58 research outputs found
Alarming signs of serious infections in febrile children: Studies in primary care and hospital emergency care
__Abstract__
Children constitute a substantial part of the workload of physicians in primary care and hospital
emergency care. In the Netherlands, about 70% of the 3.9 million inhabitants less than 20 years
of age had one or more contacts with their general practitioner (GP) in 2011. Primary out-ofhours
care is annually visited by approximately 600,000 children younger than 14 years of age
and hospital emergency departments (EDs) by nearly 400,000 children in this age group.
Fever is one of the most common reasons for children to consult a physician. The incidence
of fever as a reason for contacting primary care is approximately 430 per 1,000 patients/year
under the age of 5 years. The overall incidence rate of the diagnosis of fever (without apparent
source) in primary care is 19.2 per 1,000 patients/year, with the highest rate for children less
than one year (100 per 1,000 patients/year) and the lowest rate for children aged 10 to 17 years
(2.7 per 1,000 patients/year). At the ED, fever is also one of the main presenting problems and
accounts for about 10% to 30% of all visits by children.
Most acute febrile illnesses are caused by self-limiting viral infections, which do not require
antibiotic treatment, diagnostic procedures, or hospitalization. However, a minority of febrile
children develop a serious infection, such as meningitis, sepsis, pneumonia or urinary tract
infection, for which timely diagnosis and targeted therapy are necessary to prevent harm. In
primary care, the annual incidence of serious infections is about 1%, with a peak incidence
rate among the youngest children (0 to 4 years: 21.1 per 1,000 patients/year). At the hospital
ED about 15% to 20% of febrile children are diagnosed with a serious infection. Serious
infections are an important cause of morbidity and mortality, especially in young children.
Infections accounted for about 15% to 20% of all childhood deaths by natural cause in the
Netherlands and the United Kingdom
Alarming signs and symptoms in febrile children in primary care: An observational cohort study in The Netherlands
__Abstract__
Context: Febrile children in primary care have a low risk for serious infection. Although several alarming signs and symptoms are proposed to have predictive value for serious infections, most are based on research in secondary care. The frequency of alarming signs/symptoms has not been established in primary care; however, in this setting differences in occurrence may influence their predictive value for serious infections. Objective: To determine the frequency of alarming signs/symptoms in febrile children in primary care. Design: Observational cohort study. Clinical information was registered in a semi-structured way and manually recoded. Setting: General practitioners' out-of-hours service. Subjects: Face-to-face patient contacts concerning children (aged ≤16 years) with fever were eligible for inclusion. Main outcome measures: Frequency of 18 alarming signs and symptoms as reported in the literature. Results: A total of 10,476 patient contacts were included. The frequency of alarming signs/symptoms ranged from n = 1 (ABC instability; 40°C as reported by the parents; 12.9%) to 8,647 contacts (parental concern; 82.5%). Conclusion: Although the prevalence of specific alarming signs/symptoms is low in primary care, ≥50% of children have one or more alarming signs/symptoms. There is a need to determine the predictive value of alarming signs/symptoms not only for serious infections in primary care, but as well for increased risk of a complicated course of the illness
The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction
Purpose: Neurodevelopmental disorders (NDD) caused by protein
phosphatase 2A (PP2A) dysfunction have mainly been associated
with de novo variants in PPP2R5D and PPP2CA, and more rarely in
PPP2R1A. Here, we aimed to better understand the latter by
characterizing 30 individuals with de novo and often recurrent
variants in this PP2A scaffolding Aα subunit.
Methods: Most cases were identified through routine clinical
diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits.
Results: We describe 30 individuals with 16 different variants in
PPP2R1A, 21 of whom had variants not previously reported. The severity
of developmental delay ranged from mild learning problems to severe
intellectual disability (ID) with or without epilepsy. Common features
were language delay, hypotonia, and hypermobile joints. Macrocephaly
was only seen in individuals without B55α subunit-binding deficit, and
these patients had less severe ID and no seizures. Biochemically more
disruptive variants with impaired B55α but increased striatin binding
were associated with profound ID, epilepsy, corpus callosum hypoplasia,
and sometimes microcephaly.
Conclusion: We significantly expand the phenotypic spectrum of
PPP2R1A-related NDD, revealing a broader clinical presentation of the
patients and that the functional consequences of the variants are more
diverse than previously reported
Do employees benefit from collaborations between out of hours general practitioners and emergency departments?
Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy
Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harboring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20), delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: defective cell membrane expression (1), impaired LGI1-binding (2), and/or impaired interaction with the postsynaptic density protein PSD-95 (3). We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics
Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy
Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics. Van der Knoop et al. describe the clinical features of 21 individuals with biallelic pathogenic variants in ADAM22 and confirm the deleteriousness of the variants with functional studies. Clinical hallmarks of this rare disorder comprise progressive encephalopathy and infantile-onset refractory epilepsy.Peer reviewe
Correction to: Putting genome-wide sequencing in neonates into perspective
The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article
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