Novel KIF26A variants associated with pediatric intestinal pseudo-obstruction (PIPO) and brain developmental defects.

Pediatric intestinal pseudo-obstruction (PIPO) is a rare congenital disorder of the enteric nervous system with distal colon aganglionosis potentially leading to intestinal obstruction. Recently, biallelic variants in KIF26A, encoding a crucial motor protein for the migration and differentiation of enteric neural crest cells, have been associated with a neurodevelopmental condition featuring cortical defects and PIPO-like features, though in absence of aganglionosis. So far, only 10 patients have been reported. In this study, we investigated three subjects with congenital hydrocephalus, neurodevelopmental impairment, and intestinal obstruction megacolon syndrome. Brain MRI revealed malformations within cortical dysplasia spectrum, including polymicrogyria and heterotopia. Pathology study of the intestine revealed aganglionosis and elevated acetylcholinesterase activity in parasympathetic nerve fibers. Through trio-exome sequencing (ES), we detected four novel biallelic KIF26A variants, including two missense changes (#1) and two distinct homozygous truncating variants in (#2 and #3). All variants are rare and predicted to be deleterious according to in silico tools. To characterize the impact of the missense variants, we performed 3D protein modeling using Alphafold3 and YASARA. Mutants exhibited increased energy scores compared to wild-type protein, supporting a significant structural destabilization of the protein. Our study expands the genotype and phenotype spectrum of the emerging KIF26A-related disorder.

Sudden Intrauterine Unexplained Death (SIUD) and Oxidative Stress: Placental Immunohistochemical Markers.

BACKGROUND: Intrauterine fetal death and perinatal death represent one of the most relevant medical scientific problems since, in many cases, even after extensive investigation, the causes remain unknown. The considerable increase in medical legal litigation in the obstetrical field that has witnessed in recent years, especially in cases of stillborn births, has simultaneously involved the figure of the forensic pathologist in scientific research aimed at clarifying the pathophysiological processes underlying stillbirth. METHODS: our study aims to analyze cases of sudden intrauterine unexplained death syndrome (SIUD) to evaluate the role of oxidative stress in the complex pathogenetic process of stillbirth. In particular, the immunohistochemical expression of specific oxidative stress markers (NOX2, NT, iNOS, 8-HODG, IL-6) was evaluated in tissue samples of placentas of SIUDs belonging to the extensive case series (20 cases), collected from autopsy cases of the University of Ferrara and Politecnica delle Marche between 2017 and 2023. RESULTS: The study demonstrated the involvement of oxidative stress in intrauterine fetal deaths in the placenta of the cases examined. In SIUD, the most expressed oxidative stress markers were NOX2 and 8-HODG. CONCLUSIONS: The study contributes to investigating the role of oxidative stress in modulating different pathways in unexplained intrauterine fetal death (SIUD) tissues.

Frozen Section of Placental Membranes and Umbilical Cord: A Valid Diagnostic Tool for Early-Onset Neonatal Sepsis Management.

Early-onset neonatal sepsis (EONS), a serious infection in newborns within 3 days, is challenging to diagnose. The current methods often lack accuracy, leading to unnecessary antibiotics or delayed treatment. This study investigates the role of the frozen section examination of placental membranes and umbilical cord (FSMU) to improve EONS diagnosis in the daily lab practice. This retrospective study reviewed data from 59 neonates with EONS risk factors who underwent FSMU according to our institutional protocol. Concordance between the FSMU and the Final Pathological Report (FPR) was assessed. The FSMU demonstrated a high concordance (Kappa = 0.88) for funisitis diagnosis, with excellent accuracy (98.3%). A moderate concordance was observed for chorioamnionitis stage and grade. The FSMU shows promise as a rapid and accurate tool for diagnosing EONS, particularly for funisitis. This study suggests that the FSMU could be a valuable tool for EONS diagnosis, enabling a more judicious antibiotic use and potentially improving outcomes for newborns.

A Rare Case of Fatal Thyroid Hemorrhage After Fine-Needle Aspiration: Case Report and Review of the Literature.

ABSTRACT: Sudden death due to massive hemorrhage after a mini-invasive ambulatory diagnostic procedure is extremely rare. Fine-needle aspiration (FNA) of thyroid nodules is very safe, displaying a low rate of complications, all of which mild and often self-limiting. In few cases do these complications necessitate surgical decompression, and rarely does FNA of a thyroid nodule lead to the death of the patient.We report a case of sudden death caused by respiratory insufficiency after compression of the vascular and nervous structures of the neck and obstruction of the upper airways by hemorrhages dissecting the thyroidal and perithyroidal tissues in a 78-year-old woman. These hemorrhages were the result of vascular lacerations caused during diagnostic FNA of a nodule suspected of malignancy. In such cases, it is important to conduct a complete autopsy and histological analysis to ascertain the origin of massive hemorrhage involving the structures of the neck and to attribute the cause of death to the aforementioned procedure. The forensic pathologist must bear in mind that even extremely small damage, such as that produced by a fine needle, may cause a fatal hemorrhage in subjects with a subverted anatomo-pathological picture (such as, for example, the massive fibrosis of an organ).

Sudden Onset of Severe Pulmonary Hypertension in a Preterm Infant: A Case Report on the Role of Maternal Use of Serotonin Re-Uptake Inhibitors During Pregnancy and Concurrent Risk Factors.

Persistent pulmonary hypertension of the newborn (PPHN) is a severe condition caused by failed circulatory adaptation at birth. Pulmonary hypertension is most common in full-term infants and rare in preterms, although it is increasingly diagnosed also in extremely preterm infants. Previous studies demonstrated the association between maternal use of selective serotonin re-uptake inhibitors during gestation and pulmonary hypertension. This brief report describes the complex physiopathological correlations that were identified in a case of severe pulmonary hypertension in a fetal growth restricted (FGR) preterm infant, with a history of maternal use of antidepressants during pregnancy. Perinatal factors, triggers and aggravating mechanisms caused a dramatic clinical course. Maternal history of escitalopram therapy throughout pregnancy was noted. Uteroplacental insufficiency, fetal hypoxia, FGR, preeclampsia, preterm delivery, antenatal steroids, and cesarean section were documented as concurrent risk factors. Myocardial immaturity and dysfunction, secondary to FGR and prematurity aggravated the hemodynamic compromise. The short time gap between pharmacological ductal closure and the onset of PPHN may suggest a cause-effect relationship, as observed in previous reports. Placental histopathologic findings are reported.

An example of parenchymal renal sparing in the context of complex malformations due to a novel mutation in the PBX1 gene.

INTRODUCTION: PBX1 encodes the pre-B cell leukemia factor 1, a Three Amino acid Loop Extension (TALE) transcription factor crucial to regulate basic developmental processes. PBX1 loss-of-function variants have been initially described in association with renal malformations in both isolated and syndromic forms. CASE REPORT: Herein, we report a male infant presenting multiple organ malformations (cleidosternal dysostosis, micrognathia, left lung hypoplasia, wide interatrial defect, pulmonary hypertension, total anomalous pulmonary venous return, intestinal malrotation) and carrying the heterozygous de novo c.868C > T (p.Arg290Trp) variant in PBX1. This novel variant affects the highly conserved homeodomain of the protein, leading to a non-conservative substitution and consequently altering its tridimensional structure and DNA-binding capacity. CONCLUSION: So far, PBX1 has been reported in association with a broad spectrum of renal anomalies. However, given the role of this gene in many different developing processes, whole-exome sequencing can detect mutations in PBX1 even in patients with different phenotypes, not necessarily involving the renal primordium. This report presents a novel PBX1 variant with a predicted strong deleterious effect. The mutation leads to a non-conservative substitution in a very highly conserved domain of the protein, thus altering its tertiary structure and DNA-binding capacity.

Proteomic profiling of human amnion for preterm birth biomarker discovery.

Spontaneous preterm birth (PTB) complicates about 12% of pregnancies worldwide, remaining the main cause of neonatal morbidity and mortality. Spontaneous preterm birth PTBs is often caused by microbial-induced preterm labor, mediated by an inflammatory process threatening both maternal and newborn health. In search for novel predictive biomarkers of PTB and preterm prelabor rupture of the membranes (pPROM), and to improve understanding of infection related PTB, we performed an untargeted mass spectrometry discovery study on 51 bioptic mid zone amnion samples from premature babies. A total of 6352 proteins were identified. Bioinformatics analyses revealed a ranked core of 159 proteins maximizing the discrimination between the selected clinical stratification groups allowing to distinguish conditions of absent (FIR 0) from maximal Fetal Inflammatory Response (FIR 3) stratified in function of Maternal Inflammatory Response (MIR) grade. Matrix metallopeptidase-9 (MMP-9) was the top differentially expressed protein. Gene Ontology enrichment analysis of the core proteins showed significant changes in the biological pathways associated to inflammation and regulation of immune and infection response. Data suggest that the conditions determining PTB would be a transversal event, secondary to the maternal inflammatory response causing a breakdown in fetal-maternal tolerance, with fetal inflammation being more severe than maternal one. We also highlight matrix metallopeptidase-9 as a potential predictive biomarker of PTB that can be assayed in the maternal serum, for future investigation.

Multidisciplinary study of sudden unexpected infant death in Liguria (Italy): a nine-year report.

INTRODUCTION: We conducted a retrospective analysis of cases of sudden unexpected infant death (SUID) referred to the SIDS-ALTE Center of the Liguria Region (Italy) from 2010 to 2018. In all cases, the death scene was inspected, and a multidisciplinary post-mortem evaluation was conducted. Our aim was to analyze the epidemiological data and etiological distribution. EVIDENCE ACQUISITION: We examined 15 cases initially classified as sudden infant death. EVIDENCE SYNTHESIS: In all cases, the death was initially unexplained. Seven cases involved males and eight involved females. Their mean age was 67.47 days; the youngest victim was 2 days old, while the oldest was 8.5 months (253 days). In 7 cases, the post-mortem analysis showed an infection of lung. In 4 cases, the prone position of the infant during sleep was identified as a risk factor. Only in one case the cause of death remains unexplained, and it was classified as sudden infant death syndrome II according to San Diego Classification. CONCLUSIONS: In the forensic approach to cases of SUID, it is always important to conduct a thorough multidisciplinary investigation. In order to avoid procedural errors that might compromise the post-mortem investigation, it is necessary to consider the medical and social history of both mother and child, in addition to the circumstances of the death. Moreover, a complete pediatric post-mortem examination and multidisciplinary discussion are required in order to identify potentially important causative or contributory factors.

Sudden and unexpected death in childhood due to an undiagnosed hepatoblastoma: Case report and review of literature.

The sudden and unexpected death of an infant or child due to cancer is a particularly rare event. Most of the cases concern primary growths located in vital organs such as the heart or the brain. Only in an extremely small number of cases does it occur in infants or children affected by liver cancer. Herein we report the sudden and unexpected death of a 3-and-a-half-year-old infant, who due to an undiagnosed tumor of the liver, namely hepatoblastoma, suffered a major intra-abdominal (hemoperitoneum) bleed, leading to a fatal hemorrhagic trauma. In cases like these, it is of utmost importance to carry out both an autopsy as well as complete histological tests in order to determine if the hepatic tumor is the real cause of death or if it was a mere chance finding. In the case of sudden and unexplained deaths in infancy and childhood, the forensic pathologist should always consider that other complications, for example, those correlated with hepatoblastoma could, in fact, cause sudden death given that this particular tumor is often scarcely symptomatic and can remain undiscovered for a long period of time.

Prenatal genetic diagnosis: Fetal therapy as a possible solution to a positive test.

BACKGROUND: Fetal abnormalities cause 20% of perinatal deaths. Advances in prenatal genetic and other types of screening offer great opportunities for identifying high risk pregnancies. METHODS: Through a literature search, here we summarise what are the prenatal diagnostic technique that are being used and how those techniques may allow for prenatal interventions. RESULTS: Next generation sequencing and non-invasive prenatal testing are fundamental for clinical diagnostics because of their sensitivity and accuracy in identifying point mutations, aneuploidies, and microdeletions, respectively. Timely identification of genetic disorders and other fetal abnormalities enables early intervention, such as in-utero gene therapy, fetal drug therapy and prenatal surgery. CONCLUSION: Prenatal intervention is mainly focused on conditions that may cause death or lifelong disabilities, like spina bifida, congenital diaphragm hernia and sacrococcygeal teratoma; and may be an alternative therapeutic option to termination of pregnancy. However, it is not yet widely available, due to lack of specialized centers.

Placental Pathology Findings and the Risk of Intraventricular and Cerebellar Hemorrhage in Preterm Neonates.

Placental pathology as a predisposing factor to intraventricular hemorrhage remains a matter of debate, and its contribution to cerebellar hemorrhage development is still largely unexplored. Our study aimed to assess placental and perinatal risk factors for intraventricular and cerebellar hemorrhages in preterm infants. This retrospective cohort study included very low-birth weight infants born at the Gaslini Children's Hospital between January 2012 and October 2016 who underwent brain magnetic resonance with susceptibility-weighted imaging at term-equivalent age and whose placenta was analyzed according to the Amsterdam Placental Workshop Group Consensus Statement. Of the 286 neonates included, 68 (23.8%) had intraventricular hemorrhage (all grades) and 48 (16.8%) had a cerebellar hemorrhage (all grades). After correction for gestational age, chorioamnionitis involving the maternal side of the placenta was found to be an independent risk factor for developing intraventricular hemorrhage, whereas there was no association between maternal and fetal inflammatory response and cerebellar hemorrhage. Among perinatal factors, we found that intraventricular hemorrhage was significantly associated with cerebellar hemorrhage (odds ratio [OR], 8.14), mechanical ventilation within the first 72 h (OR, 2.67), and patent ductus arteriosus requiring treatment (OR, 2.6), whereas cesarean section emerged as a protective factor (OR, 0.26). Inotropic support within 72 h after birth (OR, 5.24) and intraventricular hemorrhage (OR, 6.38) were independent risk factors for cerebellar hemorrhage, whereas higher gestational age was a protective factor (OR, 0.76). Assessing placental pathology may help in understanding mechanisms leading to intraventricular hemorrhage, although its possible role in predicting cerebellar bleeding needs further evaluation.

Unexpected and Sudden Death Due to Undiagnosed Moraxella catarrhalis Meningoencephalitis in a 40-day-old Infant: Case Report and Literature Review.

Acute bacterial meningitis in infants and newborns represents a medical emergency and a significant cause of mortality and morbidity worldwide. Moraxella catarrhalis has been considered a microorganism with low pathogenic potential, and only in exceptional cases has it been found to cause meningitis in infants and immunocompetent people. We will now document an unusual case of an unexpected and sudden death of a 40-day-old infant due to acute meningitis from M. catarrhalis, apparently asymptomatic and subsequently diagnosed by an autopsy. According to our knowledge this is the first case of unexpected infant death due to undiagnosed M. catarrhalis meningitis.The suggested case, as well as for the rarity of such a fatal event, should be considered a caution to pediatrics and neonatologists for M. catarrhalis can cause paucisymptomatic meningoencephalitis in infants which can be potentially fatal.From a forensic point of view, an autopsy accompanied by a multidisciplinary assessment is always necessary in cases of unexpected infant deaths to identify the causes.

Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development.

Mutations in the WWOX gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous WWOX mutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of a WWOX-deficient human fetus from this family. A similar disorganization of cortical layers was identified in lde/lde rats (carrying a homozygous truncating mutation which disrupts the active Wwox C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of the WWOX gene in migrating neurons across different species.

Unexpected Infant Death Due to Undiagnosed Biliary Atresia: A Case of Fatal Neglect.

Biliary atresia (BA) is a fatal condition resulting in the lack of effective biliary drainage leading invariably to liver failure and cirrhosis within a year, and it is often lethal within a few months in the absence of corrective surgery or liver transplantation. In fact, BA is the most common indication for pediatric liver transplantation.Herein, we present a rare case of unexpected infant death due to BA diagnosed only postmortem in a context of child neglect and carelessness on the part of the parents. It emerged from the clinical history that after a few months, the parents no longer took their daughter to any medical checkups despite the indications and express recommendations for follow-up. The autopsy revealed agenesis of the gallbladder with BA and complete disruption of the hepatic architecture and parenchyma from biliary cirrhosis. Histological examinations documented severe biliary cirrhosis from hypoplasia of the biliary ducts.The child neglect in this case proved fatal inasmuch as an early diagnosis by a pediatrician would have likely allowed appropriate surgical treatment, thus avoiding the untimely death of the child. We highlight the importance of educating and informing parents (especially the disadvantaged) in matters of health. At the same time, primary care physicians should closely monitor the conditions and development of infants so as to recognize the early warning signs and symptoms of BA, bearing in mind that a timely diagnosis and proper surgical treatment can save the lives of most of these children.

Medico-legal considerations on "Lotus Birth" in the Italian legislative framework.

The term "Lotus Birth" identifies the practice of not cutting the umbilical cord and of leaving the placenta attached to the newborn after its expulsion until it detaches spontaneously, which generally occurs 3-10 days after birth. The first reported cases of Lotus Birth date back to 2004 in Australia.Supporters of such a procedure claim that the newborn is better perfused, endowed with a more robust immune system and "less stressed".However, it should be pointed out that histopathological study of the placenta is increasingly being requested in order to investigate problems of an infective nature or dysmaturity affecting the foetus, and situations of risk affecting the mother. Moreover, from the legal standpoint, there is no uniform position on the question of whether the placenta belongs to the mother or to the newborn. Lastly, a proper conservation of the embryonic adnexa is very difficult and includes problems of a hygiene/health, infectivological and medico-legal nature.The authors analyzed all these aspect in the Italian legislative framework, reaching the conclusion that Lotus Birth is inadvisable from both the scientific and logical/rational points of view.

Intensivists Performed Percutaneous Bicaval Double-Lumen Echo-Guided Extracorporeal Membrane Oxygenation Cannulation at Bedside in Newborns and Children: A Retrospective Analysis.

OBJECTIVES: To describe a single institution experience on echo-guided percutaneous bicaval double lumen extracorporeal membrane oxygenation cannulation performed at the bedside by intensivists. DESIGN: Retrospective observational study. SETTING: Extracorporeal membrane oxygenation team of a tertiary care children's hospital. PATIENTS: All patients 0-14 years old undergoing venovenous extracorporeal membrane oxygenation from January 1, 2013, to January 1, 2018. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty children underwent 32 extracorporeal membrane oxygenation runs. Median age at enrollment was 2 months (interquartile range, 0-20.5 mo), 65.6% of the runs (21 patients) were performed in newborns (n = 13, 40.6%) or infants (n = 8, 25%). Median preextracorporeal membrane oxygenation index was 66.9 (interquartile range, 50-85.6). Major comorbidities were present in 50% of patients. All patients were cannulated percutaneously. In two cases cannulation occurred from the left internal jugular vein. Extracorporeal membrane oxygenation was effective in increasing pH, arterial oxygen saturation, PaO2, and lowering PaCO2. The overall differences in pre and postextracorporeal membrane oxygenation values were statistically significant, while stratifying patients according to the cannula diameter (mm)/major diameter of the cannulated internal jugular vein (mm) ratio (> 0.67 or ≤ 0.67), statistical significance was reached only for the highest ratio. Complications were observed in three runs: two cannula tip dislocations in the right atrium and one limited flow in the only case in which an Avalon cannula was not used. In 20 cases (62.5% of 32 runs), the cannulated vessel was patent at follow-up or autopsy. A ratio less than or equal to 0.67 or greater than 0.67 did not influence the occurrence rate of complications, nonpatency of the internal jugular vein, death for intracranial bleeding and death at 30 days from extracorporeal membrane oxygenation discontinuation. Overall cumulative survival at 30 days from extracorporeal membrane oxygenation discontinuation was 60% (95% CI, 40-75), with a survival advantage in the case of ratio greater than 0.67 (65%; 95% CI, 44-80 vs 25%; 95% CI, 0-60). CONCLUSIONS: The described technique proved to be feasible, safe, and effective. Further investigation is needed.

Giant Hepatic Hemangioma and Placental Chorangiosis: A Unique Case of Stillbirth?

INTRODUCTION: Hepatic hemangiomas (HH) are benign vascular tumors, and when large, may contribute to fetal morbidity/mortality. Chorangiosis is placental villus capillary hypervascularity, probably linked with fetal hypoxia. CASE REPORT: We present a macrosomic stillbirth at 39 + 3 weeks of gestation with congestive heart failure (CHF) and myocardial infarction. A giant right hepatic lobe HH was present, along with placental chorangiosis. CONCLUSION: A common pathogenetic pathway between congenital HH and placental chorangiosis has not been reported. Our case suggests that the effects of HH and chorangiosis increase the risk of late fetal loss due to the high-output CHF.