BackgroundGermline pathogenic variants in DICER1 cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (Global developmental delay, Lung cysts, Overgrowth, Wilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.MethodsWhole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with DICER1 RNase III domain mutations were performed.ResultsA de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of DICER1 was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome.ConclusionThe phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to DICER1 hotspot mutations in the RNase IIIb domain. We show that an individual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome (‘DICER1 syndrome plus’), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.
IntroductionMild traumatic brain injury (mTBI) is one of the most common reasons for emergency department (ED) visits. A portion of patients with mTBI will develop an intracranial lesion that might require medical or surgical intervention. In these patients, swift diagnosis and management is paramount. Several guidelines have been developed to help direct patients with mTBI for head CT scanning, but they lack specificity, do not consider the interactions between risk factors and do not provide an individualised estimate of intracranial lesion risk. The aim of this study is to create a model that estimates individualised intracranial lesion risks in patients with mTBI who present to the ED.Methods and analysisThis will be a retrospective cohort study conducted at ED hospitals in Stockholm, Sweden. Eligible patients are adults (≥15 years) with mTBI who presented to the ED within 24 hours of injury and performed a CT scan. The primary outcome will be a traumatic lesion on head CT. The secondary outcomes will be any clinically significant lesion, defined as an intracranial finding that led to neurosurgical intervention, hospital admission ≥48 hours due to TBI or death due to TBI. Machine-learning models will be applied to create scores predicting the primary and secondary outcomes. An estimated 20 000 patients will be included.Ethics and disseminationThe study has been approved by the Swedish Ethical Review Authority (Dnr: 2020-05728). The research findings will be disseminated through peer-reviewed scientific publications and presentations at international conferences.Trial registration numberNCT04995068.
Background Recent molecular studies of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have started to delineate the nature and timing of genetic variants and those responsible for subsequent progression to overt leukemia. However, the etiology behind both initiation and progression remains largely unknown. Nonetheless, theories, but also epidemiological evidence, of how exposure to common infections and other microbes in our environment modulates the risk of developing childhood BCP-ALL, have emerged. In light of these theories and the well-known phenomena of seasonality in infectious disease spread, childhood ALL has been analyzed for signs of seasonal variation, with differing results. Methods In this study we applied the Bayesian Generalized Auto Regressive Integrated Moving Average with external variables (GARIMAX) model, adapted for count data via a negative binomial distribution, to study seasonal variation of incidence in a Swedish population-based cohort of 1601 BCP-ALL cases. The studied cases were aged 0-18 years at diagnosis and identified from the Swedish Childhood Cancer Registry (SCCR). Also, two subgroups of BCP-ALL represented by the most abundant genetic subtypes, ETV6/RUNX1 and HeH respectively, were analyzed accordingly. All analyses were performed in two stages. The first stage identified the presence of the repeatable pattern using harmonic functions, and the second stage consisted of the identification of the peak months in the series. Results An informative seasonal variation in BCP-ALL incidence numbers, displaying a peak in August and September, was detected in the total cohort of 1601 individuals. No seasonality was detected analyzing the subtype groups HeH and ETV6/RUNX1 positive BCP-ALL, respectively. Conclusion The manifested seasonality in BCP-ALL with a peak in August-September may suggest that the prolonged period of minimal viral spread during Swedish summer vacation causes a temporary halt in the last step of progression to overt disease and consequently an accumulated number of cases presenting in August-September.
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