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ABSTRACT: This study investigated the temporal dynamics of childhood sepsis by analyzing gene expression changes associated with proinflammatory processes. Five datasets, including four meningococcal sepsis shock (MSS) datasets (two temporal and two longitudinal) and one polymicrobial sepsis dataset, were selected to track temporal changes in gene expression. Hierarchical clustering revealed three temporal phases: early, intermediate, and late, providing a framework for understanding sepsis progression. Principal component analysis supported the identification of gene expression trajectories. Differential gene analysis highlighted consistent upregulation of vascular endothelial growth factor A (VEGF-A) and nuclear factor κB1 (NFKB1), genes involved in inflammation, across the sepsis datasets. NFKB1 gene expression also showed temporal changes in the MSS datasets. In the postmortem dataset comparing MSS cases to controls, VEGF-A was upregulated and VEGF-B downregulated. Renal tissue exhibited higher VEGF-A expression compared with other tissues. Similar VEGF-A upregulation and VEGF-B downregulation patterns were observed in the cross-sectional MSS datasets and the polymicrobial sepsis dataset. Hexagonal plots confirmed VEGF-R (VEGF receptor)-VEGF-R2 signaling pathway enrichment in the MSS cross-sectional studies. The polymicrobial sepsis dataset also showed enrichment of the VEGF pathway in septic shock day 3 and sepsis day 3 samples compared with controls. These findings provide unique insights into the dynamic nature of sepsis from a transcriptomic perspective and suggest potential implications for biomarker development. Future research should focus on larger-scale temporal transcriptomic studies with appropriate control groups and validate the identified gene combination as a potential biomarker panel for sepsis.
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Sepse , Fator A de Crescimento do Endotélio Vascular , Humanos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Transcriptoma , Fator B de Crescimento do Endotélio Vascular , Estudos Transversais , Sepse/genética , BiomarcadoresRESUMO
This expert opinion provides detailed guidance on assessing obesity in secondary paediatric practice. This guidance builds on existing recommendations from National Institute of Health and Clinical Excellence in the UK, and is evidence based where possible. Guidance is provided on which obese children and young people are appropriate to be seen in secondary care and relevant history and investigations, and guidance on when further investigation of causes and obesity-related comorbidity is appropriate.
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Obesidade/etiologia , Obesidade/terapia , Encaminhamento e Consulta , Glicemia/análise , Índice de Massa Corporal , Criança , Jejum , Humanos , Insulina/análise , Lipídeos/sangue , Testes de Função Hepática , Anamnese , Síndrome Metabólica/diagnóstico , Exame Físico , Sono , Apneia Obstrutiva do Sono/diagnósticoRESUMO
AIM: To date, there is a lack of international guidelines regarding the management of the endocrine features of individuals with Noonan syndrome (NS). The aim was to develop a clinical practice survey to gather information on current treatment and management of these patients across Europe. MATERIALS AND METHODS: A group of 10 experts from three clinical specialities involved in the management of NS patients (clinical geneticists, paediatric endocrinologists, and paediatric cardiologists) developed a 60-question clinical practice survey. The questionnaire was implemented in Survey Monkey and sent to physicians from these three specialities via European/national societies. Contingency tables and the Chi-Squared test for independence were used to examine differences between specialities and countries. RESULTS: In total, responses of 364 specialists (paediatric endocrinologists, 40%; geneticists, 30%; paediatric cardiologists, 30%) from 20 European countries were analysed. While endocrinologists mostly referred to national growth charts for the general population, geneticists mostly referred to NS-specific growth charts. Approximately half of the endocrinologists perform growth hormone (GH) stimulation tests in short patients with low IGF1 levels. Two thirds of endocrinologists begin GH treatment for short patients in early childhood (4-6.9 years), and over half of them selected a threshold of -2 standard deviation score (SDS) according to national growth charts. The main concerns about GH treatment appear to be presence of hypertrophic cardiomyopathy (HCM) (59%), increased risk of malignancy (46%), and limited efficacy (31%). When asked if they consider HCM as a contraindication for GH treatment, one third of respondents skipped this question, and among those who replied, two thirds selected 'cannot answer', suggesting a high level of uncertainty. A total of 21 adverse cardiac responses to GH treatment were reported. Although most respondents had not encountered any malignancy during GH treatment, six malignancies were reported. Finally, about half of the endocrinologists expected a typical final height gain of 1-1.5 SDS with GH treatment. CONCLUSION: This survey describes for the first time the current clinical practice of endocrine aspects of NS across Europe and helps us to identify gaps in the management but also in the knowledge of this genetic disorder.
Assuntos
Nanismo/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Síndrome de Noonan/tratamento farmacológico , Nanismo/diagnóstico , Endocrinologistas , Europa (Continente) , Humanos , Síndrome de Noonan/diagnóstico , Padrões de Prática Médica , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The majority of children with Noonan syndrome (NS) or other diseases from the RASopathy spectrum suffer from congenital heart disease. This study aims to survey cardiac care of this patient cohort within Europe. METHODS: A cross-sectional exploratory survey assessing the treatment and management of patients with NS by paediatric endocrinologists, cardiologists and clinical geneticists was developed. This report details responses of 110 participating paediatric cardiologists from multiple countries. RESULTS: Most paediatric cardiologists responding to the questionnaire were associated with university hospitals, and most treated <10 patients/year with congenital heart disease associated with the NS spectrum. Molecular genetic testing for diagnosis confirmation was initiated by 81%. Half of the respondents reported that patients with NS and congenital heart disease typically present <1y of age, and that a large percentage of affected patients require interventions and pharmacotherapy early in life. A higher proportion of infant presentation and need for pharmacotherapy was reported by respondents from Germany and Sweden than from France and Spain (p = 0.031; p = 0.014; Fisher's exact test). Older age at first presentation was reported more from general hospitals and independent practices than from university hospitals (p = 0.031). The majority of NS patients were followed at specialist centres, but only 37% reported that their institution offered dedicated transition clinic to adult services. Very few NS patients with hypertrophic cardiomyopathy (HCM) were reported to carry implantable cardioverter defibrillators for sudden cardiac death prevention. Uncertainty was evident in regard to growth hormone treatment in patients with NS and co-existing HCM, where 13% considered it not a contra-indication, 24% stated they did not know, but 63% considered HCM either a possible (20%) or definite (15%) contraindication, or a cause for frequent monitoring (28%). Regarding adverse reactions for patients with NS on growth hormone therapy, 5/19 paediatric cardiology respondents reported a total of 12 adverse cardiac events. CONCLUSIONS: Congenital heart disease in patients with NS or other RASopathies is associated with significant morbidity during early life, and specialty centre care is appropriate. More research is needed regarding the use of growth hormone in patients with NS with congenital heart disease, and unmet medical needs have been identified.
Assuntos
Cardiopatias Congênitas , Síndrome de Noonan , Padrões de Prática Médica , Cardiologistas , Criança , Testes Genéticos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/etiologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/terapia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Síndrome de Noonan/complicações , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Síndrome de Noonan/terapia , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Noonan syndrome (NS) is a rare genetic disorder caused by mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Patients with NS exhibit certain characteristic features, including cardiac defects, short stature, distinctive facial appearance, skeletal abnormalities, cognitive deficits, and predisposition to certain cancers. Here, a clinical practice survey was developed to learn more about differences in the diagnosis and management of this disease across Europe. The aim was to identify gaps in the knowledge and management of this rare disorder. MATERIALS AND METHODS: The European Medical Education Initiative on NS, which comprised a group of 10 experts, developed a 60-question clinical practice survey to gather information from European physicians on the diagnosis and clinical management of patients with diseases in the NS phenotypic spectrum. Physicians from three specialities (clinical genetics, paediatric endocrinology, paediatric cardiology) were invited to complete the survey by several national and European societies. Differences in answers provided by respondents between specialities and countries were analysed using contingency tables and the Chi-Squared test for independence. The Friedman's test was used for related samples. RESULTS: Data were analysed from 364 respondents from 20 European countries. Most respondents came from France (21%), Spain (18%), Germany (16%), Italy (15%), United Kingdom (8%) and the Czech Republic (6%). Respondents were distributed evenly across three specialities: clinical genetics (30%), paediatric endocrinology (40%) and paediatric cardiology (30%). Care practices were generally aligned across the countries participating in the survey. Delayed diagnosis did not emerge as a critical issue, but certain unmet needs were identified, including transition of young patients to adult medical services and awareness of family support groups. CONCLUSION: Data collected from this survey provide a comprehensive summary of the diagnosis and clinical management practices for patients with NS across different European countries.
Assuntos
Síndrome de Noonan/diagnóstico , Síndrome de Noonan/terapia , Padrões de Prática Médica , Europa (Continente) , Testes Genéticos , Humanos , Síndrome de Noonan/genética , Inquéritos e QuestionáriosRESUMO
CONTEXT: Growth hormone (GH) is used to treat short children born small for gestational age (SGA); however, the effects of treatment on pubertal timing and adult height are rarely studied. OBJECTIVE: To evaluate adult height and peak height velocity in short GH-treated SGA children. METHODS: Prospective longitudinal multicenter study. Participants were short children born SGA treated with GH therapy (nâ =â 102). Adult height was reported in 47 children. A reference cohort of Danish children was used. Main outcome measures were adult height, peak height velocity, age at peak height, and pubertal onset. Pubertal onset was converted to SD score (SDS) using Danish reference data. RESULTS: Gain in height SDS from start of treatment until adult height was significant in both girls (0.94 [0.75; 1.53] SDS, Pâ =â .02) and boys (1.57 [1.13; 2.15] SDS, Pâ <â .001). No difference in adult height between GH dosage groups was observed. Peak height velocity was lower than a reference cohort for girls (6.5 [5.9; 7.6] cm/year vs 7.9 [7.4; 8.5] cm/year, Pâ <â .001) and boys (9.5 [8.4; 10.7] cm/year vs 10.1 [9.7; 10.7] cm/year, Pâ =â .002), but no difference in age at peak height velocity was seen. Puberty onset was earlier in SGA boys than a reference cohort (1.06 [-0.03; 1.96] SDS vs 0 SDS, Pâ =â .002) but not in girls (0.38 [-0.19; 1.05] SDS vs 0 SDS, Pâ =â .18). CONCLUSION: GH treatment improved adult height. Peak height velocity was reduced, but age at peak height velocity did not differ compared with the reference cohort. SGA boys had an earlier pubertal onset compared with the reference cohort.
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Estatura , Transtornos do Crescimento , Hormônio do Crescimento Humano , Recém-Nascido Pequeno para a Idade Gestacional , Puberdade , Adulto , Estatura/efeitos dos fármacos , Estatura/fisiologia , Criança , Feminino , Idade Gestacional , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/farmacologia , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Masculino , Estudos Prospectivos , Puberdade/efeitos dos fármacos , Puberdade/fisiologia , Fatores de TempoRESUMO
Homozygous loss-of-function mutations in the transcription factor LHX3 have been associated with hypopituitarism with structural anterior pituitary defects and cervical abnormalities with or without restricted neck rotation. We report two novel recessive mutations in LHX3 in four patients from two unrelated pedigrees. Clinical evaluation revealed that all four patients exhibit varying degrees of bilateral sensorineural hearing loss, which has not been previously reported in association with LHX3 mutations, in addition to hypopituitarism including adrenocorticotropic hormone deficiency and an unusual skin and skeletal phenotype in one family. Furthermore, re-evaluation of three patients previously described with LHX3 mutations showed they also exhibit varying degrees of bilateral sensorineural hearing loss. We have investigated a possible role for LHX3 in inner ear development in humans using in situ hybridization of human embryonic and fetal tissue. LHX3 is expressed in defined regions of the sensory epithelium of the developing inner ear in a pattern overlapping that of SOX2, which precedes the onset of LHX3 expression and is known to be required for inner ear and pituitary development in both mice and humans. Moreover, we show that SOX2 is capable of binding to and activating transcription of the LHX3 proximal promoter in vitro. This study therefore extends the phenotypic spectrum associated with LHX3 mutations to encompass variable sensorineural hearing loss and suggests a possible interaction between LHX3 and SOX2 likely to be important for development of both the inner ear and the anterior pituitary in human embryonic development.
Assuntos
Perda Auditiva Neurossensorial/genética , Proteínas de Homeodomínio/genética , Hipopituitarismo/genética , Mutação , Adolescente , Animais , Sequência de Bases , Células CHO , Criança , Cricetinae , Cricetulus , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Orelha Interna/embriologia , Orelha Interna/crescimento & desenvolvimento , Orelha Interna/metabolismo , Embrião de Mamíferos/metabolismo , Feminino , Expressão Gênica , Proteínas HMGB/genética , Proteínas HMGB/metabolismo , Perda Auditiva Neurossensorial/embriologia , Perda Auditiva Neurossensorial/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Hipopituitarismo/embriologia , Hipopituitarismo/metabolismo , Lactente , Proteínas com Homeodomínio LIM , Masculino , Camundongos , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXB1 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação TranscricionalRESUMO
Congenital hyperinsulinism (CHI) causes dysregulated insulin secretion which can lead to life-threatening hypoglycaemia if not effectively managed. CHI can be sub-classified into three distinct groups: diffuse, focal and mosaic pancreatic disease. Whilst the underlying causes of diffuse and focal disease have been widely characterised, the genetic basis of mosaic pancreatic disease is not known. To gain new insights into the underlying disease processes of mosaic-CHI we studied the islet tissue histopathology derived from limited surgical resection from the tail of the pancreas in a patient with CHI. The underlying genetic aetiology was investigated using a combination of high depth next-generation sequencing, microsatellite analysis and p57kip2 immunostaining. Histopathology of the pancreatic tissue confirmed the presence of a defined area associated with marked islet hypertrophy and a cytoarchitecture distinct from focal CHI but compatible with mosaic CHI localised to a discrete region within the pancreas. Analysis of DNA extracted from the lesion identified a de novo mosaic ABCC8 mutation and mosaic paternal uniparental disomy which were not present in leukocyte DNA or the surrounding unaffected pancreatic tissue. This study provides the first description of two independent disease-causing somatic genetic events occurring within the pancreas of an individual with localised mosaic CHI. Our findings increase knowledge of the genetic causes of islet disease and provide further insights into the underlying developmental changes associated with ß-cell expansion in CHI.
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Hiperinsulinismo Congênito/genética , Ilhotas Pancreáticas/patologia , Mosaicismo , Receptores de Sulfonilureias/genética , Hiperinsulinismo Congênito/patologia , Feminino , Humanos , Recém-Nascido , Mutação , Dissomia Uniparental/genéticaRESUMO
BACKGROUND: Some children born small for gestational age (SGA) experience supra-physiological insulin-like growth factor-I (IGF-I) concentrations during GH treatment. However, measurements of total IGF-I concentrations may not reflect the bioactive fraction of IGF-I which reaches the IGF-I receptor at target organs. We examined endogenous IGF-bioactivity using an IGF-I kinase receptor activation (KIRA) assay that measures the ability of IGF-I to activate the IGF-IR in vitro. AIM: To compare responses of bioactive IGF and total IGF-I concentrations in short GH treated SGA children in the North European Small for Gestational Age Study (NESGAS). MATERIAL AND METHOD: In NESGAS, short SGA children (n = 101, 61 males) received GH at 67 µg/kg/day for 1 year. IGF-I concentrations were measured by Immulite immunoassay and bioactive IGF by in-house KIRA assay. RESULTS: Bioactive IGF increased with age in healthy pre-pubertal children (n = 94). SGA children had low-normal bioactive IGF levels at baseline (-0.12 (1.8 SD), increasing significantly after one year of high-dose GH treatment to 1.1 (1.4) SD, P < 0.01. Following high-dose GH, 68% (n = 65) of SGA children had a total IGF-I concentration >2SD (mean IGF-I 2.8 SDS), whereas only 15% (n = 15) had levels of bioactive IGF slightly above normal reference values. At baseline, bioactive IGF (SDS) was significantly correlated to height (SDS) (r = 0.29, P = 0.005), in contrast to IGF-I (SDS) (r = 0.17, P = 0.10). IGF-I (SDS) was inversely correlated to delta height (SDS) after one year of high-dose GH treatment (r = -0.22, P = 0.02). CONCLUSION: In contrast to total IGF-I concentrations, bioactive IGF stayed within the normal reference ranges for most SGA children during the first year of GH treatment.
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Biomarcadores/sangue , Estatura/efeitos dos fármacos , Transtornos do Crescimento/sangue , Hormônio do Crescimento Humano/administração & dosagem , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Fator de Crescimento Insulin-Like I/análise , Estudos de Casos e Controles , Criança , Feminino , Seguimentos , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/patologia , Humanos , Recém-Nascido Pequeno para a Idade Gestacional/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Masculino , PrognósticoRESUMO
Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury. Accurate calculations of the incidence of rare diseases such as CHI are important as they inform health care planning and can aid interpretation of genetic testing results when assessing the frequency of variants in large-scale, unselected sequencing databases. Whilst minimal incidence rates have been calculated for four European countries, the incidence of CHI in the UK is not known. In this study we have used referral rates to a central laboratory for genetic testing and annual birth rates from census data to calculate the minimal incidence of CHI within the UK from 2007 to 2016. CHI was diagnosed in 278 individuals based on inappropriately detectable insulin and/or C-peptide measurements at the time of hypoglycaemia which persisted beyond 6 months of age. From these data, we have calculated a minimum incidence of 1 in 28,389 live births for CHI in the UK. This is comparable to estimates from other outbred populations and provides an accurate estimate that will aid both health care provision and interpretation of genetic results, which will help advance our understanding of CHI.
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Hiperinsulinismo Congênito/epidemiologia , Testes Genéticos/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Doenças Raras/epidemiologia , Encaminhamento e Consulta/estatística & dados numéricos , Pré-Escolar , Hiperinsulinismo Congênito/diagnóstico , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/cirurgia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Nascido Vivo/epidemiologia , Masculino , Triagem Neonatal/métodos , Pancreatectomia/estatística & dados numéricos , Doenças Raras/diagnóstico , Doenças Raras/genética , Reino Unido/epidemiologiaRESUMO
INTRODUCTION: 3beta-Hydroxysteroid dehydrogenase (3beta-HSD) deficiency is a rare cause of congenital adrenal hyperplasia caused by inactivating mutations in the HSD3B2 gene. Most mutations are located within domains regarded crucial for enzyme function. The function of the C terminus of the 3beta-HSD protein is not known. OBJECTIVE: We studied the functional consequences of three novel C-terminal mutations in the 3beta-HSD protein (p.P341L, p.R335X and p.W355X), detected in unrelated 46,XY neonates with classical 3beta-HSD type II deficiency showing different degrees of under-virilization. METHODS AND RESULTS: In vitro expression of the two truncated mutant proteins yielded absent conversion of pregnenolone and dehydroepiandrosterone (DHEA), whereas the missense mutation p.P341L showed a residual DHEA conversion of 6% of wild-type activity. Additional analysis of p.P341L, including three-dimensional protein modeling, revealed that the mutant's inactivity predominantly originates from a putative structural alteration of the 3beta-HSD protein and is further aggravated by increased protein degradation. The stop mutations cause truncated proteins missing the final G-helix that abolishes enzymatic activity irrespective of an augmented protein degradation. Genital appearance did not correlate with the mutants' residual in vitro activity. CONCLUSIONS: Three novel C-terminal mutants of the HSD3B2 gene are responsible for classical 3beta-HSD deficiency. The C terminus is essential for the enzymatic activity. However, more studies are needed to clarify the exact function of this part of the protein. Our results indicate that the genital phenotype in 3beta-HSD deficiency cannot be predicted from in vitro 3beta-HSD function alone.
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3-Hidroxiesteroide Desidrogenases/genética , Hiperplasia Suprarrenal Congênita/genética , Isoenzimas/genética , Mutação Puntual , 3-Hidroxiesteroide Desidrogenases/química , 3-Hidroxiesteroide Desidrogenases/metabolismo , Sequência de Aminoácidos , Animais , Células CHO , Células COS , Chlorocebus aethiops , Cricetinae , Cricetulus , Humanos , Lactente , Recém-Nascido , Modelos Moleculares , Dados de Sequência MolecularAssuntos
Hormônio do Crescimento , Hormônio do Crescimento Humano , Recém-Nascido , Feminino , Criança , Humanos , Adulto , Idade Gestacional , Hormônio do Crescimento Humano/uso terapêutico , Puberdade/fisiologia , Retardo do Crescimento Fetal , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimentoRESUMO
OBJECTIVE: The effect of a common polymorphism in the Growth Hormone (GH) receptor (d3-GHR) gene on growth, metabolism and body composition was examined in short children born small for gestational age (SGA) on GH treatment. DESIGN: In 96 prepubertal, short SGA children treated with high-dose GH (67µg/kg/day) in the NESGAS study, insulin sensitivity (IS), insulin secretion and disposition index (DI) were determined during the first year of treatment. Body composition was analysed by DXA. The d3-GHR locus was determined by simple multiplex PCR. RESULTS: At baseline, children in the d3-GHR group (d3/fl (n=37), d3/d3 (n=7)) had significantly lower IS (median (25-75 percentile)) (223.3% (154.4-304.8)) vs. (269.7% (185.1-356.7)) (p=0.03) and higher concentrations of glucose (mean (SD)) (4.4mmol/L (0.6) vs. 4.2mmol/L (0.7)) (p=0.03), C-peptide (232.1pmol/L (168.8-304.1) vs. 185.1pmol/L (137.7-253.9)) (p=0.04) and insulin (19.2pmol/L (11.8-32.2)) vs. (13.7pmol/L (9.3-20.8)) (p=0.04) compared to children homozygous for the full length allele (fl/fl-GHR (n=52)). There were no differences in DI or insulin secretion. Postnatal, spontaneous growth was significantly greater in the d3-GHR group compared to the fl/fl-GHR group (p=0.02). There were no significant differences in growth response, body composition or metabolism after one year of GH therapy. CONCLUSION: Short SGA children carrying the d3-GHR polymorphism had increased spontaneous growth, lower IS and a compensatory increase in glucose, C-peptide and insulin before GH therapy compared to children homozygous for the full-length allele.