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We report three unrelated individuals with atypical clinical findings for cardio-facio-cutaneous (CFC) syndrome, all of whom have the same novel, heterozygous de novo p.H119Y (c.355 C>T) transition variant in MAP2K1, identified by exome sequencing. MAP2K1 encodes MEK1, dual specificity mitogen-activated protein kinase kinase 1, and is one of four genes in the canonical RAS/MAPK signal transduction pathway associated with CFC syndrome. The p.H119Y variant is a non-conservative amino acid substitution that is predicted to impact the tertiary protein structure, and it occurs at a position in the protein kinase domain of MAP2K1 that is highly conserved across species. The clinical findings in these three individuals include facial features that are nonclassical for CFC syndrome, extremely poor weight gain, absence of congenital cardiac defects or cardiomyopathy, normal cognition or only mild intellectual disabilities, normal hair, mild skin abnormalities, and consistent behavioral features of anxiety, photophobia, and sensory hypersensitivities. These individuals expand the phenotypic spectrum of MAP2K1-related RASopathy.
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PURPOSE: Can certain characteristics identify as solvable some undiagnosed patients who seek extensive evaluation and thorough record review, such as by the Undiagnosed Diseases Network (UDN)? METHODS: The UDN is a national research resource to solve medical mysteries through team science. Applicants provide informed consent to access to their medical records. After review, expert panels assess if applicants meet inclusion and exclusion criteria to select participants. When not accepting applicants, UDN experts may offer suggestions for diagnostic efforts. Using minimal information from initial applications, we compare features in applicants who are not accepted with those who are accepted and either solved or still not solved by the UDN. The diagnostic suggestions offered to nonaccepted applicants and their clinicians were tallied. RESULTS: Nonaccepted applicants were more often female, older at first symptoms and application, and longer in review compared with accepted applicants. The accepted and successfully diagnosed applicants were younger, shorter in review time, more often non-White, of Hispanic ethnicity, and presenting with nervous system features. Half of nonaccepted applicants were given suggestions for further local diagnostic evaluation. A few seemed to have 2 major diagnoses or a provocative environmental exposure history. CONCLUSION: Comprehensive UDN record review generates possibly helpful advice.
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Using a new analytic method ("unique non-overlapping region" (UNOR) analysis), we characterized the genotypes and phenotypes of a large cohort of individuals diagnosed with chromosome 9p deletion syndrome (9PMS) and defined critical genomic regions. We extracted phenotypic information from 48 individuals with 9PMS from medical records and used a guided interview with caregivers to clarify ambiguities. Using high-resolution whole-genome sequencing for breakpoint definition, we aligned deletions and drew virtual breakpoints to obtain UNORs associated with phenotypic characteristics. We next extracted genotype and phenotype data for 57 individuals identified from a systematic review of the 9PMS literature and analyzed these as above. Common phenotypic features included developmental delay/intellectual disability, dysmorphic features, hypotonia, genital defects in XY individuals, psychiatric diagnoses, chronic constipation, atopic disease, vision problems, autism spectrum disorder, gastroesophageal reflux disease, trigonocephaly, congenital heart disease, and neonatal hypoglycemia. Our approach confirmed previous literature reports of an association of FREM1 with trigonocephaly and suggested a possible modifier element for this phenotype. In conclusion, the UNOR approach delineated phenotypic characteristics for 9PMS and confirmed the critical role of FREM1 and a possible long-distance regulatory element in pathogenesis of trigonocephaly that will need to be replicated in future studies.
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Deleção Cromossômica , Transtornos Cromossômicos , Cromossomos Humanos Par 9 , Deficiência Intelectual , Fenótipo , Humanos , Cromossomos Humanos Par 9/genética , Feminino , Masculino , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/patologia , Criança , Pré-Escolar , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/diagnóstico , Genótipo , Adolescente , Lactente , Adulto , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/diagnósticoRESUMO
PURPOSE: We identified 2 individuals with de novo variants in SREBF2 that disrupt a conserved site 1 protease (S1P) cleavage motif required for processing SREBP2 into its mature transcription factor. These individuals exhibit complex phenotypic manifestations that partially overlap with sterol regulatory element binding proteins (SREBP) pathway-related disease phenotypes, but SREBF2-related disease has not been previously reported. Thus, we set out to assess the effects of SREBF2 variants on SREBP pathway activation. METHODS: We undertook ultrastructure and gene expression analyses using fibroblasts from an affected individual and utilized a fly model of lipid droplet (LD) formation to investigate the consequences of SREBF2 variants on SREBP pathway function. RESULTS: We observed reduced LD formation, endoplasmic reticulum expansion, accumulation of aberrant lysosomes, and deficits in SREBP2 target gene expression in fibroblasts from an affected individual, indicating that the SREBF2 variant inhibits SREBP pathway activation. Using our fly model, we discovered that SREBF2 variants fail to induce LD production and act in a dominant-negative manner, which can be rescued by overexpression of S1P. CONCLUSION: Taken together, these data reveal a mechanism by which SREBF2 pathogenic variants that disrupt the S1P cleavage motif cause disease via dominant-negative antagonism of S1P, limiting the cleavage of S1P targets, including SREBP1 and SREBP2.
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Fibroblastos , Mutação de Sentido Incorreto , Proteína de Ligação a Elemento Regulador de Esterol 2 , Humanos , Proteína de Ligação a Elemento Regulador de Esterol 2/genética , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Animais , Fibroblastos/metabolismo , Mutação de Sentido Incorreto/genética , Masculino , Feminino , Gotículas Lipídicas/metabolismo , Fenótipo , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/genética , Serina Endopeptidases , Pró-Proteína ConvertasesRESUMO
African swine fever (ASF) causes significant morbidity and mortality in both domestic and wild suids (Sus scrofa), and disease outbreaks convey profound economic costs to impacted industries due to death loss, the cost of culling exposed/infected animals as the primary disease control measure, and trade restrictions. The co-occurrence of domestic and wild suids significantly complicates ASF management given the potential for wild populations to serve as persistent sources for spillover. We describe the unique threat of African swine fever virus (ASFV) introduction to the United States from epidemiological and ecological perspectives with a specific focus on disease management at the wild-domestic swine interface. The introduction of ASF into domestic herds would require a response focused on containment, culling, and contact tracing. However, detection of ASF among invasive wild pigs would require a far more complex and intensive response given the challenges of detection, containment, and ultimately elimination among wild populations. We describe the state of the science available to inform preparations for an ASF response among invasive wild pigs, describe knowledge gaps and the associated studies needed to fill those gaps, and call for an integrated approach for preparedness that incorporates the best available science and acknowledges sociological attributes and the policy context needed for an integrated disease response.
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Mutations in ATP-binding cassette A3 (ABCA3), a phospholipid transporter critical for surfactant homeostasis in pulmonary alveolar type II epithelial cells (AEC2s), are the most common genetic causes of childhood interstitial lung disease (chILD). Treatments for patients with pathological variants of ABCA3 mutations are limited, in part due to a lack of understanding of disease pathogenesis resulting from an inability to access primary AEC2s from affected children. Here, we report the generation of AEC2s from affected patient induced pluripotent stem cells (iPSCs) carrying homozygous versions of multiple ABCA3 mutations. We generated syngeneic CRISPR/Cas9 gene-corrected and uncorrected iPSCs and ABCA3-mutant knockin ABCA3:GFP fusion reporter lines for in vitro disease modeling. We observed an expected decreased capacity for surfactant secretion in ABCA3-mutant iPSC-derived AEC2s (iAEC2s), but we also found an unexpected epithelial-intrinsic aberrant phenotype in mutant iAEC2s, presenting as diminished progenitor potential, increased NFκB signaling, and the production of pro-inflammatory cytokines. The ABCA3:GFP fusion reporter permitted mutant-specific, quantifiable characterization of lamellar body size and ABCA3 protein trafficking, functional features that are perturbed depending on ABCA3 mutation type. Our disease model provides a platform for understanding ABCA3 mutation-mediated mechanisms of alveolar epithelial cell dysfunction that may trigger chILD pathogenesis.
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Transportadores de Cassetes de Ligação de ATP , Doenças Pulmonares Intersticiais , Células-Tronco Pluripotentes , Humanos , Células Epiteliais Alveolares/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Pulmão/patologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/metabolismo , Doenças Pulmonares Intersticiais/patologia , Mutação , Células-Tronco Pluripotentes/metabolismo , Tensoativos/metabolismoRESUMO
BACKGROUND: In 2020, a new disease was reported by Polovitskaya et al., caused by a monoallelic, gain-of-function mutation in CLCN6, encoding the ClC-6 Cl-/H±exchanger. METHODS: Here, we report the ophthalmic findings of one of the first three patients with this disease (the proband) and review the findings in the other two patients in the literature. RESULTS: The CLCN6 gene is part of the voltage-dependent chloride channel protein family. It functions as either a chloride channel aiding in cell-volume regulation and acidification of intracellular organelles or as an antiporter, which are membrane proteins involved in the transport of molecules across a phospholipid membrane. This particular gene is found in late endosomes. Ion transport across endosome membranes is essential for endosomal function. The proband carried a de novo c.1658A>G (p.Tyr553Cys) mutation in CLCN6. The patient reported herein has a notable optic nerve appearance. The nerve initially appeared elevated. Over time, the optic nerve elevation appearance decreased, associated with progressive vision loss with a visual acuity of 20/470 at last follow-up. CONCLUSION: While Clcn6-/- mice have been found to have a mild neuronal lysosomal storage phenotype, the three reported children with a de novo c.1658A>G (p.Tyr553Cys) variant displayed significant developmental delay and neurodegeneration.
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A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.
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Interferon Tipo I , Complexo de Endopeptidases do Proteassoma , Animais , Humanos , Camundongos , Adenosina Trifosfatases/genética , Drosophila melanogaster , Expressão Gênica , Complexo de Endopeptidases do Proteassoma/metabolismo , ProteômicaRESUMO
BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive ciliopathy characterized by early onset retinal dystrophy, renal anomalies, postaxial polydactyly, and cognitive impairment with considerable phenotypic heterogeneity. BBS results from biallelic pathogenic variants in over 20 genes that encode key proteins required for the assembly or primary ciliary functions of the BBSome, a heterooctameric protein complex critical for homeostasis of primary cilia. While variants in BBS1 are most frequently identified in affected individuals, the renal and pulmonary phenotypes associated with BBS1 variants are reportedly less severe than those seen in affected individuals with pathogenic variants in the other BBS-associated genes. CASE-DIAGNOSIS: We report an infant with severe renal dysplasia and lethal pulmonary hypoplasia who was homozygous for the most common BBS1 pathogenic variant (c.1169 T > G; p.M390R) and also carried a predicted pathogenic variant in TTC21B (c.1846C > T; p.R616C), a genetic modifier of disease severity of ciliopathies associated with renal dysplasia and pulmonary hypoplasia. CONCLUSIONS: This report expands the phenotypic spectrum of BBS with the first infant with lethal neonatal respiratory failure associated with biallelic, pathogenic variants in BBS1 and a monoallelic, predicted pathogenic variant in TTC21B. BBS should be considered among the ciliopathies in the differential diagnosis of neonates with renal dysplasia and severe respiratory failure.
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Síndrome de Bardet-Biedl , Insuficiência Respiratória , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação , FenótipoRESUMO
Child health is defined by a complex, dynamic network of genetic, cultural, nutritional, infectious, and environmental determinants at distinct, developmentally determined epochs from preconception to adolescence. This network shapes the future of children, susceptibilities to adult diseases, and individual child health outcomes. Evolution selects characteristics during fetal life, infancy, childhood, and adolescence that adapt to predictable and unpredictable exposures/stresses by creating alternative developmental phenotype trajectories. While child health has improved in the United States and globally over the past 30 years, continued improvement requires access to data that fully represent the complexity of these interactions and to new analytic methods. Big Data and innovative data science methods provide tools to integrate multiple data dimensions for description of best clinical, predictive, and preventive practices, for reducing racial disparities in child health outcomes, for inclusion of patient and family input in medical assessments, and for defining individual disease risk, mechanisms, and therapies. However, leveraging these resources will require new strategies that intentionally address institutional, ethical, regulatory, cultural, technical, and systemic barriers as well as developing partnerships with children and families from diverse backgrounds that acknowledge historical sources of mistrust. We highlight existing pediatric Big Data initiatives and identify areas of future research. IMPACT: Big Data and data science can improve child health. This review highlights the importance for child health of child-specific and life course-based Big Data and data science strategies. This review provides recommendations for future pediatric-specific Big Data and data science research.
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Big Data , Saúde da Criança , Humanos , Gravidez , Feminino , Criança , Estados Unidos , Ciência de Dados , Cuidado Pré-NatalRESUMO
OBJECTIVE: To identify associations between weight status and clinical outcomes in children with lower respiratory tract infection (LRTI) or asthma requiring hospitalization. METHODS: We performed a retrospective cohort study of 2 to 17 year old children hospitalized for LRTI and/or asthma from 2009 to 2019 using electronic health record data from the PEDSnet clinical research network. Children <2 years, those with medical complexity, and those without a calculable BMI were excluded. Children were classified as having underweight, normal weight, overweight, or class 1, 2, or 3 obesity based on Body Mass Index percentile for age and sex. Primary outcomes were need for positive pressure respiratory support and ICU admission. Subgroup analyses were performed for children with a primary diagnosis of asthma. Outcomes were modeled with mixed-effects multivariable logistic regression incorporating age, sex, and payer as fixed effects. RESULTS: We identified 65 132 hospitalizations; 6.7% with underweight, 57.8% normal weight, 14.6% overweight, 13.2% class 1 obesity, 5.0% class 2 obesity, and 2.8% class 3 obesity. Overweight and obesity were associated with positive pressure respiratory support (class 3 obesity versus normal weight odds ratio [OR] 1.62 [1.38-1.89]) and ICU admission (class 3 obesity versus normal weight OR 1.26 [1.12-1.42]), with significant associations for all categories of overweight and obesity. Underweight was also associated with positive pressure respiratory support (OR 1.39 [1.24-1.56]) and ICU admission (1.40 [1.30-1.52]). CONCLUSIONS: Both underweight and overweight or obesity are associated with increased severity of LRTI or asthma in hospitalized children.
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Asma , Transtornos Respiratórios , Infecções Respiratórias , Adolescente , Asma/epidemiologia , Asma/terapia , Índice de Massa Corporal , Criança , Criança Hospitalizada , Pré-Escolar , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Sobrepeso , Estudos Retrospectivos , Magreza/complicações , Magreza/epidemiologiaRESUMO
Genetic diseases disrupt the functionality of an infant's genome during fetal-neonatal adaptation and represent a leading cause of neonatal and infant mortality in the United States. Due to disease acuity, gene locus and allelic heterogeneity, and overlapping and diverse clinical phenotypes, diagnostic genome sequencing in neonatal intensive care units has required the development of methods to shorten turnaround times and improve genomic interpretation. From 2012 to 2021, 31 clinical studies documented the diagnostic and clinical utility of first-tier rapid or ultrarapid whole-genome sequencing through cost-effective identification of pathogenic genomic variants that change medical management, suggest new therapeutic strategies, and refine prognoses. Genomic diagnosis also permits prediction of reproductive recurrence risk for parents and surviving probands. Using implementation science and quality improvement, deployment of a genomic learning healthcare system will contribute to a reduction of neonatal and infant mortality through the integration of genome sequencing into best-practice neonatal intensive care.
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Testes Genéticos , Unidades de Terapia Intensiva Neonatal , Testes Genéticos/métodos , Genômica , Humanos , Recém-Nascido , Sequenciamento Completo do Genoma/métodosRESUMO
ABCA3 is a phospholipid transporter protein required for surfactant assembly in lamellar bodies of alveolar type II cells. Biallelic pathogenic ABCA3 variants cause severe neonatal respiratory distress syndrome or childhood interstitial lung disease. However, ABCA3 genotype alone does not explain the diversity in disease presentation, severity, and progression. Additionally, monoallelic ABCA3 variants have been reported in infants and children with ABCA3-deficient phenotypes. The effects of most ABCA3 variants identified in patients have not been characterized at the RNA level. ABCA3 allele-specific expression occurs in some cell types due to epigenetic regulation. We obtained lung tissue at transplant or autopsy from 16 infants and children with ABCA3 deficiency due to compound heterozygous ABCA3 variants for biologic characterization of the predicted effects of ABCA3 variants at the RNA level and determination of ABCA3 allele expression. We extracted DNA and RNA from frozen lung tissue and reverse-transcribed cDNA from mRNA. We performed Sanger sequencing to assess allele-specific expression by comparing the heights of variant nucleotide peaks in amplicons from genomic DNA and cDNA. We found similar genomic and cDNA variant nucleotide peak heights and no evidence of allele-specific expression among explant or autopsy samples with biallelic missense ABCA3 variants (n = 6). We observed allele-specific expression of missense alleles in trans with frameshift (n = 4) or nonsense (n = 1) variants, attributable to nonsense-mediated decay. The missense variant c.53 A > G;p.Gln18Arg, located near an exon-intron junction, encoded abnormal splicing with skipping of exon 4. Biologic characterization of ABCA3 variants can inform discovery of variant-specific disease mechanisms.
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Epigênese Genética , Síndrome do Desconforto Respiratório do Recém-Nascido , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Criança , DNA/metabolismo , DNA Complementar/metabolismo , Humanos , Recém-Nascido , Pulmão/patologia , Mutação , Nucleotídeos/metabolismo , RNA/metabolismo , Síndrome do Desconforto Respiratório do Recém-Nascido/metabolismoRESUMO
BACKGROUND: Weight control programs for children monitor BMI changes using BMI z-scores that adjust BMI for the sex and age of the child. It is, however, uncertain if BMIz is the best metric for assessing BMI change. OBJECTIVE: To identify which of 6 BMI metrics is optimal for assessing change. We considered a metric to be optimal if its short-term variability was consistent across the entire BMI distribution. SUBJECTS: 285 643 2- to 17-year-olds with BMI measured 3 times over a 10- to 14-month period. METHODS: We summarized each metric's variability using the within-child standard deviation. RESULTS: Most metrics' initial or mean value correlated with short-term variability (|r| ~ 0.3 to 0.5). The metric for which the within-child variability was largely independent (r = 0.13) of the metric's initial or mean value was the percentage of the 50th expressed on a log scale. However, changes in this metric between the first and last visits were highly (r ≥ 0.97) correlated with changes in %95th and %50th. CONCLUSIONS: Log %50 was the metric for which the short-term variability was largely independent of a child's BMI. Changes in log %50th, %95th, and %50th are strongly correlated.
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Índice de Massa Corporal , Adolescente , Feminino , Humanos , GravidezRESUMO
While 9p deletion and duplication syndromes have been studied for several years, small sample sizes and minimal high-resolution data have limited a comprehensive delineation of genotypic and phenotypic characteristics. In this study, we examined genetic data from 719 individuals in the worldwide 9p Network Cohort: a cohort seven to nine times larger than any previous study of 9p. Most breakpoints occur in bands 9p22 and 9p24, accounting for 35% and 38% of all breakpoints, respectively. Bands 9p11 and 9p12 have the fewest breakpoints, with each accounting for 0.6% of all breakpoints. The most common phenotype in 9p deletion and duplication syndromes is developmental delay, and we identified eight known neurodevelopmental disorder genes in 9p22 and 9p24. Since it has been previously reported that some individuals have a secondary structural variant related to the 9p variant, we examined our cohort for these variants and found 97 events. The top secondary variant involved 9q in 14 individuals (1.9%), including ring chromosomes and inversions. We identified a gender bias with significant enrichment for females (p = 0.0006) that may arise from a sex reversal in some individuals with 9p deletions. Genes on 9p were characterized regarding function, constraint metrics, and protein-protein interactions, resulting in a prioritized set of genes for further study. Finally, we achieved precision genomics in one child with a complex 9p structural variation using modern genomic technologies, demonstrating that long-read sequencing will be integral for some cases. Our study is the largest ever on 9p-related syndromes and provides key insights into genetic factors involved in these syndromes.
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OBJECTIVE: To assess the odds of a psychiatric or neurodevelopmental diagnosis among youth with a diagnosis of gender dysphoria compared with matched controls in a large electronic health record dataset from 6 pediatric health systems, PEDSnet. We hypothesized that youth with gender dysphoria would have higher odds of having psychiatric and neurodevelopmental diagnoses than controls. STUDY DESIGN: All youth with a diagnosis of gender dysphoria (n = 4173 age at last visit 16.2 ± 3.4) and at least 1 outpatient encounter were extracted from the PEDSnet database and propensity-score matched on 8 variables to controls without gender dysphoria (n = 16 648, age at last visit 16.2 ± 4.8) using multivariable logistic regression. The odds of having psychiatric and neurodevelopmental diagnoses were examined using generalized estimating equations. RESULTS: Youth with gender dysphoria had higher odds of psychiatric (OR 4.0 [95% CI 3.8, 4.3] P < .0001) and neurodevelopmental diagnoses (1.9 [1.7, 2.0], P < .0001). Youth with gender dysphoria were more likely to have a diagnosis across all psychiatric disorder subcategories, with particularly high odds of mood disorder (7.3 [6.8, 7.9], P < .0001) and anxiety (5.5 [5.1, 5.9], P < .0001). Youth with gender dysphoria had a greater odds of autism spectrum disorder (2.6, [2.2, 3.0], P < .0001). CONCLUSIONS: Youth with gender dysphoria at large pediatric health systems have greater odds of psychiatric and several neurodevelopmental diagnoses compared with youth without gender dysphoria. Further studies are needed to evaluate changes in mental health over time with access to gender affirming care.
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Ansiedade/etiologia , Disforia de Gênero/complicações , Transtornos do Humor/etiologia , Transtornos do Neurodesenvolvimento/etiologia , Adolescente , Ansiedade/epidemiologia , Estudos de Casos e Controles , Criança , Feminino , Disforia de Gênero/psicologia , Humanos , Modelos Logísticos , Masculino , Transtornos do Humor/epidemiologia , Transtornos do Neurodesenvolvimento/epidemiologia , Razão de Chances , Pontuação de Propensão , Fatores de Risco , Adulto JovemRESUMO
Importance: Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management. Objective: To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US. Design, Setting, and Participants: This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020. Interventions: Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study. Main Outcomes and Measures: The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality. Results: A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed. Conclusions and Relevance: In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population. Trail Registration: ClinicalTrials.gov Identifier: NCT03290469.
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Doença Aguda , Doenças Genéticas Inatas , Sequenciamento Completo do Genoma , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Avaliação de Resultados em Cuidados de SaúdeRESUMO
BACKGROUND: Congenital tracheobiliary or bronchobiliary fistulae are rare developmental malformations associated with high morbidity and mortality primarily because of concomitant anomalies as well as delays in diagnosis. TECHNICAL REPORT: We report a case of a neonate who presented with bilious emesis and progressive respiratory failure requiring bronchoscopy and fluoroscopic bronchography for diagnosis with successful management through video-assisted thoracoscopic surgery. We also review the published literature on tracheobiliary fistula. CONCLUSION: Use of video-assisted thoracoscopic surgery for fistula resection has been reported in only one other neonate and provides a clinically less invasive option compared with open surgical ligation and resection. To our knowledge, this is the first English language report of thoracoscopic resection in a neonate with congenital tracheobiliary fistula.