Refining the evaluation of growth and the growth hormone/insulin-like growth factor-I axis in children

Introduction: The growth hormone (GH)/Insulin-like growth factor-I (IGF) axis is a key mediator of childhood growth. Current diagnostic tests have poor specificity for disorders affecting this system, namely the growth hormone stimulation test (GHST) and IGF-I measurement. Aim: To improve the diagnostic evaluation of children with poor growth and possible GH deficiency (GHD) through 1) modifying the GHST and diagnostic fasting study; 2) utilising liquid chromatography mass spectrometry (LCMS) to measure IGF concentrations; 3) exploring genetic causes of poor growth; and 4) studying the association between body composition and infant growth. Methods: These include: additional GH measurements during the GHST and fasting study; IGF-I and –II measurement by LCMS in a well-characterised cohort; focused whole exome testing for rare clinical phenotypes; and body composition analysis using air displacement plethysmography. Results: Serial additional GH measurement after intravenous catheter placement will improve the specificity of the GHST. Similarly, serial GH measurement after a diagnostic fasting study will improve specificity for GHD. In normal infants, adiposity doubles in the first two months. Using LCMS, I have described reference data for IGF-I and –II at birth and demonstrated a relationship between these measurements and this rapid early accumulation of body fat. In our genetic studies, we have also identified a novel IGF1R mutation in a child with a phenotype consistent with IGF-I resistance. Conclusions: Diagnosing disorders of the GH/IGF-I axis remain a significant clinical challenge. I have expanded the clinical approach to evaluating the child with short stature through refining the GHST, diagnostic fasting study and body composition evaluation; describing reference data for body composition and IGFs in infancy; and exploring novel genetic causes of disordered growth. Future work will focus on studying other clinical tools in evaluating the child with short stature and predicting the clinical response to GH treatment

Fat-bone interaction within the bone marrow milieu: Impact on hematopoiesis and systemic energy metabolism

The relationship between fat, bone and systemic metabolism is a growing area of scientific interest. Marrow adipose tissue is a well-recognized component of the bone marrow milieu and is metabolically distinct from current established subtypes of adipose tissue. Despite recent advances, the functional significance of marrow adipose tissue is still not clearly delineated. Bone and fat cells share a common mesenchymal stem cell (MSC) within the bone marrow, and hormones and transcription factors such as growth hormone, leptin, and peroxisomal proliferator-activated receptor γ influence MSC differentiation into osteoblasts or adipocytes. MSC osteogenic potential is more vulnerable than adipogenic potential to radiation and chemotherapy, and this confers a risk for an abnormal fat-bone axis in survivors following cancer therapy and bone marrow transplantation. This review provides a summary of data from animal and human studies describing the relationship between marrow adipose tissue and hematopoiesis, bone mineral density, bone strength, and metabolic function. The significance of marrow adiposity in other metabolic disorders such as osteoporosis, diabetes mellitus, and estrogen and growth hormone deficiency are also discussed. We conclude that marrow adipose tissue is an active endocrine organ with important metabolic functions contributing to bone energy maintenance, osteogenesis, bone remodeling, and hematopoiesis. Future studies on the metabolic role of marrow adipose tissue may provide the critical insight necessary for selecting targeted therapeutic interventions to improve altered hematopoiesis and augment skeletal remodeling in cancer survivors. © 2018 Elsevier Inc

Is hospital based MMR vaccination for children with egg allergy here to stay?

Egg allergy is incorrectly considered to constitute a contraindication to MMR in the community, despite a long history of its safe administration to egg allergic children. The product insert perpetuates this misinformation but the Irish guidelines from the RCPI are unequivocal. We reviewed all paediatric cases vaccinated in our hospital in 2007-2008. Forty seven of 91 children receiving vaccinations in hospital, had been referred for MMR due to concerns regarding egg allergy. In 32% (n=15), GP referral for vaccination was made despite correspondence from the clinic advising routine vaccination in the community. Nineteen were second MMR immunisations, which should all have occurred in the community. Unnecessary hospital referral for MMR vaccination is an extra burden on hospital resources, and causes unwarranted anxiety amongst parents of children with egg allergy. A change in practice seems difficult to achieve, as many referrals happen despite individualised correspondence to GPs and other referring clinicians outlining the current guidelines

Parental patterns of use of over the counter analgesics in children

Over-The-Counter Analgesics (OTCA) account for over a fifth of Irish pharmacy sales. Little is known about patterns of use, specifically in children. This study investigated parents use of OTCAs in children. A questionnaire exploring use of OTCAs and knowledge of side-effects was distributed to guardians of children attending three GP surgeries in South of Ireland from June-September 2010. The questionnaire was completed by 183 parents (response rate 95%). Many respondents (n=121, 66.1%) were using analgesics when not required or using an inappropriate analgesic for a child symptom. Private patients demonstrated better use (n=31, 40%) than those with Medical Cards (n=18, 22.5%) (p=0.016). Identification of potential side-effects was poor, with drowsiness (n=88, 49%), rash (n=39, 22%) and nausea (n=32, 18%) listed as potential side-effects. Inappropriate use of OTCAs is prevalent in Irish children. Parents need more information and guidance on their use

Preventing type 2 diabetes:A research agenda for behavioural science

Aims The aim of this narrative review was to identify important knowledge gaps in behavioural science relating to type 2 diabetes prevention, to inform future research in the field. Methods Seven researchers who have published behaviour science research applied to type 2 diabetes prevention independently identified several important gaps in knowledge. They met to discuss these and to generate recommendations to advance research in behavioural science of type 2 diabetes prevention. Results A total of 21 overlapping recommendations for a research agenda were identified. These covered issues within the following broad categories: (a) evidencing the impact of whole population approaches to type 2 diabetes prevention, (b) understanding the utility of disease-specific approaches to type 2 diabetes prevention such as Diabetes Prevention Programmes (DPPs) compared to generic weight loss programmes, (c) identifying how best to increase reach and engagement of DPPs, whilst avoiding exacerbating inequalities, (d) the need to understand mechanism of DPPs, (e) the need to understand how to increase maintenance of changes as part of or following DPPs, (f) the need to assess the feasibility and effectiveness of alternative approaches to the typical self-regulation approaches that are most commonly used, and (g) the need to address emotional aspects of DPPs, to promote effectiveness and avoid harms. Conclusions There is a clear role for behavioural science in informing interventions to prevent people from developing type 2 diabetes, based on strong evidence of reach, effectiveness and cost-effectiveness. This review identifies key priorities for research needed to improve existing interventions

Glargine co-administration with intravenous insulin in pediatric diabetic ketoacidosis is safe and facilitates transition to a subcutaneous regimen

Background: Diabetes ketoacidosis (DKA) is a common presentation and complication of type 1 diabetes (T1D). While intravenous insulin is typically used to treat acute metabolic abnormalities, the transition from intravenous to subcutaneous treatment can present a challenge. We hypothesize that co-administration of glargine, a subcutaneous long-acting insulin analog, during insulin infusion may facilitate a flexible and safe transition from intravenous to subcutaneous therapy. Objective: To determine if the practice of administering subcutaneous glargine during intravenous insulin is associated with an increased risk of hypoglycemia, hypokalemia, or other complications in children with DKA. Methods: Retrospective chart review of patients aged 2 to 21 years, presenting to our center with DKA between April 2012 and June 2014. Patients were divided into two groups: those co-administered subcutaneous glargine with intravenous insulin for over 4 hours (G+); and patients with less than 2 hours of overlap (G−). Results: We reviewed 149 DKA admissions (55 G+, 94 G−) from 129 unique patients. There was a similar incidence of hypoglycemia between groups (25% G+ vs 20% G−, P = 0.46). Hypokalemia (<3.5 mmol/L) occurred more frequently in the G+ group (OR = 3.4, 95% CI 1.7-7.0, P = 0.001). Cerebral edema occurred in 2/55 (3.6%) of the G− group and none of the G+ subjects. Conclusion: Co-administration of glargine early in the course of DKA treatment is well tolerated and convenient for discharge planning; however, this approach is associated with an increased risk of hypokalemia. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Lt

Newborn screening in the US may miss mild persistent hypothyroidism

Objective To determine if newborn screening (NBS) programs for congenital hypothyroidism in the US use thyroid-stimulating hormone (TSH) cutoffs that are age adjusted to account for the physiologic 4-fold reduction in TSH concentrations over the first few days of life. Study design All NBS programs in the US were contacted and asked to provide information on their NBS protocols, TSH cutoffs, and whether these cutoffs were age adjusted. Results Of 51 NBS programs, 28 request a repeat specimen if the initial eluted serum TSH concentration is mildly increased (between the cutoff and a median upper limit of 50 mU/L), whereas 14 programs perform a routine second screen in all infants. Although these specimens are typically collected between 1 week and 1 month of life, 16 of the 28 programs with a discretionary second test and 8 of 14 programs with a routine second test do not have age-adjusted TSH cutoffs after the first 48 hours of life. Conclusions There is variation in NBS practices for screening for congenital hypothyroidism across the US, and many programs do not adjust the TSH cutoff beyond the first 2 days of life. Samples are processed when received from older infants, often to retest borderline initial results. This approach will miss congenital hypothyroidism in infants with persistent mild TSH elevations. We recommend that all NBS programs provide age-adjusted TSH cutoffs, and suggest developing a standard approach to screening for congenital hypothyroidism in the US. © 2017 Elsevier Inc

Novel PTH gene mutations causing isolated hypoparathyroidism

Context: PTH gene mutations represent a rare cause of familial isolated hypoparathyroidism (FIH). These defects can cause hypoparathyroidism with increased or decreased serum levels of PTH through 1) impaired PTH synthesis; 2) induction of parathyroid cell apoptosis; or 3) secretion of bioinactive PTH molecules. Eight pathogenic mutations of this gene have been described previously. Objective: Through describing two novel mutations of the PTH gene, we aim to extend the molecular basis for FIH and further refine the proposed mechanisms by which PTH mutations cause hypoparathyroidism. Design: Proband case reports with extended family analysis. Patients and Other Participants: The probands in both kindreds presented before 10-days-of-age with hypocalcemia and elevated phosphate levels. Proband A had low PTH levels, while these levels were elevated in Proband B. Proband B was initially diagnosed with pseudohypoparathyroidism. Interventions: Methylation analysis of CpG dinucleotides within three GNAS differentially methylated regions; Whole genome sequencing; and PTH infusion with analysis of nephrogenous cyclic AMP. Results: Proband A had a novel heterozygous sequence change in exon 2 of the PTH gene, c.46_47delinsAA (p.Ala16Lys) and Proband B had a novel homozygous nucleotide transition in PTH exon 3 (c.128G>A; p.G43E) that led to replacement of glycine by glutamic acid at position 12 of PTH 1-84. PTH 1-34 infusion demonstrated that renal responsiveness to PTH was intact and not antagonized by circulating bioinactive PTH. Conclusions: PTH gene mutations are uncommon causes of hypoparathyroidism, but can be misdiagnosed as disorders of gland development or receptor function if PTH levels are decreased or elevated, respectively. Genetic testing should be considered early in the diagnostic approach to these presentations

Safety and efficacy of glucagon-like peptide-1 receptor agonists in children and adolescents with obesity: A meta-analysis

To determine the weight, body mass index (BMI), cardiometabolic, and gastrointestinal effects of glucagon-like peptide-1 (GLP-1) receptor agonists in children with obesity. Study design: Web of Science, PubMed/MEDLINE, and Scopus databases from 01/01/1994-01/01/2021 for randomized control trials examining the weight, BMI, cardiometabolic, or gastrointestinal effects of GLP-1 receptor agonists in children and adolescents with obesity. Data were extracted by 2 independent surveyors and a random effects model was applied to meta-analyze generic inverse variance outcomes. Primary outcomes were related to weight and cardiometabolic profile, and secondary outcomes of interest were gastrointestinal-related treatment-emergent adverse events. Results: Nine studies involving 574 participants were identified, of which 3 involved exenatide and 6 involved liraglutide. GLP-1 receptor agonists use caused a modest reduction in body weight (mean difference [MD] -1.50 [-2.50,-0.50] kg, I2 64%), BMI (MD -1.24 [-1.71,-0.77] kg/m2, I2 0%), and BMI z score (MD -0.14 [-0.23,-0.06], I2 43%). Glycemic control was improved in children with proven insulin resistance (glycated hemoglobin A1c MD -1.05 [-1.93,-0.18] %, I2 76%). Although no lipid profile improvements were noted, a modest decrease in systolic blood pressure was detected (MD -2.30 [-4.11,-0.49] mm Hg; I2 0%). Finally, analysis of gastrointestinal-related treatment-emergent adverse events revealed an increased risk of nausea (risk ratio 2.11 [1.44, 3.09]; I2 0%), without significant increases in other gastrointestinal symptoms. Conclusions: This meta-analysis indicates that GLP-1 receptor agonists are safe and effective in modestly reducing weight, BMI, glycated hemoglobin A1c, and systolic blood pressure in children and adolescents with obesity in a clinical setting, albeit with increased rates of nausea

Body mass index trajectories in the first 5 years and associated antenatal factors

Background: The increasing prevalence of childhood obesity is an important public health issue and the development of obesity in early life and associated risk factors need to be better understood. The aim of this study was to identify distinct body mass index trajectories in the first 5 years of life and to examine their associations with factors identified in pregnancy, including metabolic parameters. Methods: BMI measurements from 2,172 children in Ireland enrolled in the BASELINE cohort study with BMI assessments at birth, 2, 6, and 12 months, and 2 and 5 years were analyzed. Growth mixture modeling was used to identify distinct BMI trajectories, and multivariate multinomial logistic regression was used to assess the association between these trajectories and antenatal factors. Results: Three distinct BMI trajectories were identified: normal (89.6%); rapid gain in the first 6 months (7.8%); and rapid BMI after 12 months (2.6%). Male sex and higher maternal age increased the likelihood of belonging to the rapid gain in the first 6 months trajectory. Raised maternal BMI at 15 weeks of pregnancy and lower cord blood IGF-2 were associated with rapid gain after 1 year. Conclusion: Sex, maternal age and BMI, and IGF-2 levels were found to be associated with BMI trajectories in early childhood departing from normal growth. Further research and extended follow-up to examine the effects of childhood growth patterns are required to understand their relationship with health outcomes