No Association of Antenatal Synthetic Glucocorticoid Exposure and Hair Steroid Levels in Children and Adolescents.

Abstract: Antenatal synthetic glucocorticoid (sGC) treatment constitutes a potent programming factor of the hypothalamic-pituitary-adrenal (HPA) axis. Previous findings from our group revealed long-term changes in cortisol stress reactivity following antenatal […]

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Measurement of salivary adrenal-specific androgens as biomarkers of therapy control in 21-hydroxylase deficiency.

Monitoring of hormonal control represents a key part of the management in congenital adrenal hyperplasia (CAH). Monitoring strategies remain suboptimal as they rely on frequent blood tests and are not specific for adrenal-derived hormones. Recent evidence suggests a crucial role of adrenal-specific 11-oxygenated-C19 androgens in the pathogenesis of CAH.To establish the correlation between plasma and salivary adrenal-specific androgens in CAH as a novel non-invasive monitoring strategy.This prospective cross-sectional study recruited patients between 2015-2018.Multi-center study including 13 tertiary centers in the UK.Seventy-eight children with CAH and sixty-two matched healthy controls.Using liquid-chromatography tandem mass spectrometry, plasma and salivary concentrations of five steroids were measured: 17-hydroxyprogesterone, androstenedione, testosterone, 11-hydroxyandrostenedione and 11-ketotestosterone. The correlation between plasma and salivary steroids was analyzed to assess their use in clinical practice.Strong correlations between plasma and salivary steroid concentrations in patients with CAH were detected: 17-hydroxyprogesterone (rs=0.871, p<0.001), androstenedione (rs=0.931, p<0.001), testosterone (rs=0.867, p<0.001), 11-hydroxyandrostenedione (rs=0.876, p<0.001), 11-ketotestosterone (rs=0.944, p<0.001). These results were consistent for patient subgroups based on gender and age. Analyzing patient subgroups based on 17-hydroxyprogesterone concentrations established clear correlations between plasma and salivary concentrations of the adrenal specific androgen 11-ketotestosterone.The present study identified tight correlations between plasma and saliva for the adrenal-derived 11oxygenated-C19 androgen 11-ketotestosterone, as well as 17-hydroxyprogesterone and androstenedione, which are widely used for monitoring treatment in CAH. This novel combination of steroid hormones will serve as an improved non-invasive salivary test for disease monitoring of patients with CAH.

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The Effects of Amiodarone on Thyroid Function in Pediatric and Young Adult Patients.

Amiodarone is used in patients with arrhythmias, but thyroid dysfunction (amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH)) is a common adverse effect. As the onset of AIT and AIH have not been studied in children, the timing of dysfunction and long term monitoring are not known in this population.To describe the incidence and timing of amiodarone-induced thyroid dysfunction in children and adolescents with a secondary aim to identify risk factors for amiodarone-induced thyroid dysfunction; and to identify variance in thyroid hormone surveillance and treatment.Retrospective review of thyroid dysfunction in children and young adults treated with amiodarone between 2007 and 2018.The Children’s Hospital of Philadelphia.Children and young adults treated with amiodarone.Prevalence of amiodarone-induced thyroid dysfunction.Of 484 patients, 190 had thyroid function testing. 17.3% were found to have subclinical hypothyroidism and 13.7% testing developed hypothyroidism. Hyperthyroidism occurred in 2.1%. In patients with subclinical hypothyroidism, 63% returned to normal thyroid function without thyroid hormone replacement. Only 26% of patients with hypothyroidism had spontaneous normalization of thyroid function. 25% of AIT patients had spontaneous normalization of thyroid function.This is the first study to look at a pediatric and young adult population in an effort to describe the natural history of amiodarone induced thyroid dysfunction. Based upon our data, we recommend that a complete thyroid function panel be obtained within the first week and then at weekly intervals for the first five weeks after initiation. The majority of thyroid dysfunction was noted within the first 35 days of treatment.

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Characteristics of familial type 1 diabetes: effects of the relationship to the affected family member on phenotype and genotype at diagnosis.

In previous studies, the risk of developing familial type 1 diabetes has been reported to be more than two times higher in the offspring of affected fathers than in those of affected mothers. We tested the hypothesis that index children with an affected father may have a more aggressive disease process at diagnosis than those with other affected first-degree relatives.A cross-sectional, observational study was performed using the Finnish Pediatric Diabetes Register. Clinical and metabolic characteristics, beta cell autoantibodies and HLA class II genetics were analysed from index children in Finland diagnosed before the age of 15 years between January 2003 and December 2016. Information on the presence of type 1 diabetes in first-degree relatives was collected at diagnosis using a structured questionnaire.Out of 4993 newly diagnosed index children, 519 (10.4%) had familial type 1 diabetes. More than 5% (n?=?253, 5.1%) had an affected father, 2.8% (n?=?141) had an affected mother, 1.9% (n?=?95) had an affected sibling and 0.6% (n?=?30) had two or more affected family members. All clinical and metabolic variables were markedly poorer in children with sporadic vs familial diabetes. The index children with an affected father or mother were younger than those with an affected sibling (median age 7.59 vs 6.74 vs 10.73 years, respectively; p?< 0.001). After age- and sex-adjusted analyses, index children with an affected father presented more often with ketoacidosis (9.7% vs 3.6%; p?= 0.033) and had greater weight loss before diagnosis (3.2% vs 0%; p?= 0.006) than those with an affected mother. Children with familial disease tested negative for all autoantibodies more often (3.5% vs 2.1%; p?= 0.041) and had insulin autoantibodies more frequently (49.8% vs 42.2%; p?=?0.004) than those with sporadic disease. Both major HLA risk haplotypes (DR3-DQ2 and DR4-DQ8) were more often lacking among children with sporadic vs familial disease (15.9% vs 11.2%; p?=?0.006). The DR4-DQ8 haplotype was more frequent in the familial vs the sporadic group (75.7% vs 68.5%; p?=?0.001) and especially among children with an affected father when compared with children with sporadic disease (77.5% vs 68.5%; p? » Read more

Children Exposed to Maternal Obesity or Gestational Diabetes Mellitus During Early Fetal Development Have Hypothalamic Alterations That Predict Future Weight Gain.

Exposure in utero to maternal obesity or gestational diabetes mellitus (GDM) is linked to a high risk for obesity in offspring. Animal studies suggest that these exposures disrupt the development of the hypothalamus, a brain region that regulates body weight, predisposing offspring to develop obesity. This study tested the hypothesis in humans that in utero exposure to maternal obesity and/or GDM is associated with alterations in the hypothalamic response to glucose and the altered hypothalamic response would predict greater increases in child adiposity 1 year later.Participants were 91 children aged 7-11 years with and without in utero exposure to GDM. Maternal prepregnancy BMI and GDM exposures were determined from electronic medical records. Arterial spin labeling MRI was used to determine the child’s hypothalamic blood flow response to oral glucose. Anthropometric measures were acquired in all children at their initial visit and again 1 year later in a subset of 44 children.Children exposed to GDM diagnosed at ?26 weeks’ gestation had increased hypothalamic blood flow (a marker of hypothalamic activation) in response to glucose when compared with unexposed children, and results remained after adjustments for child age, sex, BMI, and maternal prepregnancy BMI. Maternal prepregnancy BMI was positively associated with the child’s hypothalamic response to glucose. Greater hypothalamic response to glucose predicted greater increases in child’s BMI 1 year later.Increased glucose-linked hypothalamic activation during childhood represents a possible mechanism by which exposure to maternal metabolic disorders during fetal development increases future risk for obesity.

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Characteristics of Slow Progression to Type 1 Diabetes in Children With Increased HLA-Conferred Disease Risk.

Characterization of slow progression to type 1 diabetes (T1D) may reveal novel means for prevention of T1D. Slow progressors might carry natural immunomodulators that delay ?-cell destruction and mediate preservation of ?-cell function.To identify demographic, genetic, and immunological characteristics of slow progression from seroconversion to clinical T1D.HLA-susceptible children (n=7410) were observed from birth for islet cell (ICA), insulin (IAA), GAD65 (GADA), and islet antigen-2 autoantibodies (IA-2A), and for clinical T1D. Disease progression that lasted ?7.26 years (slowest tertile) from initial seroconversion to diagnosis was considered slow. Autoantibody and genetic characteristics including 45 non-HLA single nucleotide polymorphisms (SNPs) predisposing to T1D were analyzed.By the end of 2015, altogether 1528 children (21%) had tested autoantibody positive, and 247 (16%) had progressed to T1D. The median delay from seroconversion to diagnosis was 8.7 years in slow (n=62, 25%) and 3.0 years in other progressors. Compared to other progressors, slow progressors were less often multipositive, had lower ICA and IAA titers, and lower frequency of IA-2A at seroconversion. Slow progressors were born more frequently in the fall, while other progressors were born more often in the spring. Compared to multipositive non-progressors, slow progressors were younger, had higher ICA titers, and higher frequency of IAA and multiple autoantibodies at seroconversion. We found no differences in the distributions of non-HLA SNPs between progressors.We observed differences in autoantibody characteristics and the season of birth among progressors, but no characteristics present at seroconversion that were specifically predictive for slow progression.

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Educational and Health Outcomes of Children Treated for Type 1 Diabetes: Scotland-Wide Record Linkage Study of 766,047 Children.

This study was conducted to determine the association between childhood type 1 diabetes and educational and health outcomes.Record linkage of nine Scotland-wide databases (diabetes register, dispensed prescriptions, maternity records, hospital admissions, death certificates, annual pupil census, school absences/exclusions, school examinations, and unemployment) produced a cohort of 766,047 singleton children born in Scotland who attended Scottish schools between 2009 and 2013. We compared the health and education outcomes of schoolchildren receiving insulin with their peers, adjusting for potential confounders.The 3,330 children (0.47%) treated for type 1 diabetes were more likely to be admitted to the hospital (adjusted hazard ratio [HR] 3.97, 95% CI 3.79-4.16), die (adjusted HR 3.84, 95% CI 1.98-7.43), be absent from school (adjusted incidence rate ratio [IRR] 1.34, 95% CI 1.30-1.39), and have learning difficulties (adjusted odds ratio [OR] 1.19, 95% CI 1.03-1.38). Among children with type 1 diabetes, higher mean HbA1c (particularly HbA1c in the highest quintile) was associated with greater absenteeism (adjusted IRR 1.75, 95% CI 1.56-1.96, P < 0.001), increased school exclusion (adjusted IRR 2.82, 95% CI 1.14-6.98), poorer attainment (adjusted OR 3.52, 95% CI 1.72-7.18), and higher risk of unemployment (adjusted OR 2.01, 95% CI 1.05-3.85).Children with type 1 diabetes fare worse than their peers in respect of education and health outcomes, especially if they have higher mean HbA1c. Interventions are required to minimize school absence and ensure that it does not affect educational attainment.

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Treatment of Children with Growth Hormone in the US and Europe: Long-term Follow-up from NordiNet IOS and ANSWER Program.

Understanding real-world prescribing of growth hormone (GH) may help improve treatment of eligible patients.Overall: to assess real-world effectiveness and safety of GH (Norditropin). This analysis: to compare clinical characteristics of GH-treated children in the USA and Europe.ANSWER (2002-2016, USA) and NordiNet IOS (2006-2016, Europe) were multicenter longitudinal observational cohort studies.Data were recorded in 207 (USA) and 469 (Europe) clinics.Patients with GH deficiency, Turner syndrome, Noonan syndrome, idiopathic short stature, Prader-Willi Syndrome, or born small for gestational age, who commenced GH treatment aged <1 year.GH was prescribed by treating physicians according to local practice.Baseline data and drug doses were recorded. Data on effectiveness and safety were collected.ANSWER had 19,847 patients in the full analysis set (FAS; patients with birthdate information and ?1 GH prescription) and 12,660 in the effectiveness analysis set (EAS; GH-naïve patients with valid baseline information). NordiNet IOS had 17,711 (FAS) and 11,967 (EAS). Boys accounted for 69% (ANSWER) and 57% (NordiNet IOS). Treatment start occurred later than optimal to improve growth. The proportion of boys treated was generally larger, children were older at treatment start, and GH doses were higher in the USA vs Europe. No new safety signals of concern were noted.In most indications, more boys than girls were treated, and treatment started late. Earlier diagnosis of GH-related disorders is needed. The data support a favorable benefit-risk profile of GH therapy in children.

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Childhood Adiposity and Adolescent Sex Steroids in the EPOCH (Exploring Perinatal Outcomes among Children) Study.

It is unclear how childhood adipose tissue deposition influences sex hormone profiles in later adolescence.Prospective cohort study.Children (n=418) with a mean age of 10.5 (1.5) years at visit 1 and 16.7 (1.2) at visit 2 in the Exploring Perinatal Outcomes among Children (EPOCH) Study.We used reverse-scale Cox proportional hazard models to assess associations between pubertal dehydroepiandrosterone (DHEA), testosterone (T), and estradiol (E2) and childhood-to-puberty rate of change in visceral (VAT) and subcutaneous adipose tissue (SAT). Models stratified by sex and adjusted for childhood adiposity, maternal factors, birthweight, and pubertal onset, and then further adjusted for insulin, luteinizing hormone (LH), leptin and hepatic fat fraction.Among boys, more rapid accumulation of either VAT or SAT was associated with lower testosterone at visit 2 (HR 0.86, and 0.96, respectively, both p<0.0001), independently of race/ethnicity, LH, leptin, and hepatic fat fraction. Among boys, more childhood VAT was associated with lower testosterone in adolescence (HR 0.98, p=0.003), but this association did not persist after adjustment for leptin or insulin. No associations were observed between either fat measure and estradiol or DHEA in boys. In girls, no associations between childhood fat or fat accumulation and sex hormones were observed.More rapid accumulation of fat is associated with lower testosterone in boys. These associations suggest that fat growth influences androgen profiles in adolescent boys. Since fat accumulation is a modifiable risk factor, the study results provide a possible intervention target and time period for improving adult health. This article is protected by copyright. All rights reserved.

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Circulating CXCR5-PD-1hi peripheral T helper cells are associated with progression to type 1 diabetes.

Type 1 diabetes is preceded by a period of asymptomatic autoimmunity characterised by positivity for islet autoantibodies. Therefore, T helper cell responses that induce B cell activation are likely to play a critical role in the disease process. Here, we aimed to evaluate the role of a recently described subset, C-X-C motif chemokine receptor type 5-negative, programmed cell death protein 1-positive (CXCR5-PD-1hi) peripheral T helper (Tph) cells, in human type 1 diabetes.The phenotype of blood CXCR5-PD-1hi CD4+ T cells was analysed by multicolour flow cytometry. The frequencies of circulating CXCR5-PD-1hi T cells were analysed in a cohort of 44 children with newly diagnosed type 1 diabetes, 40 autoantibody-positive (AAb+) at-risk children and 84 autoantibody-negative healthy control children, and the findings were replicated in a separate cohort of 15 children with newly diagnosed type 1 diabetes and 15 healthy control children.Circulating CXCR5-PD-1hi Tph cells share several features associated with B cell helper function with circulating CXCR5+PD-1hi follicular T helper (Tfh) cells. Moreover, the frequency of circulating Tph cells was increased in children with newly diagnosed type 1 diabetes, especially in those who are positive for multiple autoantibodies. Importantly, circulating Tph cells were also increased in autoantibody-positive at-risk children who later progressed to type 1 diabetes.Our results demonstrate that circulating CXCR5-PD-1hi Tph cells are associated with progression to clinical type 1 diabetes. Consequently, Tph cells could have potential both as a biomarker of disease progression and as a target for immunotherapy in type 1 diabetes.

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