ABSTRACT
For neurodevelopmental disorders (NDDs), a molecular diagnosis is key for management, predicting outcome, and counseling. Often, routine DNA-based tests fail to establish a genetic diagnosis in NDDs. Transcriptome analysis (RNA sequencing [RNA-seq]) promises to improve the diagnostic yield but has not been applied to NDDs in routine diagnostics. Here, we explored the diagnostic potential of RNA-seq in 96 individuals including 67 undiagnosed subjects with NDDs. We performed RNA-seq on single individuals' cultured skin fibroblasts, with and without cycloheximide treatment, and used modified OUTRIDER Z scores to detect gene expression outliers and mis-splicing by exonic and intronic outliers. Analysis was performed by a user-friendly web application, and candidate pathogenic transcriptional events were confirmed by secondary assays. We identified intragenic deletions, monoallelic expression, and pseudoexonic insertions but also synonymous and non-synonymous variants with deleterious effects on transcription, increasing the diagnostic yield for NDDs by 13%. We found that cycloheximide treatment and exonic/intronic Z score analysis increased detection and resolution of aberrant splicing. Importantly, in one individual mis-splicing was found in a candidate gene nearly matching the individual's specific phenotype. However, pathogenic splicing occurred in another neuronal-expressed gene and provided a molecular diagnosis, stressing the need to customize RNA-seq. Lastly, our web browser application allowed custom analysis settings that facilitate diagnostic application and ranked pathogenic transcripts as top candidates. Our results demonstrate that RNA-seq is a complementary method in the genomic diagnosis of NDDs and, by providing accessible analysis with improved sensitivity, our transcriptome analysis approach facilitates wider implementation of RNA-seq in routine genome diagnostics.
Subject(s)
Gene Expression Profiling , Neurodevelopmental Disorders , Humans , RNA-Seq , Cycloheximide , Sequence Analysis, RNA/methods , Neurodevelopmental Disorders/diagnosis , Neurodevelopmental Disorders/geneticsABSTRACT
The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl- channels and Cl-/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3-/- mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.
Subject(s)
Chloride Channels/genetics , Disease Models, Animal , Ion Channels/physiology , Mutation , Neurodevelopmental Disorders/pathology , Phenotype , Adolescent , Animals , Child , Child, Preschool , Female , Homozygote , Humans , Infant , Infant, Newborn , Male , Mice , Mice, Knockout , Neurodevelopmental Disorders/etiology , Neurodevelopmental Disorders/metabolismABSTRACT
Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder characterized by macrocephaly/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures. It is caused by dominant missense mutations in MTOR. The pathogenicity of novel variants in MTOR in patients with neurodevelopmental disorders can be difficult to determine and the mechanism by which variants cause disease remains poorly understood. We report 7 patients with SKS with 4 novel MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR activation and interrogate disease mechanisms. We complete structural analyses to understand the 3D properties of pathogenic variants. We examine the accuracy of relative accessible surface area, a quantitative measure of amino acid side-chain accessibility, as a predictor of MTOR variant pathogenicity. We describe novel clinical features of patients with SKS. We confirm MTOR Complex 1 activation and identify MTOR Complex 2 activation as a new potential mechanism of disease in SKS. We find that pathogenic MTOR variants disproportionately cluster in hotspots in the core of the protein, where they disrupt alpha helix packing due to the insertion of bulky amino acid side chains. We find that relative accessible surface area is significantly lower for SKS-associated variants compared to benign variants. We expand the phenotype of SKS and demonstrate that additional pathways of activation may contribute to disease. Incorporating 3D properties of MTOR variants may help in pathogenicity classification. We hope these findings may contribute to improving the precision of care and therapeutic development for individuals with SKS.
Subject(s)
Neurodevelopmental Disorders/genetics , TOR Serine-Threonine Kinases/genetics , Adult , Child, Preschool , Developmental Disabilities/genetics , Female , Humans , Intellectual Disability/genetics , Male , Megalencephaly/genetics , Middle Aged , Mutation , Mutation, Missense , Neurodevelopmental Disorders/physiopathology , Phenotype , TOR Serine-Threonine Kinases/metabolismABSTRACT
The key features of patients with a microduplication 5q35.2q35.3 (including the NSD1 gene) are short stature, microcephaly, mild developmental delay, behavioral problems, digital anomalies and congenital anomalies of internal organs. This core phenotype can be viewed as the reversed phenotype of Sotos syndrome, which is caused by a microdeletion in the same chromosomal region or a pathogenic variant in the NSD1 gene, and includes tall stature and macrocephaly, developmental delay, and epilepsy. Here, we report on a patient and his mother, both with a 5q35.2q35.3 duplication, adding a fifth family to the recently published overview of 39 patients of Quintero-Rivera et al. Our patient had several congenital anomalies, intrauterine growth restriction with a persisting short stature, while his mother was only mildly affected with decreased growth parameters. In addition, he had hemophagogocytic lymphohistiocytosis (HLH) triggered by Haemophilus influenzae and was recently diagnosed with Ewing sarcoma. Our cases carry the smallest duplication published (ca 332 kb, arr[hg19] 5q35.2q35.3(176493106-176824785)x3) further narrowing the distal side of the critical region of the 5q35.2q35.3 duplication. Besides broadening the clinical phenotypic spectrum, our report indicates that the 5q35.2q35.3 microduplication also shows a large intra-familial variability and expression.
Subject(s)
Abnormalities, Multiple , Dwarfism , Microcephaly , Sotos Syndrome , Male , Female , Humans , Sotos Syndrome/genetics , Abnormalities, Multiple/genetics , Microcephaly/diagnosis , Microcephaly/genetics , Mothers , PhenotypeABSTRACT
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.
Subject(s)
ADAM Proteins , Brain Diseases , Drug Resistant Epilepsy , Nerve Tissue Proteins , ADAM Proteins/genetics , ADAM Proteins/metabolism , Atrophy , Brain Diseases/genetics , Disks Large Homolog 4 Protein , Humans , Intracellular Signaling Peptides and Proteins , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolismABSTRACT
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 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.
Subject(s)
Neurofibromatosis 1 , Humans , Neurofibromatosis 1/diagnosis , Neurofibromatosis 1/genetics , Neurofibromatosis 1/pathology , Mutation , RNA Splicing/genetics , DNA , Fibroblasts/pathology , Neurofibromin 1/geneticsABSTRACT
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.
Subject(s)
Intellectual Disability , Microcephaly , Neurodevelopmental Disorders , Humans , Intellectual Disability/genetics , Muscle Hypotonia , Neurodevelopmental Disorders/epidemiology , Neurodevelopmental Disorders/genetics , Protein Phosphatase 2/genetics , Transcription FactorsABSTRACT
PURPOSE: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. METHODS: We retrospectively evaluated all genetic NICU consultations in a 2-year period. RESULTS: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. CONCLUSIONS: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.
Subject(s)
Infant, Newborn, Diseases/diagnosis , Infant, Newborn, Diseases/genetics , Chromosome Mapping/methods , Exome/genetics , Female , Genetic Testing/economics , Genome-Wide Association Study/methods , Humans , Infant, Newborn , Intensive Care, Neonatal , Male , Retrospective Studies , Exome Sequencing/economics , Exome Sequencing/methodsABSTRACT
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.
ABSTRACT
A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10-8 Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.
Subject(s)
BRCA1 Protein/genetics , Breast Neoplasms/genetics , Mutation/genetics , Ovarian Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Adult , Aged , Alternative Splicing/genetics , Breast Neoplasms/pathology , DNA Mutational Analysis , Exons/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , Ovarian Neoplasms/pathology , RNA Splice Sites/genetics , RNA Splicing/geneticsABSTRACT
OBJECTIVES: To assess whether the flowcharts and discriminators of the Manchester Triage System (MTS) can be used as indicators of alarming signs of serious febrile illness to predict the risk of hospitalization for febrile children who present at the emergency department (ED). STUDY DESIGN: Observational study, which included 2455 children (<16 years) who came to the ED of a university hospital with fever as their main complaint (May 2007-July 2009). Alarming signs for serious febrile illness were matched with MTS flowcharts and discriminators. At triage, the percentage of alarming signs positive was calculated. The diagnostic ability of the percentage of alarming signs positive to identify children at risk of hospitalization was assessed by calculating positive and negative likelihood ratios. RESULTS: Thirty percent of children had at least 1 alarming sign positive at triage. Twenty-three percent were hospitalized. Positive likelihood ratios of hospitalization were 5.0 (95% CI: 3.9-6.5) for children with >20% of alarming signs positive at triage and 12.0 (95% CI: 5.2-27.6) for those with >40% of alarming signs positive. Negative likelihood ratios were 0.8 (95% CI: 0.8-0.8) and 1.0 (95% CI: 0.9-1.0), respectively. CONCLUSIONS: By alternatively using the flowcharts and discriminators of the MTS as alarming signs, rather than urgency classifiers, the MTS can function as a simple, readily available tool to identify febrile children at risk of hospitalization early in the care process. This knowledge may help to improve ED throughput times as well as admission and discharge management at pediatric EDs.
Subject(s)
Fever/complications , Hospitalization , Pediatrics/methods , Triage/methods , Adolescent , Algorithms , Child , Child, Preschool , Decision Support Techniques , Emergency Service, Hospital , Female , Humans , Infant , Male , Pediatrics/standards , Prospective Studies , Risk , Severity of Illness IndexABSTRACT
BACKGROUND: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. METHODS: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. RESULTS: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. CONCLUSION: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.
Subject(s)
Hamartoma Syndrome, Multiple , Megalencephaly , Humans , Hamartoma Syndrome, Multiple/genetics , Hamartoma Syndrome, Multiple/pathology , Cohort Studies , Genetic Association Studies , PTEN Phosphohydrolase/genetics , Megalencephaly/genetics , PhenotypeABSTRACT
BACKGROUND: Due to emergency care overcrowding, right care at the right place and time is necessary. Uniform triage of patients contacting different emergency care settings will improve quality of care and communication between health care providers. OBJECTIVE: Validation of the computer-based Netherlands Triage System (NTS) developed for physical triage at emergency departments (EDs) and telephone triage at general practitioner cooperatives (GPCs). METHODS: Prospective observational study with patients attending the ED of a university-affiliated hospital (September 2008 to November 2008) or contacting an urban GPC (December 2008 to February 2009). For validation of the NTS, we defined surrogate urgency markers as best proxies for true urgency. For physical triage (ED): resource use, hospitalization and follow-up. For telephone triage (GPC): referral to ED, self-care advice after telephone consultation or GP advice after physical consultation. Associations between NTS urgency levels and surrogate urgency markers were evaluated using chi-square tests for trend. RESULTS: We included nearly 10 000 patients. For physical triage at ED, NTS urgency levels were associated with resource use, hospitalization and follow-up. For telephone triage at GPC, trends towards more ED referrals in high NTS urgency levels and more self-care advices after telephone consultation in lower NTS urgency levels were found. The association between NTS urgency classification and GP advice was less explicit. Similar results were found for children; however, we found no association between NTS urgency level and GP advice. CONCLUSIONS: Physically and telephone-assigned NTS urgency levels were associated with majority of surrogate urgency markers. The NTS as single triage system for physical and telephone triage seems feasible.
Subject(s)
After-Hours Care , Emergency Service, Hospital , General Practice/organization & administration , Triage/methods , Adolescent , Adult , Child , Diagnosis, Computer-Assisted , Hotlines , Humans , Netherlands , Physical Examination , Prospective StudiesABSTRACT
Cockayne syndrome (CS) is a multisystem degenerative disorder divided in 3 overlapping subtypes, with a continuous phenotypic spectrum: CS2 being the most severe form, CS1 the classical form and CS3 the late-onset form. Failure to thrive and growth difficulties are among the most consistent features of CS, leaving affected individuals vulnerable to numerous medical complications, including adverse effects of undernutrition, abrupt overhydration and overfeeding. There is thus a significant need for specific growth charts. We retrospectively collected growth parameters from genetically-confirmed CS1 and CS2 patients, used the GAMLSS package to construct specific CS growth charts compared to healthy children from WHO and CDC databases. Growth data were obtained from 88 CS patients with a total of 1626 individual growth data points. 49 patients were classified as CS1 and 39 as CS2 with confirmed mutations in CSB/ERCC6, CSA/ERCC8 or ERCC1 genes. Individuals with CS1 initially have normal growth parameters; microcephaly occurs from 2 months whereas onset of weight and height restrictions appear later, between 5 and 22 months. In CS2, growth parameters are already below standard references at birth or drop below the 5th percentile before 3 months. Microcephaly is the first parameter to show a delay, appearing around 2 months in CS1 and at birth in CS2. Height and head circumference are more severely affected in CS2 compared to CS1 whereas weight curves are similar in CS1 and CS2 patients. These new growth charts will serve as a practical tool to improve the nutritional management of children with CS.
Subject(s)
Body Height , Cockayne Syndrome/diagnosis , Growth Charts , Child , Child, Preschool , Cockayne Syndrome/genetics , DNA Helicases/genetics , DNA Repair Enzymes/genetics , DNA-Binding Proteins/genetics , Endonucleases/genetics , Female , Humans , Infant , Male , Mutation , Poly-ADP-Ribose Binding Proteins/genetics , Transcription Factors/geneticsABSTRACT
BACKGROUND: Clinical prediction rules (CPRs) to identify children with serious infections lack validation in low-prevalence populations, which hampers their implementation in primary care practice. AIM: To evaluate the diagnostic value of published CPRs for febrile children in primary care. DESIGN AND SETTING: Observational cohort study among febrile children (<16 years) who consulted five GP cooperatives (GPCs) in the Netherlands. METHOD: Alarm signs of serious infection and clinical management were extracted from routine clinical practice data and manually recoded with a structured electronic data-entry program. Eight CPRs were selected from literature. CPR-variables were matched with alarm signs and CPRs were applied to the GPC-population. 'Referral to emergency department (ED)' was used as a proxy outcome measure for 'serious infection'. CPR performance was assessed by calibration analyses, sensitivity, specificity, and area under the ROC-curve (ROC-area). RESULTS: A total of 9794 GPC-contacts were eligible, 54% male, median age 2.3 years (interquartile range 1.0-4.6 years) and 8.1% referred to ED. Frequencies of CPR-variables varied from 0.5% (cyanosis, drowsy) to 25% (temperature ≥40°C). Alarm signs frequently included in CPRs were 'ill appearance', 'inconsolable', and 'abnormal circulatory or respiratory signs'. The height of the CPR's predicted risks generally corresponded with being (or not being) referred to the ED in practice. However, calibration-slopes indicated that three CPRs underestimated the risk of serious infection in the GPC-population. Sensitivities ranged from 42% to 54%, specificities from 68% to 89%. ROC-areas ranged from 0.52 to 0.81, with best performance of CPRs for children aged <3 months. CONCLUSION: Published CPRs performed moderately well in the primary out-of-hours care population. Advice is given on how to improve translation of CPRs to primary care practice.
Subject(s)
Bacterial Infections , Decision Support Techniques , Fever , Bacterial Infections/complications , Bacterial Infections/diagnosis , Bacterial Infections/epidemiology , Bacterial Infections/therapy , Child, Preschool , Cohort Studies , Emergency Service, Hospital/statistics & numerical data , Female , Fever/diagnosis , Fever/etiology , Humans , Infant , Male , Netherlands/epidemiology , Patient Care Management/methods , Primary Health Care/methods , Primary Health Care/statistics & numerical data , ROC Curve , Referral and Consultation/statistics & numerical data , Symptom Assessment/methods , Symptom Assessment/statistics & numerical data , Translational Research, BiomedicalABSTRACT
BACKGROUND: The diagnostic value of alarm features of serious infections in low prevalence settings is unclear. AIM: To explore to what extent alarm features play a role in referral to the emergency department (ED) by GPs who face a febrile child during out-of-hours care. DESIGN AND SETTING: Observational study using semi-structured, routine clinical practice data of febrile children (<16 years) presenting to GP out-of-hours care. METHOD: Logistic regression analyses were performed to assess the association between alarm features of serious infections (selected from two guidelines and one systematic review) and referral to the ED. Adherence to the guideline was explored by a 2×2 contingency table. RESULTS: In total 794 (8.1%) of 9794 eligible patients were referred to the ED. Alarm signs most strongly associated with referral were 'age <1 month', 'decreased consciousness', 'meningeal irritation', and 'signs of dehydration'. Nineteen percent of 3424 children with a positive referral indication according to the guideline were referred to the ED. The majority of those not referred had only one or two alarm features present. A negative referral indication was adhered to for the majority of children. Still, in 20% of referred children, alarm features were absent. CONCLUSION: In contrast to guidance, GPs working in primary out-of-hours care seem more conservative in referring febrile children to the ED, especially if only one or two alarm features of serious infection are present. In addition, in 20% of referred children, alarm features were absent, which suggests that other factors may be important in decisions about referral of febrile children to the hospital ED.
Subject(s)
Fever/etiology , Infections/diagnosis , Referral and Consultation/statistics & numerical data , Adolescent , After-Hours Care/methods , Child , Child, Preschool , Emergency Service, Hospital/statistics & numerical data , General Practice/methods , General Practice/statistics & numerical data , Guideline Adherence , Humans , Infant , Infant, Newborn , Male , Netherlands , Practice Guidelines as Topic , Practice Patterns, Physicians'/statistics & numerical dataABSTRACT
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 nâ=â1 (ABC instability; <0.1%) to nâ=â2,207 (vomiting & diarrhea; 21.1%). Of all children, 59.7% had one or more alarming signs and/or symptoms. Several alarming signs/symptoms were poorly registered with the frequency of missing information ranging from 1,347 contacts (temperature >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.
Subject(s)
Fever/complications , Primary Health Care/statistics & numerical data , Adolescent , Child , Child, Preschool , Cohort Studies , Female , Fever/physiopathology , Humans , Infant , Infections/complications , Male , NetherlandsABSTRACT
BACKGROUND: Although fever in children is often self-limiting, antibiotics are frequently prescribed for febrile illnesses. GPs may consider treating serious infections by prescribing antibiotics. AIM: To examine whether alarm signs and/or symptoms for serious infections are related to antibiotic prescription in febrile children in primary care. DESIGN AND SETTING: Observational cohort study involving five GP out-of-hours services. METHOD: Clinical information was registered and manually recoded. Children (<16 years) with fever having a face-to-face contact with a GP were included. Children who were already using antibiotics or referred to secondary care were excluded. The relation between alarm signs and/or symptoms for serious infections and antibiotic prescription was tested using multivariate logistic regression. RESULTS: Of the 8676 included patients (median age 2.4 years), antibiotics were prescribed in 3167 contacts (36.5%). Patient characteristics and alarm signs and/or symptoms positively related to antibiotic prescription were: increasing age (odds ratio [OR] = 1.03; 95% confidence interval [95% CI] = 1.02 to 1.05), temperature measured by GP (OR = 1.72; 95% CI = 1.59 to 1.86), ill appearance (OR = 3.93; 95% CI = 2.85 to 5.42), being inconsolable (OR = 2.27; 95% CI = 1.58 to 3.22), shortness of breath (OR = 2.58; 95% CI = 1.88 to 3.56), duration of fever (OR = 1.31; 95% CI = 1.26 to 1.35). Negative associations were found for neurological signs (OR = 0.45; 95% CI = 0.27 to 0.76), signs of urinary tract infection (OR = 0.63; 95% CI = 0.49 to 0.82), and vomiting and diarrhoea (OR = 0.65; 95% CI = 0.57 to 0.74). These variables explained 19% of the antibiotic prescriptions. CONCLUSION: Antibiotics are often prescribed for febrile children. These data suggest that treatment of a supposed serious bacterial infection is a consideration of GPs. However, the relatively low explained variation indicates that other considerations are also involved.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Diarrhea/drug therapy , Drug Prescriptions/statistics & numerical data , Dyspnea/drug therapy , Fever/drug therapy , Fever/etiology , Practice Patterns, Physicians'/statistics & numerical data , Primary Health Care , Urinary Tract Infections/drug therapy , Vomiting/drug therapy , After-Hours Care , Age Distribution , Child, Preschool , Cohort Studies , Female , Humans , Infant , Logistic Models , Male , Multivariate Analysis , Netherlands/epidemiology , Odds RatioABSTRACT
OBJECTIVE: The goal of this study was to evaluate parents' capability to assess their febrile child's severity of illness and decision to present to the emergency department. We compared children referred by a general practitioner (GP) with those self-referred on the basis of illness-severity markers. METHODS: This was a cross-sectional observational study conducted at the emergency departments of a university and a teaching hospital. GP-referred or self-referred children with fever (aged <16 years) who presented to the emergency department (2006-2008) were included. Markers for severity of illness were urgency according to the Manchester Triage System, diagnostic interventions, therapeutic interventions, and follow-up. Associations between markers and referral type were assessed by using logistic regression analysis. Subgroup analyses were performed for patients with the most common presenting problems that accompanied the fever (ie, dyspnea, gastrointestinal complaints, neurologic symptoms, fever without specific symptoms). RESULTS: Thirty-eight percent of 4609 children were referred by their GP and 62% were self-referred. GP-referred children were classified as high urgency (immediate/very urgent categories) in 46% of the cases and self-referrals in 45%. Forty-three percent of GP referrals versus 27% of self-referrals needed extensive diagnostic intervention, intravenous medication/aerosol treatment, hospitalization, or a combination of these (odds ratio: 2.0 [95% confidence interval: 1.75-2.27]). In all subgroups, high urgency was not associated with referral type. GP-referred and self-referred children with dyspnea had similar frequencies of illness-severity markers. CONCLUSIONS: Although febrile self-referred children were less severely ill than GP-referred children, many parents properly judged and acted on the severity of their child's illness. To avoid delayed or missed diagnoses, recommendations regarding interventions that would discourage self-referral to the emergency department should be reconsidered.