Adolescent and young adult (AYA) survivors of pediatric oncology related cerebral insult are vulnerable to numerous treatment-induced deficits that significantly enhance cardiovascular disease risk. Regular exercise improves endothelial function, fitness, body composition and musculoskeletal function which may reduce predisposition for cardiovascular disease. Here we assessed the feasibility and effectiveness of a 24-week exercise intervention on cardiovascular, physical and metabolic outcomes in this population. Thirteen survivors (6 male, 7 female; median age 19 y (range 16–23 y) were recruited to participate in a 48-week study consisting of a 24-week control period (regular care) followed by a 24-week exercise intervention. Outcome measures were collected at entry (week 0) and following regular care (24-week) and exercise (48-week). Assessed variables included endothelial function (flow mediated dilation, FMD), blood pressure, heart rate (HR), aerobic capacity, anthropometry, body composition, muscular strength (3 repetition maximum testing), muscular endurance (repetitions/min) and physical activity levels (accelerometry). Compared to baseline, delta diameter (p = 0.008) and FMD (p = 0.029) of the brachial artery increased following exercise. Bicep-curl strength also increased following exercise compared to baseline (p = 0.019), while submaximal (6 min mark) measures of ventilation (p = 0.012), rating of perceived exertion (p = 0.012), HR (p = 0.001), absolute (p = 0.000) and relative (p = 0.000) aerobic capacity decreased. Breaks in sedentary time increased (p = 0.043) following exercise compared to regular care. Although the sample was small and heterogeneous, this study demonstrates that exercise is achievable and has positive effects on vascular function, submaximal fitness, local strength and physical activity in a population of AYA survivors of pediatric oncology related cerebral insult.

SummaryObjectiveWe examined parental and early‐life variables in order to identify risk factors for adulthood overweight and obesity in offspring. We report here on the longitudinal prevalence of overweight and obesity in Australian children born between 1989 and 1991 and followed from birth to age 22.MethodsData were analysed on 1355 participants from the Western Australian Pregnancy Cohort (Raine) Study, with anthropometry collected during pregnancy, at birth, one year and at three yearly intervals thereafter. Multivariate analyses and cross‐sectional logistic regression quantified the timing and contribution of early‐life risk factors for overweight and obesity in young‐adulthood.ResultsAt five years of age 12.6% of children were overweight and 5.2% were obese. By early adulthood, the prevalence of obesity had increased to 12.8%, whilst overweight remained relatively stable at 14.2% (range from early childhood to adulthood 11–16%). Parental pre‐pregnancy body mass index (BMI) was the strongest determinant of adult offspring BMI. Although rapid first year weight gain was associated with increased offspring BMI, the impact of first year weight‐gain diminished over childhood, whilst the impact of parental BMI increased over time.ConclusionsParental pre‐pregnancy BMI and rapid early‐life weight gain predispose offspring to obesity in adulthood.

Craniopharyngioma is associated with significant long-term morbidity. Attention to an integrated care pathway that includes standardised neurocognitive and psychological and behavioural assessment would facilitate early appropriate intervention and support leading to an improved quality of life for children with craniopharyngioma.

Background: Autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in children. The natural outcome of AIT in childhood has been reported previously however follow-up duration is generally short and results variable.Objectives: To characterize clinical and biochemical findings at presentation of AIT, evaluate long-term outcomes and assess which factors at presentation predict evolution over time.Study cohort: 201 children under 18 years of age at presentation (82% female) were enrolled. Subjects were divided into five subgroups according to thyroid stimulating hormone (TSH) level at referral.Results: Mean follow-up was 8.1 years (range 0-29 years). At presentation, 34% of patients had overt hypothyroidism, 32% subclinical hypothyroidism (SCH), 16% compensated hypothyroidism, 14% were euthyroid, and 3.7% had Hashitoxicosis. Children with overt hypothyroidism were younger (10.6 vs. 13.2 years) and had higher thyroid peroxidase antibody titers. At the time of the study, levothyroxine (LT 4 ) therapy was required in 26% of children who were euthyroid at presentation, 56% of SCH patients, 83-84% of those with TSH above 10 mIU/L, and 57% of those with Hashitoxicosis. Over the years, 16% of children presenting with overt hypothyroidism stopped therapy. Free T 4 at presentation was the only predictor of outcome over time.Conclusions: Our findings suggest that only 26% children who were euthyroid at presentation developed hypothyroidism, whereas over 50% of those with SCH went on to require treatment. Of those presenting with overt hypothyroidism, 16% recovered with time. The only predictive parameter for LT 4 therapy at the end of the study was free T 4 levels at presentation. Long-term follow-up is required to determine ongoing therapy needs and screen for additional autoimmune diseases.

Background Survivors of paediatric brain cancer and/or cranial radiotherapy (CRT) are at an increased risk of developing serious comorbidities. Established risk factors for chronic disease include central obesity, endothelial abnormalities and diminished fitness. Objectives Here we characterised anthropometry, body composition, bone mineral density (BMD), heart rate (HR), blood pressure (BP), endothelial function, muscular strength and endurance and aerobic fitness in adolescent and young adult (AYA) survivors. Methods Twenty survivors (10 male, 10 female; 20 ± 2 years) were compared with 19 matched controls. Muscular strength was assessed using three repetition maximum tests, while muscular endurance was determined as number of repetitions performed per minute. Peak oxygen uptake (VO2 peak) was assessed on a treadmill using a modified chronotropic protocol. Anthropometric measurements, HR and BP were taken using standard clinical protocols, while body composition and BMD were determined using dual X-ray absorptiometry (DXA). Endothelial function was measured using the flow mediated dilation technique. Results Survivors demonstrated deficits in muscular strength (latissimus dorsi pull-down, p = 0.020; bicep curl, p = 0.009), muscular endurance (squats, p = 0.012; sit-ups, p = 0.030; push-ups, p = 0.013), minute ventilation at peak exericse (p = 0.002) and VO2peak (L/min, p = 0.002; mL/kg/min, p = 0.008; mL/kg LBM/min, p = 0.010). Additionally, survivors had greater waist-to-hip ratios (p = 0.032), resting HR (p = 0.048) and higher percentage of total body (p = 0.017), central (p = 0.009) and peripheral (p = 0.032) fat. Lean body mass (p = 0.004) and BMD (p = 0.005) were lower in the survivor group. Conclusion AYA survivors of paediatric brain cancer and/or CRT exhibit altered body composition, increased resting HR and reduced BMD, muscular strength, muscular endurance and cardiorespiratory fitness compared to controls.

Sulfonylureas are commonly prescribed for type 2 diabetes mellitus; however, overdose or accidental ingestion may result in profound and prolonged hypoglycaemia with permanent neurological sequelae and death. We describe two cases of children with hypoglycaemia due to presumed accidental ingestion of sulfonylureas, where traditional methods of raising blood sugar levels were unsatisfactory. Two studies describe Octreotide for adults with hypoglycaemia, but there are no studies examining the use of Octreotide in children for this indication. Given that Octreotide has been shown to be safe in children when used for other indications, we used Octreotide to safely restore euglycaemia.

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Context:Intronic DNA frequently encodes potential exonic sequences called pseudoexons. In recent years, mutations resulting in aberrant pseudoexon inclusion have been increasingly recognized to cause disease.Objectives:To find the genetic cause of familial glucocorticoid deficiency (FGD) in two siblings.Patients:The proband and his affected sibling, from nonconsanguineous parents of East Asian and South African origin, were diagnosed with FGD at the ages of 21 and 8 months, respectively.Design:Whole exome sequencing was performed on genomic DNA (gDNA) of the siblings. Variants in genes known to cause FGD were assessed for causality. Further analysis of gDNA and cDNA was performed by PCR/RT-PCR followed by automated Sanger sequencing.Results:Whole exome sequencing identified a single, novel heterozygous variant (p.Arg71*) in nicotinamide nucleotide transhydrogenase (NNT) in both affected individuals. Follow-up cDNA analysis in the proband identified a 69-bp pseudoexon inclusion event, and Sanger sequencing of his gDNA identified a 4-bp duplication responsible for its activation. The variants segregated with the disease: p.Arg71* was inherited from the mother, the pseudoexon change was inherited from the father, and an unaffected sibling had inherited only the p.Arg71* variant.Conclusions:FGD in these siblings is caused by compound heterozygous mutations in NNT; one causing pseudoexon inclusion in combination with another leading to Arg71*. Discovery of this pseudoexon activation mutation highlights the importance of identifying sequence changes in introns by cDNA analysis. The clinical implications of these findings include: facilitation of antenatal genetic diagnosis, early institution of potentially lifesaving therapy, and the possibility of preventative or curative intervention.