Showing papers in "Hormone Research in Paediatrics in 2018"
TL;DR: This review focuses on the current knowledge of the effects of thyroid hormones on central nervous system differentiation and development in animals and the human fetal brain, focusing on how therapies could affect and especially improve the outcomes of children with congenital hypothyroidism and newborns withhypothyroid pregnant mothers.
Abstract: This review focuses on the current knowledge of the effects of thyroid hormones on central nervous system differentiation and development in animals and the human fetal brain. The outcomes of children with congenital hypothyroidism and of newborns with hypothyroid pregnant mothers are emphasized, focusing on how therapies could affect and especially improve the outcomes.
101 citations
TL;DR: The results showed a reasonable agreement between the FGM SG readings and capillary blood glucose measurements in children, there was, however, a large interindividual variability in the accuracy parameters.
Abstract: BACKGROUND/AIMS The FreeStyle® Libre Flash Glucose Monitoring System (FGM, Abbott) measures glucose concentrations in the interstitial fluid for up to 14 days. It has been approved for use in children aged > 4 years in January 2016. Experience in children is still limited. We evaluated the accuracy and usability of the FGM in children with type 1 diabetes mellitus (DM). METHODS 67 children with type 1 DM (35 girls), aged 4-18 years, were included. Subjects wore a sensor on the back of their upper arm. For the first 14 days, they regularly measured capillary blood glucose (BG) with their usual BG meter (Accu-Chek® Mobile [ACM], Roche [n = 24]; Contour® Next Link [CNL], Bayer [n = 26]; OneTouch® Verio® IQ [OTV], LifeScan [n = 17]) followed by a sensor glucose (SG) scanning. SG readings were compared to BG measurements by consensus error grid (CEG) analysis; the mean difference (MD), the mean relative difference (MRD), the mean absolute difference (MAD), and the mean absolute relative difference (MARD) were calculated. After 14 days, subjects were asked to fill in a questionnaire on the usability of the FGM. RESULTS 2,626 SG readings were paired with BG results. FGM readings were highly correlated with BG (r = 0.926, p < 0.001). 80.3% of the data pairs were in zone A (= no effect on clinical action) and 18.4% were in zone B (= altered clinical action with little or no effect on the clinical outcome) of the CEG. Overall MD was +7.5 mg/dL; MD varied with the BG meter: ACM +10.4 mg/dL, CNL +14.2 mg/dL, OTV -3.6 mg/dL (p < 0.001). Overall, MARD was 16.7%. We observed a large interindividual variability in the accuracy parameters. MD and MRD were inversely related to BMI (r = -0.261 [p < 0.05]; r = -0.266 [p < 0.05], respectively). MARD was inversely related to age (r = -0.266 [p < 0.05]). Twenty-nine patients (43.3%) reported sensor problems, mainly early detachment of the sensor. Nonetheless, the usability questionnaire indicated high levels of satisfaction. CONCLUSIONS Our results showed a reasonable agreement between the FGM SG readings and capillary BG measurements in children. There was, however, a large interindividual variability. The wearing of the sensor requires special attention. Further studies in children are imperative in order to document the accuracy and safety of the FGM in the paediatric population.
52 citations
TL;DR: The integration of the HPA axis with modern neurology and psychiatry has cemented the role of endocrinology in contemporary studies of behavior.
Abstract: The hypothalamic-pituitary-adrenal (HPA) axis is central to homeostasis, stress responses, energy metabolism, and neuropsychiatric function. The history of this complex system involves discovery of the relevant glands (adrenal, pituitary, hypothalamus), hormones (cortisol, corticotropin, corticotropin-releasing hormone), and the receptors for these hormones. The adrenal and pituitary were identified by classical anatomists, but most of this history has taken place rather recently, and has involved complex chemistry, biochemistry, genetics, and clinical investigation. The integration of the HPA axis with modern neurology and psychiatry has cemented the role of endocrinology in contemporary studies of behavior.
48 citations
TL;DR: The scope of the adherence problem evident amongst the paediatric GHD population is highlighted and a wide range of potentially modifiable factors that explain this health-related behaviour are presented.
Abstract: Background: Despite the developments of recombinant growth hormone (rhGH) treatment and the benefits in long-term clinical health outcomes, evidence has shown that many children with growth hormone deficiency (GHD) still fail to achieve their target adult height. Suboptimal outcomes have been largely attributed to treatment non-adherence. Methods: A search of 11 electronic databases was undertaken to identify relevant articles, published in English, between 1985 and 2018. Additional search strategies included hand-searching topic review articles to identify eligible studies. Articles were screened against the inclusion eligibility criteria and data on sample characteristics, study design, outcomes, and key findings was extracted. The results were narratively synthesised and categorised using the COM-B theoretical framework. Results: Twenty-one full-text articles were assessed for eligibility, of which 6 articles met the inclusion criteria. The prevalence of non-adherence in the included studies varied from 7 to 71%. Potentially modifiable factors associated with rhGH non-adherence were categorised within the COM-B framework; key factors included: a lack of knowledge and understanding of the condition and treatment, discomfort and pain associated with injections, and the quality of the healthcare professional-patient relationship. Conclusion: This review highlights the scope of the adherence problem evident amongst the paediatric GHD population and in addition presents the wide range of potentially modifiable factors that explain this health-related behaviour.
47 citations
TL;DR: Patients with severe, salt-wasting CAH have joint hypermobility and a spectrum of other comorbidities associated with their connective tissue disorder, including chronic arthralgia, joint subluxations, hernias, and cardiac defects.
Abstract: Mutations of the CYP21A2 gene encoding adrenal 21-hydroxylase cause congenital adrenal hyperplasia (CAH). The CYP21A2 gene is partially overlapped by the TNXB gene, which encodes an extracellular matrix protein called Tenascin-X (TNX). Mutations affecting both alleles of TNXB cause a severe, autosomal recessive form of Ehlers-Danlos syndrome (EDS). Rarely, patients with severe, salt-wasting CAH have deletions of CYP21A2 that extend into TNXB, resulting in a "contiguous gene syndrome" consisting of CAH and EDS. Heterozygosity for TNXB mutations causing haploinsufficiency of TNX may be associated with the mild "hypermobility form" of EDS, which principally affects small and large joints. Studies of patients with salt-wasting CAH found that up to 10% had clinical features of EDS, associated joint hypermobility, haploinsufficiency of TNX and heterozygosity for TNXB mutations, now called "CAH-X." These patients have joint hypermobility and a spectrum of other comorbidities associated with their connective tissue disorder, including chronic arthralgia, joint subluxations, hernias, and cardiac defects. Other disorders are beginning to be associated with TNX deficiency, including familial vesicoureteral reflux and neurologic disorders. Further work is needed to delineate the full spectrum of TNX-deficient disorders, with and without associated CAH.
45 citations
TL;DR: The clinicopathological data of children with ACC were investigated, prognostic factors were identified, and a histopathological criterion was validated to differentiate ACC from adrenocortical adenoma was validated.
Abstract: Background/Aims: Adrenocortical carcinoma (ACC) is an aggressive childhood cancer. Limited evidence exists on a definite histopathological criterion to differentiate ACC from adrenocortical adenoma. The aim of this study was to investigate the clinicopathological data of children with ACC, identify prognostic factors, and validate a histopathological criterion to differentiate ACC from adrenocortical adenoma. Methods: This retrospective cohort included 41 children, followed at the Mayo Clinic from 1950 to 2017 (onset of symptoms ≤21 years). Outcomes of interest were: alive with no evidence of disease, alive with evidence of disease, and dead of disease. Results: Median age at onset of symptoms was 15.7 years (n = 41; range, 0.2–21 years). Female:male ratio was 3.6: 1. Mixed symptomatology (> 1 hormone abnormality) was the most common presentation (54%, n = 22). Sixty-six percent of patients (n = 27 out of 41) underwent total adrenalectomy. Metastatic disease was more common in children aged > 12 years (p = 0.002 compared to < 4 years). The most common sites of metastases were the liver and lungs. Overall 2-year and 5-year survival rates were 61% (95% CI 45–77) and 46% (95% CI 30–62), respectively. Metastasis at the time of diagnosis was independently associated with poor prognosis (risk ratio 13.7%; 95% CI 3.9–87.7). Weiss criteria (29%) and modified Weiss criteria (33%) were less accurate in younger patients (< 12 years), compared to the Wieneke index (100%). Conclusion: The presence of metastases was an independent prognostic factor. The Wieneke index was the most accurate in predicting clinical outcomes in younger children.
41 citations
TL;DR: The existing definitions of an AC are assessed and a new definition for use in research and the clinic is offered, and areas for further investigation that are aimed at reducing the incidence and health impact of ACs in the paediatric age group are suggested.
Abstract: Adrenal crises (AC) are life-threatening physiological disturbances that occur at a rate of 5-10/100 patient years in patients with adrenal insufficiency (AI). Despite their seriousness, there is a paucity of information on the epidemiology of AC events in the paediatric population specifically, as most investigations have focused on AI and ACs in adults. Improved surveillance of AC-related morbidity and mortality should improve the delineation of AC risk overall and among different subgroups of paediatric patients with AI. Valid incidence measures are essential for this purpose and also for the evaluation of interventions aimed at reducing adverse health outcomes from ACs. However, the absence of an agreed AC definition limits the potential benefit of research and surveillance in this area. While approaches to the treatment and prevention of ACs have much in common across the lifespan, there are important differences between children and adults with regards to the physiological, psychological, and social milieu in which these events occur. Education is considered to be an essential element of AC prevention but studies have shown that ACs occur even among well-educated patients, suggesting that new strategies may be needed. In this review, we examine the current knowledge regarding AC events in children with AI; assess the existing definitions of an AC and offer a new definition for use in research and the clinic; and suggest areas for further investigation that are aimed at reducing the incidence and health impact of ACs in the paediatric age group.
41 citations
TL;DR: This first international survey examining the variations in availability and provisions of services for children and adolescents with GD serves as a starting block for further dialogue and future studies.
Abstract: Background/Aims: Increasing numbers of children and adolescents seek medical care because they experience incongruence between their physical sex and their gender identity. Methods: The ESPE working group on gender dysphoria (GD) undertook a survey to investigate the structure and the type of medical care in centers that offer specialist care for transgender adolescents. Results: The personnel of each center varied from country to country, and a nationally organized network or plan for managing GD did not exist in all centers. The majority of young people were transitioning from female to male, and the number of new referrals increased remarkably during the past 3 years. Almost all centers follow the guidelines issued by the Endocrine Society and World Professional Association for Transgender Health. GnRH analogues were used as the initial treatment in the majority of the centers. The age from which adolescents are treated with gender-affirming hormones varied between centers. Several legal restrictions that concern or influence the treatment of children and adolescents with GD were finally addressed. Conclusion: This first international survey examining the variations in availability and provisions of services for children and adolescents with GD serves as a starting block for further dialogue and future studies.
38 citations
TL;DR: 11-oxyandrogens are the dominant active androgens in many patients with 21-hydroxylase deficiency, and their biosynthesis and metabolism, abundance in normal and pathologic states, and potential as biomarkers of adrenal developmental changes and disease are reviewed.
Abstract: The 11-oxyandrogens, particularly 11-ketotestosterone, have been recognized as a biologically important gonadal androgen in teleost (bony) fishes for decades, and their presence in human beings has been known but poorly understood. Today, we recognize that 11-oxyandrogens derive from the human adrenal glands and are major bioactive androgens, particularly in women and children. This article will review their biosynthesis and metabolism, abundance in normal and pathologic states, and potential as biomarkers of adrenal developmental changes and disease. Specifically, 11-oxyandrogens are the dominant active androgens in many patients with 21-hydroxylase deficiency.
38 citations
TL;DR: Stress exposure is highly prevalent in the general population; however, the experience of stress during vulnerable periods of development has substantial and permanent effects on brain structure and function and physical health in adulthood.
Abstract: Stress exposure is highly prevalent in the general population; however, the experience of stress during vulnerable periods of development has substantial and permanent effects on brain structure and function and physical health in adulthood. Stress, the state of threatened homeostasis, is generally associated with a time-limited activation of the stress system, i.e., the hypothalamic-pituitary-adrenal axis and the arousal/sympathetic nervous system, tailored to the stressful stimulus also known as the stressor. On the other hand, chronic stress may be associated with lingering hyper- or hyposecretion of mediators of the stress system. This chronic condition is called dyshomeostasis, allostasis, or cacostasis and is associated with increased mental and physical morbidity in the long term. Stressful or traumatic experiences during fetal life, early childhood, and adolescence have been related to persistent neuroendocrine and epigenetic changes. Further, brain structures involved in the stress response, such as those of the stress system, the hippocampus, and the amygdala, may be programmed early on for a life of adversity.
37 citations
TL;DR: Current information suggests that for girls with mildly early onset of puberty (ages 7–9 years), an informed assent discussion with the family should include the consideration of reassurance and observation for many girls who might otherwise receive 2–4 years of GnRHa treatment for a poorly defined benefit and at a cost of at least $20–30,000 per year.
Abstract: The use of gonadotropin-releasing hormone analogs (GnRHa) for the treatment of central precocious puberty (CPP), especially in girls, has increased rapidly in recent years. In the context of a secular trend towards earlier puberty onset, many girls now treated for CPP are healthy children experiencing puberty onset within the early end of the normal range. Justifications for GnRHa treatment include the preservation of adult height (AH) potential and the alleviation of presumed distress of early maturation and menarche. With a case of a family requesting treatment for an 8-year-old girl in early puberty as a background, studies of the effect of untreated CPP and of GnRHa treatment of CPP on AH are reviewed. In addition, the limited evidence relating CPP to significant psychological distress - in part due to early menses, and for the amelioration of such distress by GnRHa treatment - is discussed. Taken together, current information suggests that for girls with mildly early onset of puberty (ages 7-9 years), an informed assent discussion with the family should include the consideration of reassurance and observation for many girls who might otherwise receive 2-4 years of GnRHa treatment for a poorly defined benefit and at a cost of at least $20-30,000 per year.
TL;DR: The vulnerability of the fetal HPA axis to endogenous GCs and exogenous sGCs is explored, which suggests that exposure to s GCs in utero at critical developmental stages can alter the function of organ systems and that these effects may have sequelae that extend into adult life.
Abstract: Glucocorticoids (GCs), cortisol in humans, influence multiple essential maturational events during gestation. In the human fetus, fetal hypothalamic-pituitary-adrenal (HPA) axis function, fetal adrenal steroidogenesis, placental 11β- hydroxysteroid dehydrogenase type 2 activity, maternal cortisol concentrations, and environmental factors impact fetal cortisol exposure. The beneficial effects of synthetic glucocorticoids (sGCs), such as dexamethasone and betamethasone, on fetal lung maturation have significantly shifted the management of preterm labor and threatened preterm birth. Accumulating evidence suggests that exposure to sGCs in utero at critical developmental stages can alter the function of organ systems and that these effects may have sequelae that extend into adult life. Maternal stress and environmental influences may also impact fetal GC exposure. This article explores the vulnerability of the fetal HPA axis to endogenous GCs and exogenous sGCs.
TL;DR: In pediatric clinical practice, the limited use of mid- to low-potency TCS is rarely associated with clinically significant adrenal insufficiency or adrenal crisis and there is little need to test the HPA axis of these patients.
Abstract: Background/aims A meta-analysis was performed to determine the likelihood of hypothalamic-pituitary-adrenal (HPA) axis suppression following short-term cutaneous treatment of atopic dermatitis with topical corticosteroids (TCS) in pediatric patients. Methods All published pediatric clinical trials evaluating TCS use with pre- and post-treatment HPA axis assessment by cosyntropin stimulation testing were included. Results Of 128 eligible trials, 12 were selected for meta-analysis with a total of 522 participants. There were 20 observed cases of HPA axis suppression (3.8%, 95% CI 2.4-5.8). The percentage of HPA axis suppression with low- (classes 6-7), medium- (classes 3-5) and high-potency (classes 1-2) TCS use was 2% (3 of 148 patients, 95% CI 0.7-5.8), 3.1% (7 of 223 patients, 95% CI 1.5-6.3), and 6.6% (10 of 151 patients, 95% CI 3.6-11.8), respectively. Conclusion There is a low rate of reversible HPA axis suppression with the use of mid- to low-potency TCS compared to more potent formulations. In pediatric clinical practice, the limited use of mid- to low-potency TCS is rarely associated with clinically significant adrenal insufficiency or adrenal crisis. In the absence of signs and symptoms of adrenal insufficiency, there is little need to test the HPA axis of these patients.
TL;DR: This study supports an evolving demographic trend with more AFAB than AMAB youth now presenting to gender clinics and corroborate studies indicating that extensive laboratory testing may not be a necessary part of caring for these youths.
Abstract: Background/Aims: To examine characteristics, including mental health comorbidities, among adolescents presenting to a transgender clinic and to compare these data to previous reports. Methods: Retrospective chart review among youth seen at The Hospital for Sick Children between January 2014 and June 2016. Demographic data, clinical characteristics, and mental health comorbidities were assessed. Baseline and repeat blood work were also examined. Results: Charts from 203 adolescents aged 12–18 years were reviewed (156 assigned female at birth [AFAB] (77%) aged 16.3 ± 1.63 years, 47 assigned male at birth [AMAB] aged 16.1 ± 1.70 years). There was no statistically significant difference between gender groups except for Tanner stage (AFAB, mean 4.42 ± 0.8 and AMAB, mean 4.03 ± 1.1, p = 0.040). Individuals from racial/ethnic minority populations were under-represented compared to the background population. Self-report and baseline psychological questionnaires showed high levels of gender dysphoria, mood disorders, and suicidal ideation, with higher levels of anxiety detected on questionnaires among AFAB ( p = 0.03). Laboratory abnormalities identified on baseline and repeat testing were minor; on cross-sex hormones, hemoglobin levels increased slightly in AFAB ( p = 0.002, highest = 166 g/L) and decreased among AMAB ( p = 0.02, lowest = 132 g/L). Conclusion: Our study supports an evolving demographic trend with more AFAB than AMAB youth now presenting to gender clinics. The data also corroborate studies indicating that extensive laboratory testing may not be a necessary part of caring for these youths. Why more AFAB are now presenting to clinic and racial/ethnic minorities are underrepresented is not clear, but these trends have important implications for clinical care and warrant further study.
Ghent University Hospital1, Erasmus University Medical Center2, Carlos III Health Institute3, Humboldt University of Berlin4, University of Bern5, University of Glasgow6, Istanbul University7, University of Sheffield8, Vilnius University9, Boston Children's Hospital10, Neelain University11, Karolinska University Hospital12, Utrecht University13, Radboud University Nijmegen Medical Centre14, Erasmus University Rotterdam15
TL;DR: Although development of GGCC seems rare, gonadectomy after puberty is broadly recommended in CAIS; in PAIS this is more variable, reflecting the need for evidence-based guidelines regarding prophylactic Gonadectomy in AIS.
Abstract: Background: Complete and partial androgen insensitivity syndrome (CAIS, PAIS) are associated with an increased risk of gonadal germ cell cancer (GGCC). Recent guidelines recommend gonadectomy in women with CAIS in late adolescence. Nevertheless, many adult women prefer to retain their gonads. Aims: This study aims to explore attitudes towards gonadectomy in AIS in centres around the world, estimate the proportion of adults with retained gonads and/or who developed GGCC, and explore reasons for declining gonadectomy. Methods: A survey was performed among health care professionals who use the International DSD Registry (I-DSD). Results: Data were provided from 22 centres in 16 countries on 166 women (CAIS) and 26 men (PAIS). In CAIS, gonadectomy was recommended in early adulthood in 67% of centres; 19/166 (11.4%) women refused gonadectomy. Among 142 women who had gonadectomy, evidence of germ cell neoplasm in situ (GCNIS), the precursor of GGCC, was reported in 2 (1.4%) out of 8 from whom pathology results were formally provided. Nine out of 26 men with PAIS (34.6%) had retained gonads; 11% of centres recommended routine gonadectomy in PAIS. Conclusion: Although development of GGCC seems rare, gonadectomy after puberty is broadly recommended in CAIS; in PAIS this is more variable. Overall, our data reflect the need for evidence-based guidelines regarding prophylactic gonadectomy in AIS.
TL;DR: The data suggest that haploinsufficiency for KDM6A due to mosaic X chromosome monosomy may be responsible for hyperinsulinism in Turner syndrome.
Abstract: Background: Previous case reports have suggested a possible association of congenital hyperinsulinism with Turner syndrome. Objective: We examined the clinical and molecular features in girls with both congenital hyperinsulinism and Turner syndrome seen at The Children’s Hospital of Philadelphia (CHOP) between 1974 and 2017. Methods: Records of girls with hyperinsulinism and Turner syndrome were reviewed. Insulin secretion was studied in pancreatic islets and in mouse islets treated with an inhibitor of KDM6A , an X chromosome gene associated with hyperinsulinism in Kabuki syndrome. Results: Hyperinsulinism was diagnosed in 12 girls with Turner syndrome. Six were diazoxide-unresponsive; 3 had pancreatectomies. The incidence of Turner syndrome among CHOP patients with hyperinsulinism (10 of 1,050 from 1997 to 2017) was 48 times more frequent than expected. The only consistent chromosomal anomaly in these girls was the presence of a 45,X cell line. Studies of isolated islets from 1 case showed abnormal elevated cytosolic calcium and heightened sensitivity to amino acid-stimulated insulin release; similar alterations were demonstrated in mouse islets treated with a KDM6A inhibitor. Conclusion: These results demonstrate a higher than expected frequency of Turner syndrome among children with hyperinsulinism. Our data suggest that haploinsufficiency for KDM6A due to mosaic X chromosome monosomy may be responsible for hyperinsulinism in Turner syndrome.
TL;DR: Long-acting somatostatin analogues are effective in glycemic control of patients with CHI, however, in 37% of all patients increased liver enzymes were observed, so it is important to monitor liver function in all patients receiving long- acting som atostatin analogue therapy.
Abstract: Background/Aims: Congenital hyperinsulinism (CHI) is a rare disease characterized by recurrent severe hypoglycemia. In the diffuse form of CHI, pharmacotherapy is the preferred choice of treatment. Long-acting somatostatin analogues have been used in children as off-label medication. However, the efficacy, outcomes, and adverse effect profiles of long-acting somatostatin analogues have not been described in multicentered studies. The aim of this retrospective study is to summarize the experience with long-acting somatostatin analogues in a large group of children with CHI. Methods: Data were obtained retrospectively from 27 patients with CHI who received long-acting somatostatin analogues in 6 different centers in Europe. These included information on glycemic stability, auxology, and adverse effect profile in clinical follow-up assessments. Results: Blood glucose control improved in most patients (89%). No life-threatening side effects occurred. Thirteen patients (48%) experienced side effects; in 3 patients (11%), the side effects were the main reason for discontinuation of the treatment. The most frequent side effect was elevated liver enzymes (n = 10, 37%). Conclusion: Long-acting somatostatin analogues are effective in glycemic control of patients with CHI. However, in 37% of all patients increased liver enzymes were observed. It is important to monitor liver function in all patients receiving long-acting somatostatin analogue therapy. (C) 2017 S. Karger AG, Basel
TL;DR: Motor problems seem to be prominent in CHI patients, and despite a high incidence of developmental delay, a permanent cognitive defect was only detectable in 9 of 58 patients.
Abstract: Background Congenital hyperinsulinism (CHI) is hallmarked by persistent hypoketotic hypoglycemia in infancy. In the majority of all patients, CHI is caused by mutations in the KATP channel genes ABCC8 and KCNJ11, but other genes in the insulin-regulatory pathway have also been described. Repeated episodes of hypoglycemia include an increased risk of seizures and intellectual disability. So far, controlled psychometric studies on cognitive, motor, speech, and social-emotional outcome of CHI patients are missing. Until now, neurodevelopmental long-term outcome in CHI patients has only been measured by questionnaires, self-, parental-, or caregiver-administered instruments. Methods This is a prospective study of 60 patients (median age 3.3 years, range 3 months to 57 years): 48 with a diffuse, 9 with a focal, and 3 with an atypical histology. Neurodevelopmental outcome was assessed using standardized psychological tests and questionnaires. Results 28 of 60 patients showed developmental delay (46.7%). 9 of 57 patients had cognitive deficits (15.8%), 7 of 26 patients had speech problems (26.9%), and 17 of 44 patients had motor problems (38.6%). In 5 of 53 patients, social-emotional problems were reported. Outcome and the underlying genetic defect were not correlated. Conclusions Motor problems seem to be prominent in CHI patients. Despite a high incidence of developmental delay, a permanent cognitive defect was only detectable in 9 of 58 patients.
TL;DR: Serum levels of uric acid can be used as an indicator of unhealthy obesity in youth, where lower levels of UA indicate a lower risk and higher levels suggest a higher risk of MUO.
Abstract: Background: Metabolically healthy obesity (MHO) refers to those individuals who do not show cardiometabolic abnormalities. Our aim was to identify potential clinical and metabolic indicators that may help to distinguish between metabolically healthy and unhealthy individuals amongst overweight and obese children and adolescents. Methods: The study involved 246 overweight/obese and 212 normal-weight individuals enrolled in the LIFE Child study, aged between 6 and 18 years. Overweight/obese individuals without cardiovascular risk factors (fasting serum lipids, blood pressure, and glucose) were classified as MHO. Individuals meeting 1 or more criteria of cardiovascular risk factors were classified as metabolically unhealthy obesity (MUO). Results: Among the 246 overweight/obese individuals, 173 (70%) were MHO and 73 (30%) were MUO. The MHO individuals were younger, more likely to be male, and had lower BMI SDS. In the logistic regression models, uric acid (UA) SDS (OR 1.61, 95% CI 1.1–2.6, p = 0.004), waist circumference SDS (OR 2.50, 95% CI 1.2–6.4, p = 0.017), and C-peptide (OR 4.05, 95% CI 3.5–91, p = 0.003) were significant indicators of MUO. Conclusion: Our results suggest that nearly one-third of overweight/obese children are already identified as MUO. Serum levels of UA can be used as an indicator of unhealthy obesity in youth, where lower levels of UA indicate a lower risk and higher levels suggest a higher risk of MUO. We note that the relevance of identifying potential indicators remains the first most important step in future clinical research.
TL;DR: The principles of adrenal steroidogenesis are described, including the newly appreciated 11-oxygenated androgen pathway, and a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders are described.
Abstract: Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.
TL;DR: There are currently no established guidelines on what constitutes an acceptable level of risk (i.e., risk threshold) for childhood obesity prediction models, but these should be set following consideration of the consequences of false-positive and false-negative predictions, as well as any relevant clinical guidelines.
Abstract: Statistical models have been developed for the prediction or diagnosis of a wide range of outcomes. However, to our knowledge, only 7 published studies have reported models to specifically predict overweight and/or obesity in early childhood. These models were developed using known risk factors and vary greatly in terms of their discrimination and predictive capacities. There are currently no established guidelines on what constitutes an acceptable level of risk (i.e., risk threshold) for childhood obesity prediction models, but these should be set following consideration of the consequences of false-positive and false-negative predictions, as well as any relevant clinical guidelines. To date, no studies have examined the impact of using early childhood obesity prediction models as intervention tools. While these are potentially valuable to inform targeted interventions, the heterogeneity of the existing models and the lack of consensus on adequate thresholds limit their usefulness in practice.
TL;DR: Patients after HSCT require long-term surveillance for the detection of endocrine and metabolic disorders, and nonmyeloablative conditioning regimens may reduce the incidence of these complications.
Abstract: Background/Aims: The objective was to evaluate endocrine complications in survivors of hematopoietic stem cell transplantation (HSCT) performed during childhood. Methods: Endocrine dysfunction and metabolic syndrome parameters were assessed by chart review of 178 childhood HSCT survivors (median age at evaluation, 15.5 [range: 3.8–29.8] years; median follow-up, 8.5 [range: 2–23.4] years). Results: The following statistically significant associations were identified ( p 0.05 for all): growth hormone deficiency (17.4%) was associated with cranial/craniospinal irradiation, total body irradiation (TBI), allogeneic HSCT, and longer follow-up. Short adult stature (23.3% of patients who had attained adult height) was associated with cranial/craniospinal irradiation and, in females, with younger age at HSCT. Primary gonadal failure was more prevalent in females (52.6 vs. 24.1%), and was associated with TBI in males and with a primary diagnosis of hematological malignancy in females. Hypothyroidism (25.2%) was associated with previous neck/mediastinal irradiation. Metabolic disturbances included obesity (3.9%), type 2 diabetes (2.2%), impaired glucose tolerance (2.8%), and dyslipidemia (18.5%). Dyslipidemia was associated with a primary diagnosis of hematological malignancy, TBI, and a positive family history of dyslipidemia. Endocrine dysfunction was less frequent in patients who had received fludarabine. Conclusions: Patients after HSCT require long-term surveillance for the detection of endocrine and metabolic disorders. Nonmyeloablative conditioning regimens may reduce the incidence of these complications.
TL;DR: Two years of rhIGF-1 improved growth, with a tendency to improve bone mass and bone microstructure and to modulate body composition, are concluded.
Abstract: Aim: Our objective was to determine changes in bone mineral density (BMD), trabecular bone score (TBS), and body composition after 2 years of therapy with recombinant human insulin-like growth factor-1 (rhIGF-1) in 2 prepubertal children with a complete lack of circulating PAPP-A2 due to a homozygous mutation in PAPP-A2 (p.D643fs25*) resulting in a premature stop codon. Methods: Body composition, BMD, and bone structure were determined by dual-energy X-ray absorptiometry at baseline and after 1 and 2 years of rhIGF-1 treatment. Results: Height increased from 132 to 145.5 cm (patient 1) and from 111.5 to 124.5 cm (patient 2). Bone mineral content increased from 933.40 to 1,057.97 and 1,152.77 g in patient 1, and from 696.12 to 773.26 and 911.51 g in patient 2, after 1 and 2 years, respectively. Whole-body BMD also increased after 2 years of rhIGF-1 from baseline 0.788 to 0.869 g/cm 2 in patient 1 and from 0.763 to 0.829 g/cm 2 in patient 2. After 2 years of treatment, both children had an improvement in TBS. During therapy, a slight increase in body fat mass was seen, with a concomitant increase in lean mass. No adverse effects were reported. Conclusion: Two years of rhIGF-1 improved growth, with a tendency to improve bone mass and bone microstructure and to modulate body composition.
TL;DR: Pediatric radiologists’ overall impressions had similar sensitivity but better specificity for detecting malignancy than the ATA risk stratification tool by the authors' convention, however, neither US-based methods perfectly discriminated benign from malignant nodules, supporting the continued need for fine needle aspiration for suspicious nodules.
Abstract: BACKGROUND Pediatric thyroid nodules are more likely to be malignant compared to those in adults and may have different concerning ultrasound (US) features. Recent adult guidelines stratify malignancy risk by US features. Our aim is to (1) describe and confirm US features that predict pediatric malignancy, and (2) apply the Adult American Thyroid Association (ATA) Risk Stratification Guidelines to a large pediatric cohort. METHODS We identified 112 children with 145 thyroid nodules from 1996 to 2015. Two blinded pediatric radiologists independently read all US images, described multiple features, and reported their overall impression: benign, indeterminate, or malignant. Each nodule was assigned an ATA risk stratification category. Radiologists' impressions and ATA risk stratification were compared to histology and cytology results. RESULTS Multiple US features including a solid composition, presence of microcalcifications, irregular margins, increased blood flow, and hypoechogenicity were associated with increased odds of malignancy. ATA risk stratification correlated with the radiologists' overall impression (p < 0.001). The sensitivity for detecting malignancy was comparable between both ATA stratification (91%) and the radiologists' overall impression (90%). The specificity of the radiologists' malignant overall impression (80%) was better compared to the ATA high risk stratification (54%). CONCLUSIONS At our institution, pediatric radiologists' overall impressions had similar sensitivity but better specificity for detecting malignancy than the ATA risk stratification tool by our convention. However, neither US-based methods perfectly discriminated benign from malignant nodules, supporting the continued need for fine needle aspiration for suspicious nodules. Further work is needed to develop an US-based scoring system specific to pediatric patients.
TL;DR: This is the first study suggesting that permanent ADHD as well as autism in CH patients at ages 6 and 11 years are the result of early overtreatment and undertreatment, respectively.
Abstract: Objective: Congenital hypothyroidism (CH) per se, when not treated or undertreated, may lead to severe behavioural problems (cretinism), whereas overtreatment of CH seems associated with attention problems. Design and Methods: For 55 CH patients, prospectively followed from birth until 11 years, parents rated the Child Behaviour Checklist and teachers the Teacher’s Report Form at children’s ages 6 and 11 years. We related scores regarding Attention, Delinquency, and Aggression (ADA scores, indicative for attention deficit hyperactivity syndrome, ADHD), and scores regarding Withdrawn, Anxious, Social, and Thought problems (WAST scores, indicative for autism) to the occurrence of over- and undertreatment in five age periods. Over- and undertreatment were defined as free thyroxine (fT4) concentrations above/below the range of the patient’s individual fT4 steady state concentration. Results: ADA scores at 6 and 11 years for patients overtreated in the period 1–3 months postnatally were higher than those for patients who were not overtreated. Patients with severe CH undertreated in the period 3–6 months postnatally had higher WAST scores at 6 and 11 years than all other patients. Conclusions: This is the first study suggesting that permanent ADHD as well as autism in CH patients at ages 6 and 11 years are the result of early overtreatment and undertreatment, respectively.
TL;DR: Most of the evidence points towards a negative effect on executive functions where girls seem to be more susceptible than boys, and larger studies are warranted to investigate areas other than cognition and behavior and to be able to draw more definitive conclusions about prenatal DEX treatment.
Abstract: Prenatal treatment of congenital adrenal hyperplasia with dexamethasone (DEX) has been in use since the mid-1980s and has proven effective at reducing virilization of external genitalia in affected girls. However, multiple experimental studies on animals and clinical studies on humans show that prenatal administration of glucocorticoids may cause unwanted adverse effects which have raised concerns about the long-term safety of the treatment. The long-term outcome of prenatal DEX treatment on cognition has been investigated, but the results are still conflicting. Overall, most of the evidence points towards a negative effect on executive functions where girls seem to be more susceptible than boys. Some effects on social behavior have been observed, but results are still contradictory and treated children are mostly well adapted. Cardiovascular, renal, and metabolic function are still areas to be investigated. Larger studies are warranted to investigate areas other than cognition and behavior and to be able to draw more definitive conclusions about prenatal DEX treatment.
TL;DR: The interconversion of active and inactive corticosteroids – cortisol and cortisone, respectively, in humans – is modulated by isozymes of 11β-hydroxysteroid dehydrogenase (11-HSD).
Abstract: The interconversion of active and inactive corticosteroids - cortisol and cortisone, respectively, in humans - is modulated by isozymes of 11β-hydroxysteroid dehydrogenase (11-HSD). Studies of this process have provided crucial insights into glucocorticoid effects in a wide variety of tissues. The 11-HSD1 isozyme functions mainly as an oxoreductase (cortisone to cortisol) and is expressed at high levels in the liver and other glucocorticoid target tissues. Because it is required for full physiological effects of cortisol, it has emerged as a drug target for metabolic syndrome and type 2 diabetes. Mutations in the corresponding HSD11B1 gene, or in the H6PD gene encoding hexose-6-phosphate dehydrogenase (which supplies the NADPH required for the oxoreductase activity of 11-HSD1), cause apparent cortisone reductase deficiency, a rare syndrome of adrenocortical hyperactivity and hyperandrogenism. In contrast, the 11-HSD2 isozyme functions as a dehydrogenase (cortisol to cortisone) and is expressed mainly in mineralocorticoid target tissues, where it bars access of cortisol to the mineralocorticoid receptor. Mutations in the HSD11B2 gene encoding 11-HSD2 cause the syndrome of apparent mineralocorticoid excess, a severe form of familial hypertension. The role of this enzyme in the pathogenesis of common forms of low-renin hypertension remains uncertain.
TL;DR: CNVs seem to play a significant role in patients with short stature, and Chromosomal microarray should be used as a diagnostic tool for evaluation of growth disorders, especially for syndromic short stature of unknown cause.
Abstract: BACKGROUND/AIMS Genetic imbalances are responsible for many cases of short stature of unknown etiology. This study aims to identify recurrent pathogenic copy number variants (CNVs) in patients with syndromic short stature of unknown cause. METHODS We selected 229 children with short stature and dysmorphic features, developmental delay, and/or intellectual disability, but without a recognized syndrome. All patients were evaluated by chromosomal microarray (array-based comparative genomic hybridization/single nucleotide polymorphism array). Additionally, we searched databases and previous studies to recover recurrent pathogenic CNVs associated with short stature. RESULTS We identified 32 pathogenic/probably pathogenic CNVs in 229 patients. By reviewing the literature, we selected 4 previous studies which evaluated CNVs in cohorts of patients with short stature. Taken together, there were 671 patients with short stature of unknown cause evaluated by chromosomal microarray. Pathogenic/probably pathogenic CNVs were identified in 87 patients (13%). Seven recurrent CNVs, 22q11.21, 15q26, 1p36.33, Xp22.33, 17p13.3, 1q21.1, 2q24.2, were observed. They are responsible for about 40% of all pathogenic/probably pathogenic genomic imbalances found in short stature patients of unknown cause. CONCLUSION CNVs seem to play a significant role in patients with short stature. Chromosomal microarray should be used as a diagnostic tool for evaluation of growth disorders, especially for syndromic short stature of unknown cause.
TL;DR: Environmental exposure to POPs may affect genital development and result in reproductive tract alterations with potentially relevant health consequences in maturity.
Abstract: This study was funded by grants from FIS-FEDER (PI04/2018, PI09/02311, and PI13/02429), Fundacion Cajastur-Liberbank, and Universidad de Oviedo
TL;DR: Durable metabolic control of T2D with metformin monotherapy is most likely in youth presenting with lower HbA1c and with shorter diabetes duration, independent of age, race-ethnicity, and BMI.
Abstract: BACKGROUND/AIMS Many adolescents with type 2 diabetes (T2D) have rapid deterioration of glycemic control on metformin monotherapy within 2 years of diagnosis. METHODS Enrollment data from the Pediatric Diabetes Consortium T2D Registry were used to categorize 276 youth with a T2D duration ≥2 years into two groups: (1) participants with HbA1c <7.5% on metformin monotherapy (group 1, n = 75) and (2) participants treated with insulin ± metformin (group 2, n = 201). The characteristics of the groups were compared. RESULTS At enrollment, groups 1 and 2 did not differ in age (16.2 vs. 16.8 years) or BMI percentile (99 vs. 98%); group 2 had higher HbA1c (9.9% [85 mmol/mol] vs. 5.9% [41 mmol/mol], p < 0.001). Lower HbA1c and metformin monotherapy at diagnosis were associated with a greater likelihood of adequate control with metformin alone (p < 0.001). In multivariable analysis, HbA1c at diagnosis (p = 0.001) and diabetes duration (p = 0.009) were associated with adequate control on metformin. The HbA1c trajectory after diagnosis was worse in group 2. CONCLUSION Durable metabolic control of T2D with metformin monotherapy is most likely in youth presenting with lower HbA1c and with shorter diabetes duration, independent of age, race-ethnicity, and BMI. Elevated HbA1c levels in those on insulin therapy highlight the importance of early diagnosis and a better understanding of glycemic control barriers.