Background:SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of... Show moreBackground:SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data.Methods:This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity.Results:We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curacao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies.Conclusions:Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections. Show less
Douben, H.C.W.; Nellist, M.; Unen, L. van; Elfferich, P.; Kasteleijn, E.; Hoogeveen-Westerveld, M.; ... ; Ham, T.J. van 2022
Neurofibromatosis type 1 (NF1) is caused by inactivating mutations in NF1. Due to the size, complexity, and high mutation rate at the NF1 locus, the identification of causative variants can be... Show moreNeurofibromatosis type 1 (NF1) is caused by inactivating mutations in NF1. Due to the size, complexity, and high mutation rate at the NF1 locus, the identification of causative variants can be challenging. To obtain a molecular diagnosis in 15 individuals meeting diagnostic criteria for NF1, we performed transcriptome analysis (RNA-seq) on RNA obtained from cultured skin fibroblasts. In each case, routine molecular DNA diagnostics had failed to identify a disease-causing variant in NF1. A pathogenic variant or abnormal mRNA splicing was identified in 13 cases: 6 deep intronic variants and 2 transposon insertions causing noncanonical splicing, 3 postzygotic changes, 1 branch point mutation and, in 1 case, abnormal splicing for which the responsible DNA change remains to be identified. These findings helped resolve the molecular findings for an additional 17 individuals in multiple families with NF1, demonstrating the utility of skin-fibroblast-based transcriptome analysis for molecular diagnostics. RNA-seq improves mutation detection in NF1 and provides a powerful complementary approach to DNA-based methods. Importantly, our approach is applicable to other genetic disorders, particularly those caused by a wide variety of variants in a limited number of genes and specifically for individuals in whom routine molecular DNA diagnostics did not identify the causative variant. Show less
Siebelt, M.; Vos-Jakobs, S. de; Koenrades, N.; Nieuwenhoven, C.A.V. van; Oostenbrink, R.; Bramer, W.M.; ... ; Kempink, D.R.J. 2020
Background: A congenital forearm pseudarthrosis is a rare condition and is strongly associated with neurofibromatosis type 1. Several surgical techniques are described in the literature, but the... Show moreBackground: A congenital forearm pseudarthrosis is a rare condition and is strongly associated with neurofibromatosis type 1. Several surgical techniques are described in the literature, but the most optimal treatment strategy remains unclear. This systematic review aims to develop a treatment algorithm that may aid in clinical decision making. Methods: The PROSPERO registration number for this study was CRD42018099602 and adheres to the PRISMA guidelines for systematic reviews. Embase, MEDLINE, Cochrane Central, Web of Science, and Google Scholar databases were searched for published studies reporting on congenital forearm pseudarthrosis not related to other underlying pathologies like bacterial infection or fibrous dysplasia. Results were not restricted by date or study type, only English literature was allowed. Studies were assessed for quality using the critical appraisal checklist for case reports from the Joanna Briggs Institute. Patient characteristics, underlying disease, type of surgery, union rate, and functional outcome were extracted from included studies. Results: Of 829 studies identified, 47 were included in this review (17 case series and 30 case reports, a total of 84 cases). A one-bone forearm procedure showed highest union rates (92%), however, it results in loss of forearm rotation. Free vascularized fibula grafting showed high union rates (87%) and was related to good functional outcome of elbow flexion and forearm rotations. Other procedures showed disappointing outcomes. Conclusions: Congenital forearm pseudarthrosis is best treated with a free vascularized fibula grafting, a one-bone forearm procedure should be used as a salvage procedure. Evidence extracted from the case reports was sufficient to generate a treatment algorithm to be used in clinical pediatric practice. Show less
Purpose Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due... Show morePurpose Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance. Methods We investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets. Results Individuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population. Conclusions The variance and heritability of IQ in individuals with NF1 are similar to that of the general population, and hence mostly driven by genetic background differences. The only factor that significantly attenuates IQ in NF1 individuals is the NF1 chromosomal microdeletion genotype. Implications for clinical management are that individuals with intragenic NF1 variants that score <1.5-2 SD below the mean of the NF1 population should be screened for additional causes of cognitive disability. Show less
Background: Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder. Whether VWD is associated with health-related quality of life (HR-QoL) in children is unknown. Objectives:... Show moreBackground: Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder. Whether VWD is associated with health-related quality of life (HR-QoL) in children is unknown. Objectives: This nationwide cross-sectional study measured HR-QoL in children with moderate or severe VWD. Our primary aim was to compare HR-QoL of VWD patients with that of reference populations. Additionally, we studied the impact of bleeding phenotype and VWD type on HR-QoL. Methods: HR-QoL was assessed with the Infant/Toddler QoL Questionnaire (0-5 years) and Child Health Questionnaire (6-15 years), and compared with reference population scores. Multivariate analysis was used to evaluate the influence of type of VWD and bleeding phenotype on HR-QoL scores. Results: Preschool children (0-5 years, n = 46) with VWD had lower HR-QoL scores for general health perceptions and parental time than reference populations. School children (6-15 years, n = 87) with VWD had lower scores for physical functioning, role functioning - emotional/behavioral, general health perceptions, and physical summary. Type of VWD was associated with HR-QoL in school children for bodily pain, general health perceptions, parental emotion, family activities, and physical summary. Scores of children with type 3 VWD were, on average, 15 points lower than those of the reference population on the above-mentioned scales. A more severe bleeding phenotype was associated with a lower score on 11/15 physical, emotional and social scales. Conclusion: HR-QoL is lower in VWD children than in reference populations, in particular in school children. The negative impact of VWD is sensitive to type of VWD and bleeding phenotype; as well as physical scales, emotional and social scales are affected. Show less
