancy (SUDI) is defined as the sudden and unexpected death of an infant aged less than 1 year and comprises a heterogeneous group of deaths; in around one-third of cases a definite cause of death is identified at autopsy, while almost two-thirds of such deaths will remain unexplained despite a careful review of the circumstances of death and a detailed postmortem examination. We report a case of SUDI due to previously undiagnosed disseminated Langerhans cell histiocytosis (LCH) in a 10-month-old male, a disease characterized by a clonal proliferation of dendritic Langerhans cells. The diagnosis was established on histological examination, which revealed extensive infiltration by LCH of the skin, lymph nodes, thymus, spleen, and lungs. Despite a high mortality in disseminated disease, to our knowledge, this is the first reported case in the English-language literature of disseminated multisystem Langerhans cell disease presenting as SUDI. Furthermore, this case demonstrates the importance of routine microscopic tissue sampling in all SUDI, as the diagnosis required histological examination of the organs and might have been missed had histology not been performed.

Oral malignant gastrointestinal neuroectodermal tumour with junctional component mimicking mucosal melanoma.

Malignant gastrointestinal neuroectodermal tumour (GNET) is a recently characterised rare and aggressive tumour that typically arises in association with the small intestine of adults. We present a novel case of this entity and expand the spectrum of its reported morphological features. The patient was a 5-year-old female, the youngest reported patient affected by the condition, and presented with extra-abdominal disease. The histopathological features included the presence of a junctional component of the palatal tumour, which mimicked mucosal melanoma, a feature that has not been previously reported in GNET. Whole genome and RNA sequencing was performed that demonstrated the EWSR1-ATF1 translocation characteristic of GNET. Knowledge of this entity and its features, together with careful morphological assessment supplemented by judicious immunohistochemical and molecular studies should enable the correct diagnosis to be established.

A Mutation Outside the Dimerization Domain Causing Atypical STING-Associated Vasculopathy With Onset in Infancy.

BACKGROUND: Mutations in the gene encoding stimulator of interferon genes (STING) underlie a type I interferon (IFN) associated disease, STING-associated vasculopathy with onset in infancy (SAVI). Patients suffer cutaneous vasculopathy and interstitial lung disease, but are not known to suffer life-threatening infection. CASE: We describe a child who presented with Pneumocystis jirovecii pneumonia in early life, from which he recovered. He went on to suffer failure to thrive, developmental delay, livedo reticularis, and vesicular rash, but without cutaneous vasculitis, and with normal C-reactive protein and erythrocyte sedimentation rates. At 3 years of age, he developed life-threatening pulmonary hypertension. METHODS: Whole genome sequencing (WGS) was performed using the Illumina HiSeqX10 platform and the Seave platform was used for bioinformatic analysis. mRNA expression of IFN-stimulated genes and inflammatory cytokines from peripheral blood mononuclear cells was determined by quantitative polymerase chain reaction. Luciferase assay was used to model IFNß and NF-κB activity in vitro. RESULTS: WGS revealed a de novo mutation p.Arg284Ser in STING at an amino acid previously associated with SAVI. Although this mutation did not fall in the dimerization domain (DD), mRNA analysis revealed constitutive IFN-gene activation consistent with an interferonopathy, which correlated to STING activation in vitro. The patient was treated with corticosteroids and the JAK inhibitor Ruxolitinib, resulting in a rapid improvement of pulmonary hypertension, general well-being, and resolution of the IFN gene signature. However, he did go on to evolve a nasal septal erosion suggesting incomplete control of disease. CONCLUSION: This case provides molecular evidence to support the p.Arg284Ser variant in STING exerting pathogenicity through a gain-of-function mechanism. The lack of cutaneous vasculitis or elevated systemic inflammatory markers, and the occurrence of an opportunistic infection are notable, and raise the possibility that variants outside the STING DD may potentially manifest with an atypical SAVI phenotype. Nevertheless, there was an objective clinical improvement in response to JAK inhibition.

Integration of genomics, high throughput drug screening, and personalized xenograft models as a novel precision medicine paradigm for high risk pediatric cancer.

Pediatric high grade gliomas (HGG) are primary brain malignancies that result in significant morbidity and mortality. One of the challenges in their treatment is inter- and intra-tumoral heterogeneity. Precision medicine approaches have the potential to enhance diagnostic, prognostic and/or therapeutic information. In this case study we describe the molecular characterization of a pediatric HGG and the use of an integrated approach based on genomic, in vitro and in vivo testing to identify actionable targets and treatment options. Molecular analysis based on WGS performed on initial and recurrent tumor biopsies revealed mutations in TP53, TSC1 and CIC genes, focal amplification of MYCN, and copy number gains in SMO and c-MET. Transcriptomic analysis identified increased expression of MYCN, and genes involved in sonic hedgehog signaling proteins (SHH, SMO, GLI1, GLI2) and receptor tyrosine kinase pathways (PLK, AURKA, c-MET). HTS revealed no cytotoxic efficacy of SHH pathway inhibitors while sensitivity was observed to the mTOR inhibitor temsirolimus, the ALK inhibitor ceritinib, and the PLK1 inhibitor BI2536. Based on the integrated approach, temsirolimus, ceritinib, BI2536 and standard therapy temozolomide were selected for further in vivo evaluation. Using the PDX animal model (median survival 28 days) we showed significant in vivo activity for mTOR inhibition by temsirolimus and BI2536 (median survival 109 and 115.5 days respectively) while ceritinib and temozolomide had only a moderate effect (43 and 75.5 days median survival respectively). This case study demonstrates that an integrated approach based on genomic, in vitro and in vivo drug efficacy testing in a PDX model may be useful to guide the management of high risk pediatric brain tumor in a clinically meaningful timeframe.

"Delayed Villous Maturation" in Placental Reporting: Concordance among Consultant Pediatric Pathologists at a Single Specialist Center.

Delayed villous maturation (DVM) has been associated with an increased risk of adverse pregnancy outcome, including stillbirth, in the late third trimester, but there are limited published data. Moreover, it is recognized that the assessment of villous maturation is subjective and hampered by both intraobserver and interobserver variability. This audit aims to assess concordance in the reporting of DVM among pediatric pathologists at a single specialist center to improve reproducibility of this potentially important diagnosis. This is a retrospective review of singleton placentas from pregnancies at 35 weeks gestation or greater submitted for histopathologic examination between June 2013 and December 2013. Placental slides were reviewed independently by 4 pediatric pathologists, blinded to the original report, apart from gestational age; villous maturation was assessed as appropriate, accelerated, or delayed for the stated gestational age. A total of 464 placental histopathology reports were reviewed, of which 164 were greater than 35 weeks gestation; of those, 42 (26%) were originally reported as DVM. Following the audit slide review, 38 cases (23%) were assessed to show DVM by at least 1 pathologist. Consensus, with at least 3 pathologists agreeing to a diagnosis of DVM, was achieved in only 14 cases (9% of all cases reviewed; 37% of all cases called DVM). However, the proportion of overall agreement between 2 of the pathologists was 0.92. Concordance for DVM is poor among pathologists and subject to much interobserver variability. Consistency may be improved by consensus histologic review of all the placentas in which the diagnosis of DVM is being considered and stringent application of the published diagnostic criteria.

Minimally invasive perinatal autopsies using magnetic resonance imaging and endoscopic postmortem examination ("keyhole autopsy"): feasibility and initial experience.

OBJECTIVE: Perinatal autopsy provides additional diagnostic information in a significant proportion of cases but parents and relatives frequently decline traditional postmortem (PM) examination, partly due to the unacceptability of the cosmetic effects of large incisions and concerns regarding organ retention. We present a novel minimally invasive autopsy method for fetal and neonatal PMexaminations, which includes PM magnetic resonance imaging (MRI) for assessment of anatomy and endoscopic internal examination to allow direct organ visualization and targeted tissue biopsy. METHODS: Descriptive retrospective feasibility report of the first 10 perinatal cases undergoing endoscopic minimally invasive autopsy. RESULTS: A minimally invasive autopsy (MIA) approach based on postmortem MRI (PM MRI) and endoscopic autopsy with tissue biopsy is feasible and effective with minimal cosmetic consequences compared to traditional PM examination. Endoscopic examination with tissue biopsy provided additional diagnostic information to PM MRI alone in the majority of cases. CONCLUSIONS: Endoscopic MIA is a feasible and potentially more acceptable approach to perinatal autopsy and provides an additional option for parents who do not agree to a traditional PM examination. This approach could result in increased utilization of investigations after death in this group of patients.

Difficulties in interpretation of post-mortem microbiology results in unexpected infant death: evidence from a multidisciplinary survey.

BACKGROUND: Post-mortem (PM) microbiological investigations are recommended in cases of sudden unexpected death in infancy (SUDI), and infection is a recognised cause of such deaths, but no current evidence-based guidelines exist for the appropriate interpretation of results. AIM: To assess interpretive difficulties using a targeted cross-specialty questionnaire. METHODS: 109 consultant specialists involved in infant death management were given a questionnaire providing information on five hypothetical standardised SUDI cases, which differed only in their PM microbiology findings. Participants classified each case into categories: definite bacterial infection, probable bacterial infection, bacterial growth of uncertain significance and PM contamination. RESULTS: 63 (57%) specialists responded. There was no clinical scenario in which complete concordance in interpretation of PM microbiology results was established among participants. In cases with pure growth of Group 2 pathogens such as Group B ß-haemolytic Streptococcus, 96% of respondents agreed upon probable or definite bacterial infection. With mixed growth of Group 2 pathogens, 83% reported probable or definite bacterial infection. Growth of organisms such as Staphylococcus aureus caused the most difficulty, with almost equal numbers of participants interpreting the finding as significant or non-significant. There were no consistent differences in interpretation between different specialist groups. CONCLUSIONS: While there is general agreement in interpretation of PM microbiology findings in some SUDI scenarios, no consensus was achieved for any clinical setting, and variation in the presumed significance between specialists was apparent. In the absence of appropriate evidence-based guidelines, this has practical implications for the management of such deaths in a multidisciplinary setting.

Microbiological findings in sudden unexpected death in infancy: comparison of immediate postmortem sampling in casualty departments and at autopsy.

AIM: Sudden unexpected death in infancy (SUDI) represents the commonest presentation of post-neonatal infant death in the UK. This audit reviews current practice in the investigation of SUDI deaths, with particular regard to the practice of microbiological sampling in emergency departments (ED) compared with samples obtained at the time of autopsy for establishing the cause of death, as suggested by current guidelines. METHODS: Coronial autopsies performed for the indication of SUDI over a 4-year period at a single specialist centre were reviewed with particular regard to the findings of microbiological investigations performed in ED compared with those performed at the time of autopsy. RESULTS: Of 229 SUDI postmortems performed during the period, there were 136 cases in which both bacteriological samples taken in ED and at autopsy were available, including 109 with blood cultures taken at both time points. 66 cases had sterile blood cultures in ED of which 37 (56%) showed positive microbiological growth from autopsy samples including nine (14%) cases with group II pathogens. Group II pathogens were identified from ED samples in six (6%) of the total cases; all but two cases of Staphylococcus aureus were not detected at autopsy. CONCLUSION: Blood cultures obtained at autopsy are associated with a significantly higher rate of positive microbial cultures compared with blood samples taken in life. Most represent easily identified postmortem translocation or overgrowth rather than infection as the cause of death. No cases with a final infective cause of death would have been missed if ED sampling had not been performed.

Genetics and developmental pathology of twinning.

Twin pregnancy is associated with a high risk of congenital malformations. This review covers the risk of such anomalies in both dizygotic and monozygotic twin pregnancies, and discusses current insights into the associations relating to zygosity, chorionicity and genetic factors. The pathological basis of specific malformations unique to the monochorionic twinning process, including conjoined twinning and twin reversed arterial perfusion (TRAP) sequence, is discussed in more detail, and factors contributing to the higher perinatal mortality rate in multiple pregnancies are addressed.

Variation and uncertainties in the classification of sudden unexpected infant deaths among paediatric pathologists in the UK: findings of a National Delphi Study.

AIMS: Presently, pathologists in the UK use diverse terminologies for the classification of sudden unexpected infant deaths, including 'unascertained,' 'sudden unexpected death in infancy' (SUDI) and 'sudden infant death syndrome' (SIDS). This study uses the Delphi method to investigate the views of paediatric pathologists on their use of these terms in order to determine areas of consensus. METHODS: There were three Delphi rounds overall; in the final one, participants were asked to score each statement using a modified Likert scale (0-9). The scores were analysed using non-parametric statistics, and statements in which the median score was or=7 (approximately 70% agreement) were considered to have reached 'consensus agreement.' RESULTS: Twenty-five of the 36 UK paediatric pathologists who were approached in the initial round contributed to all three rounds. There was consensus that 'SIDS' be used for unexplained sudden unexpected infant deaths that occurred during sleep. 'Infancy' was defined as up to 1 year of age, but there was no consensus regarding the lower age limit of SIDS. There was agreement that 'SUDI' be used for unexplained sudden infant deaths with a history of preceding illness, deaths with minor histological abnormalities of uncertain significance and co-sleeping-associated deaths. Most paediatric pathologists used 'unascertained' for findings suspicious of a non-natural cause of death. There was consensus that co-sleeping-associated deaths should be classified as 'unascertained' if parents had consumed alcohol or used drugs in the preceding 24 h. CONCLUSIONS: The areas of consensus relating to terminology around SUDI and SIDS should guide future use by pathologists. However, there remains a significant lack of agreement, suggesting that acceptable alternative terms be identified for infant deaths which remain unexplained following autopsy in whom there are no suspicious features; the authors propose that 'unexplained SUDI,' followed by a comment, may represent the most factually correct compromise.