De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.

PURPOSE: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations. METHODS: Patients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts. RESULTS: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals presented either with early-onset stroke (n = 11) or with Leigh syndrome (n = 3). No genotype-phenotype correlation could be established. Proteomics using patient-derived fibroblasts revealed no significant differences between clinical subgroups. 3D modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting zinc-binding suggesting a gain-of-function or dominant negative effect. CONCLUSION: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome.

[Strategies for airway management in neonates : Results of a survey of German perinatal centers levels II and III]. / Strategien zur Atemwegssicherung bei Neugeborenen : Ergebnisse einer Befragung deutscher Perinatalzentren der Level I und II.

BACKGROUND: Airway management in children, especially in patients with a difficult airway, remains a major challenge for anesthesiologists, pediatricians, and emergency medicine physicians. In recent years new tools have been introduced into the clinical practice. OBJECTIVE: The aim was to present the current strategies for securing the airway in neonates in perinatal centers levels II and III in Germany, and to collect data on the rare event of coniotomy. MATERIAL AND METHODS: From 5 April 2021 to 15 June 2021, physicians practicing intensive care in pediatrics and neonatology at perinatal centers levels II and III in Germany were surveyed by means of an anonymized online questionnaire. The questionnaire was designed by the authors and verified by pretesting with the help of five pediatric specialists. Contact was made digitally via the e­mail addresses provided on the websites of the respective centers. The survey was administered through the fee for service provider LimeSurvey©. The collected data were transferred to the IBM© statistical package for the social scientists (SPSS, version 28, IBM© Corporation, Armonk, NY, USA) and statistically analyzed. Pearson's χ2-test was used to perform significance testing (significance level p = < 0.05). Only completed questionnaires were included in the analysis. RESULTS: A total of 219 participants completed the questionnaire. Available airway devices: 94.5% (n = 207) nasopharyngeal tubes, 79.9% (n = 175) video laryngoscope/fiber optic, 73.1% (n = 160) laryngeal masks, 64.8% (n = 142) oropharyngeal tube (Guedel). Of the participants 6 (2.7%) performed coniotomy (⌀ 1.6 children). Out of six cases five (83.3%) were resuscitation situations caused by complex anatomical malformations. Training of coniotomy was not provided in 98.6% (n = 216). A Standard Operating Procedure (SOP) for difficult airway in neonates was possessed by 20.1% (n = 44). CONCLUSION: The comparison with international studies showed that the equipment of German perinatal centers is above average. The trend towards acquisition of a video laryngoscope and its importance in clinical routine could be confirmed by our data; however, the fact that 20% of the respondents did not have access to video laryngoscopy suggests that further acquisitions will have to be made here in the future. Front of neck access (FONA) methods remain a critically questioned component of neonatal difficult airway algorithms due to their rarity and the resulting lack of data. In summary of the recommendations of the British Association of Perinatal Medicine (BAPM) and the collected data on the theoretical and practical education of the FONA methods in Germany, the implementation of the FONA methods by pediatricians and neonatologists cannot be recommended. As most resuscitation situations were caused by complex anatomical malformations, the early detection of such malformations by means of high-resolution ultrasound seems to be of particular importance. With improvement of early detection, neonates with potentially unmanageable airway problems can be left on uteroplacental circulation for a prolonged period in order to perform necessary interventions, such as tracheostomy, bronchoscopy, or extracorporeal membrane oxygenation (ECMO) device known as the ex utero intrapartum treatment (EXIT) procedure.

Alveolar capillary dysplasia without misalignment of pulmonary veins, hyperinflammation, megalocornea and overgrowth - Association with a homozygous 2bp-insertion in LTBP2?

We present a male infant with alveolar capillary dysplasia without misalignment of pulmonary veins, hyperinflammation, megalocornea and macrosomia/macrocephaly at birth. Whole-exome sequencing revealed a homozygous 2bp-insertion in the latent transforming growth factor-beta binding protein 2 (LTBP2) (c.278_279dup, p.(Ser94Glyfs*187)). So far, LTBP2-variants have been frequently reported with an eye-restricted phenotype including primary congenital glaucoma and megalocornea/microspherphakia and ectopia lentis with/without secondary glaucoma. Hitherto reported systemic phenotypes showed, among others, features as tall stature, finger anomalies, high-arched palate and cardiovascular anomalies. The main pathophysiological finding of our patient was an alveolar capillary dysplasia (with pulmonary arterial hypertension and right ventricular impairment but without misalignment of pulmonary veins) resulting in almost continuous oxygen demand and prolonged dependence on mechanical ventilation. He died of respiratory failure at the age of seven months. This patient may extend the LTBP2-related phenotype with resulting diagnostic implications.

Influence of probiotic supplementation on the developing microbiota in human preterm neonates.

BACKGROUND: Oral administration of probiotic bacteria to preterm neonates has been recommended to prevent the development of necrotizing enterocolitis (NEC). The influence of probiotics on the endogenous microbiome, however, has remained incompletely understood. STUDY DESIGN & METHODS: Here, we performed an observational study including 80 preterm neonates born at a gestational age <32-weeks to characterize the persistence of probiotic bacteria after no treatment or oral administration of two different probiotic formula and their influence on the microbial ecosystem during and after the intervention and their association with the development of NEC. Weekly fecal samples were profiled by 16S rRNA sequencing and monitored for the presence of the probiotic bacteria by quantitative PCR. RESULTS: Microbiota profiles differed significantly between the control group and both probiotic groups. Probiotic supplementation was associated with lower temporal variation as well as higher relative abundance of Bifidobacterium and Enterobacter combined with reduced abundance of Escherichia, Enterococcus, and Klebsiella. Colonization by probiotic bifidobacteria was observed in approximately 50% of infants although it remained transient in the majority of cases. A significantly reduced monthly incidence of NEC was observed in neonates supplemented with probiotics. CONCLUSION: Our results demonstrate successful transient colonization by probiotic bacteria and a significant influence on the endogenous microbiota with a reduced abundance of bacterial taxa associated with the development of NEC. These results emphasize that probiotic supplementation may allow targeted manipulation of the enteric microbiota and confer a clinical benefit. (Clinical Trial Registry accession number: DRKS/GCTR 00021034).

Transcranial Shear Wave Elastography of Neonatal and Infant Brains for Quantitative Evaluation of Increased Intracranial Pressure.

OBJECTIVES: Increased intracranial pressure (ICP) in neonates and infants is a severe disease state that requires adequate diagnosis and, depending on the clinical situation and whether it is increasing, a rapid and efficient therapy. Clinical evaluation, B-mode ultrasound, and Doppler ultrasound give rise to a basic noninvasive diagnosis of increased ICP. The purpose of this prospective study was 2-fold: first, to analyze the technical feasibility of obtaining shear wave elastography (SWE) measurements of an infant's brain, and second, to compare the values of healthy neonates to those who have hydrocephalus and are either suspected of having or invasively shown to have increased ICP. MATERIALS AND METHODS: This was a prospective, institutional review board-approved study of 184 neonates and infants with a mean age of 12 weeks (ranging from 1 day to 12 months). The final, technical evaluable cohort consisted of 166 infants, of whom 110 were healthy asymptomatic infants and 56 were diagnosed with hydrocephalus. Of the latter, 38 showed clinically increased ICP and 18 did not. Invasive ICP measurements were available from 47 of the children. All infants underwent systematic examination using B-mode ultrasound, Doppler ultrasound, and SWE using a high-resolution linear 15-MHz probe (Aixplorer; Supersonic), by 1 of 2 radiologists, each of whom had at least 5 years' experience examining children's brains and applying SWE. Semiquantitative and quantitative SWE measurements were performed.We compared the SWE values to each participant's clinical symptoms and to their invasive ICP measurement results. Correlations were calculated using Pearson and Spearman correlation coefficients. We used Student t test to compare the mean SWE values in healthy children to those of children with increased ICP. RESULTS: Shear wave elastography in the brain was technically feasible, giving reliable SWE measurements in 110 (88.7%) of 124 of healthy children and in 56 (93.3%) of 60 children with hydrocephalus. Shear wave elastography values and, thus, rigidity in the brain's parenchyma were significantly higher in children with hydrocephalus (n = 56) than in healthy children (n = 110; mean, 21.8 kPa vs 14.1 kPa; P = 0.0083). A thorough correlation between invasive ICP measurements and SWE values in a subgroup of patients with hydrocephalus revealed a direct correlation between increased ICP and increased SWE values (r = 0.69, P < 0.001). Mean SWE values were 30.8 kPa (range, 23.9-62.3 kPa) in patients with confirmed increased ICP (n = 35) versus 16.2 kPa (range, 10.2-41.9 kPa) in patients with nonincreased ICP (n = 12). CONCLUSIONS: Shear wave elastography is feasible in neonates with increased ICP and could be a useful additional diagnostic imaging and monitoring method for children verified or suspected to have increased ICP. However, more evidence is necessary to further evaluate the usefulness of SWE measurements in neonates with hydrocephalus. CLINICAL RELEVANCE: Shear wave elastography can be used as a surrogate marker for ICP in neonates and infants.

Plasma-derived Factor X therapy for treatment of intracranial bleeding in a patient with Factor X deficiency: a case report.

BACKGROUND: Factor X (FX) deficiency (FXD) is an extremely rare autosomal recessive hereditary hematologic disorder, affecting approximately one in 1,000,000 of the general population. CASE REPORT: This case report describes an infant with hereditary severe FXD who presented with a spontaneous, life-threatening intracranial hemorrhage and was treated with the first licensed plasma-derived FX (pdFX) concentrate. On admission, laboratory assays showed severe coagulopathy of unknown cause; the patient was empirically treated using a multimodal hemostatic approach with prothrombin complex concentrate, fresh-frozen plasma, and tranexamic acid. Subsequent single-factor coagulation and genetic analyses confirmed the hereditary FXD diagnosis, and the therapeutic regimen was changed to a targeted regimen of 250 IU pdFX daily. Based on careful monitoring of the coagulation profile, pdFX administration frequency was increased to twice daily, followed by a reduction to once every 18 hours. The patient was discharged after 7 weeks of hospitalization in good clinical condition and now receives prophylactic pdFX three times weekly.

Spontaneous movements in the first four months of life: An accelerometric study in moderate and late preterm infants.

BACKGROUND: Moderate preterm infants (MPI) and late preterm infants (LPI) account for the majority of children born preterm. Up to 5% of MPI and LPI are estimated to manifest neurodevelopmental impairments. However, information about normal early motor development in these patients is lacking. AIM: To find characteristic patterns for motor development in the first four months of life among MPI and LPI without risk factors for developmental impairment by using accelerometry of spontaneous movements. STUDY DESIGN: Prospective and observational study. SUBJECTS: Twenty-three MPI and LPI (9 female, 14 male) without known risk factors for neurodevelopmental impairment were included in this study. Spontaneous movements were measured by accelerometry at the time of hospital discharge (mean: 36.6wks postmenstrual age (PMA)) and at the corrected age of three months (mean: 53.0wks PMA). OUTCOME MEASURES: Motor development was described by analyzing 36 parameters calculated from the acceleration signal. Normal neurodevelopmental outcome was confirmed by Bayley Scales of Infant Development at the corrected age of two years. RESULTS: Statistically significant differences (p < 0.05) between the two measurements could be shown in 26 out of the 36 parameters. Striking changes in motor development were an increase in acceleration and variability of the spontaneous movements, the main criterion for analyzing spontaneous movements. Furthermore, the regularity of spontaneous movements increased significantly. CONCLUSION: Characteristic patterns of normal motor development in MPI and LPI can be identified and provide a basis for future investigations aiming at the early detection of abnormal motor development for this specific patient group.

Preterm Pulmonary Hemorrhage Is Associated with Multiple Births but Not with Intracytoplasmic Sperm Injection: A Cohort Study on Medical Records.

OBJECTIVE: Pulmonary hemorrhage (PH) is a severe complication in preterm neonates. This study aims to identify risk factors and comorbidities of PH. STUDY DESIGN: A single-center cohort study on medical records including all preterm neonates of <30 weeks' gestational age was conducted in the neonatal intensive care unit of Universitätsklinikum Aachen, Germany. The occurrence of PH served as a primary end point. Gestational age, birthweight, sex, multiple births, intracytoplasmic sperm injection (ICSI), intubation, surfactant, antenatal steroids, intraventricular hemorrhage (IVH), amniotic infection syndrome, and persistent ductus arteriosus were studied as risk factors. RESULTS: In this study, 344 preterm neonates were included, of whom 36 suffered from PH (10.5%). The mean time of the first occurrence was the third day of life (standard deviation [SD]: 1.2). On average, the patients suffered from 1.5 incidents (SD: 0.8) of PH, of whom 50% were severe. Preterm neonates born as multiples (95% confidence interval [CI]: 3.1, 26.9) and those who suffered from IVH (95% CI: 2.7, 18.9) had a significantly increased risk of PH. ICSI was not an independent risk factor. CONCLUSION: PH is significantly associated with IVH and multiple births but not with ICSI. The identification of patients at risk allows to apply prophylactic strategies of ventilation and pharmacological treatment.

Adult "termination-of-resuscitation" (TOR)-criteria may not be suitable for children - a retrospective analysis.

BACKGROUND: Only a small number of patients survive out-of-hospital-cardiac-arrest (OHCA). The duration of CPR varies considerably and transportation of patients under CPR is often unsuccessful. Termination-of-resuscitation (TOR)-criteria aim to preclude futile resuscitation efforts. Our goal was to find out to which extent existing TOR-criteria can be transferred to paediatric OHCA-patients with special regard to their prognostic value. METHODS: We performed a retrospective analysis of an eleven-year single centre patient cohort. 43 paediatric patients admitted to our institution after emergency-medical-system (EMS)-confirmed OHCA from 2003 to 2013 were included. Morrison's BLS- and ALS-TOR-rules as well as the Trauma-TOR-criteria by the American Association of EMS Physicians were evaluated for application in children, by calculating sensitivity, specificity, negative and positive predictive value for death-, as well as survival-prediction in our cohort. RESULTS: 26 patients achieved ROSC and 14 were discharged alive (n = 7 PCPC 1/2, n = 7 PCPC 5). Sensitivity for BLS-TOR-criteria predicting death was 48.3%, specificity 92.9%, the PPV 93.3% and the NPV 46.4%. ALS-TOR-criteria for death had a sensitivity of 10.3%, specificity of 100%, a PPV of 100% and an NPV of 35%. CONCLUSION: Retrospective application of the BLS-TOR-rule in our patient cohort identified the resuscitation of one later survivor as futile. ALS-TOR-criteria did not give false predictions of death. The proportion of CPRs that could have been abandoned is 48.2% for the BLS-TOR and only 10.3% for the ALS-TOR-rule. Both rules therefore appear not to be transferable to a paediatric population.

Early muscle and brain ultrastructural changes in polymerase gamma 1-related encephalomyopathy.

Mutations affecting the mitochondrial DNA-polymerase gamma 1 (POLG1) gene have been shown to cause Alpers-Huttenlocher disease. Ultrastructural data on brain and muscle tissue are rare. We report on ultrastructural changes in brain and muscle tissue of two sisters who were compound heterozygous for the c.2243G>C and c.1879C>T POLG1 mutations. Patient 1 (16 years) presented with epilepsia partialis continua that did not respond to antiepileptic treatment. Neuroimaging showed right occipital and bithalamic changes. Light microscopy from a brain biopsy performed after 3 weeks suggested chronic encephalitis showing astro- and microgliosis as well as perivascular CD8-positive T-cells. However, immunosuppressive therapy failed to improve her condition. When her 17-year-old sister (patient 2) also developed epilepsy, an intensified search for metabolic diseases led to the diagnosis. On electron microscopy mitochondrial abnormalities mainly affecting neurons were detected in the brain biopsy of patient 1, including an increase in number and size, structural changes and globoid inclusions. In patient 2, light and electron microscopy on a muscle biopsy confirmed a mitochondrial myopathy, also revealing an increase in mitochondrial size and number, as well as globoid inclusions. Neurons may be the primary target of mitochondrial dysfunction in brains of patients with Alpers disease related to POLG1 mutations. During early disease stages, brain histopathology may be misleading, showing reactive inflammatory changes.