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Intragastric Balloons are a temporary, reversible, and safer option compared to bariatric surgery to promote significant weight loss leading to improved metabolic outcomes. However due to subsequent weight regain, alternative procedures are now preferred in adults. In adolescents, more amenable to lifestyle change, balloons may be an alternative to less reversible procedures. Our aim was to assess the tolerability and efficacy of the intragastric balloon in severely obese adolescents and the impact of associated weight loss on biomedical outcomes (glucose metabolism, blood pressure, lipid profiles) and bone density. A 2-year cohort study of 12 adolescents (BMI >3.5 s.d., Tanner stage >4) following 6 months intragastric balloon placement was carried out. Subjects underwent anthropometry, oral glucose tolerance test, and DEXA scans at 0, 6 and 24 months. Results showed clinically relevant improvements in blood pressure, insulin: glucose metabolism, liver function and sleep apnoea at 6 months. Changes were not sustained at 2 years though some parameters (Diastolic BP, HBA1c, insulin AUC) demonstrated longer-term improvement despite weight regain. Despite weight loss, bone mass accrual showed age appropriate increases. In conclusion, the intra-gastric balloon was safe, well tolerated and effective in supporting short-term weight loss and clinically relevant improvement in obesity related complications, which resolved in some individuals. Benefits were not sustained in the majority at 2 years.International Journal of Obesity accepted article preview online, 05 September 2017. doi:10.1038/ijo.2017.215.

BackgroundCommunication is complex in endocrine care, particularly during transition from paediatric to adult services. The aims of this study were to examine the feasibility of interventions to support young people to interact with clinicians.MethodsDevelopment and evaluation of a complex intervention in 2 phases: Pre-intervention observational study; Intervention feasibility study.Purposive sample of recordings of 62 consultations with 58 young people aged 11–25 years with long-term endocrine conditions in two paediatric and two adult endocrine clinics.Proportion of time talked during consultations, number and direction of questions asked; Paediatric Consultation Assessment Tool (PCAT); OPTION shared decision making tool; Medical Information Satisfaction Scale (MISS- 21).Young people were invited to use one or more of: a prompt sheet to help them influence consultation agendas and raise questions; a summary sheet to record key information; and the www.explain.me.uk website.ResultsNearly two thirds of young people (63%) chose to use at least one communication intervention. Higher ratings for two PCAT items (95% CI 0.0 to 1.1 and 0.1 to 1.7) suggest interventions can support consultation skills. A higher proportion of accompanying persons (83%) than young people (64%) directed questions to clinicians. The proportion of young people asking questions was higher (84%) in the intervention phase than in the observation phase (71%).ConclusionsInterventions were acceptable and feasible. The Intervention phase was associated with YP asking more questions, which implies that the availability of interventions could promote interactivity.

Background: Severe adolescent obesity (body mass index (BMI) >99.6th centile) is a significant public health challenge. Current non-invasive treatments, including community-based lifestyle interventions, are often of limited effectiveness in this population, with NICE guidelines suggesting the use of bariatric surgery as the last line of treatment. Health professionals are understandably reluctant to commission bariatric surgery and as an alternative, the use of an intra-gastric balloon as an adjunct to a lifestyle programme might offer a reversible, potentially safer and less invasive option. Objectives: Explore the use of an intra-gastric balloon as an adjunct to a lifestyle support programme, to promote weight loss in severely obese adolescents. Outcomes included weight loss, waist and hip measurements, psychosocial outcomes including health-related quality of life (HRQoL) and physical self perceptions, physical activity and cardiorespiratory fitness. Method: Non-randomised pilot study. Results: Twelve severely obese adolescents (5 males, 7 females; mean age 15 years; BMI >3.5 s.d.; puberty stage 4 or more) and their families were recruited. Mean weight loss at 12 months (n=9) was 3.05 kg±14.69; d=0.002, P=0.550, and a BMI Z-score (n=12) change of 0.2 s.d.; d=0.7, P=0.002 was observed at 6 months with a large effect, but was not sustained at 12 months (mean change 0.1 s.d.; d=0.3, P=0.146). At 24 months (n=10), there was a weight gain from baseline of +9.9 kg±1.21 (d=0.4; P=0.433). Adolescent and parent HRQoL scores exceeded the minimal clinical important difference between baseline and 12 months for all domains but showed some decline at 24 months. Conclusion: An intra-gastric balloon as an adjunct to a lifestyle support programme represents a safe and well-tolerated treatment approach in severely obese adolescents, with short-term effects on weight change. Improvements in psychosocial health, physical activity and cardiorespiratory fitness were maintained at 12 months, with varying results at 24 months.

Approximately 3% of children and adolescents in the UK have severe obesity. The incidence of cardiovascular risk factors such as hypertension, hyperinsulinism and hyperlipidaemia approaches 20% in such individuals. Lifestyle intervention programmes and pharmacotherapy are effective in some individuals, but the relapse rate is high. In exceptional cases, bariatric surgery is effective. This review outlines the scale of the problem, highlights those at risk and discusses referral, current services, appropriate screening and therapeutic interventions.

More than three quarters of children treated for cancer survive into adulthood with this number continuing to rise. Successful transition is now recognised as an important facet of care in both paediatric and adult medicine. It encompasses “the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented health care systems” (Blum et al. 1993). It is not simply transfer of care to another provider but should be a gradual process taking into account physical and psychological maturity as well as the availability and structure of local resources.

Summary Objective Hydrocortisone via nasogastric (NG) tube is used in sick children with adrenal insufficiency; however, there is no licensed formulation for NG administration. Methods We investigated hydrocortisone recovery after passage through NG tubes in vitro for three formulations: liquid suspension, crushed tablets mixed with water, and hydrocortisone granules designed for oral administration to children. Cortisol was measured by LC‐MS/MS. Results Hydrocortisone content was variable and recovery low after preparation in syringe and prior to passage through NG tubes. For doses, 0.5 and 2.0 mg mean percentage recovery was as follows: liquid suspension 57% and 58%; crushed tablets 46% and 30%; and hydrocortisone granules 78% and 71%. Flushing the administering syringe increased recovery. Hydrocortisone recovery after passage with flushing through 6‐12Fr gauge NG tubes was variable: liquid suspension 61%‐92%, crushed tablets 40%‐174%, hydrocortisone granules 61%‐92%. Administration of hydrocortisone granules occluded 6 and 8Fr NG tubes; however, administration using a sampling needle to prevent granules being administered gave a recovery of 74%‐98%. Conclusions The administration of hydrocortisone through NG tubes is possible; however, current methods deliver a variable dose of hydrocortisone, generally less than that prescribed. Attention should be placed on the technique used to optimize drug delivery such as flushing of the administering syringe. Hydrocortisone granules block small NG tubes but behaved as well as the commonly used liquid suspension when prepared with a filtering needle that filters out granules.

Context\ud Measuring testicular volume (TV) by orchidometer is the standard method of male pubertal staging. A paucity of evidence exists as to its inter‐ and intra‐observer reliability and the impact of clinicians’ gender, training and experience on accuracy.\ud \ud Objective\ud Prosthetic testicular models were engineered to investigate accuracy and reliability of TV estimation.\ud \ud Design\ud Simulation study.\ud \ud Setting\ud Conducted over three‐day 2015 British Society for Paediatric Endocrinology and Diabetes (BSPED) meeting.\ud \ud Participants\ud 215 meeting delegates (161F, 54M): 50% consultants, 30% trainees, 9% clinical nurse specialists, 11% other professionals.\ud \ud Intervention\ud Three child‐sized mannequins displayed latex scrotum containing prosthetic testicles of 3ml, 4ml, 5ml, 10ml and 20ml. Demographic data, paediatric endocrinology experience, TV examination training, examination technique and TV estimations were collected. Delegates were asked to repeat their measurements later during the meeting. Scrotum order was changed daily.\ud \ud Main outcome measure\ud Accuracy by variance from the simulated TV. Inter‐ and intra‐observer variability.\ud \ud Results\ud 1284 individual estimations were obtained. Eighty‐five participants repeated measurements. Delegates measured TV accurately on 33.4% (±2.6) of occasions: overestimations 37.7% (±2.3), underestimations 28.7% (±1.8) (Fleiss Kappa score 0.04). The accuracy of assessing a 4 ml testis was 36‐39%. Observers underestimated the volume when paired with a 3ml testes and overestimated when paired with a 5 ml testis demonstrating a tendency impose biological symmetry. Intra‐observer reliability was lacking; individuals giving different estimations for the same size testicle on 61% (±4.2) of occasions, 20% (±3.5) of estimations were more than 1 size outside the previous measurement. On only 39% (±4.2) of occasions did individuals agree with their previous estimation (irrespective of whether or not it was initially accurate). Training did not impact on results but experience did improve accuracy.\ud \ud Conclusions\ud Overall TV estimation accuracy was poor. Considerable variation exists between and within subjects. Seniority slightly improved measurement estimation.

AIM Peer review is one component of the improvement of diabetes care delivered by the National Health Service (NHS) in England and Wales. Queensland has a decentralised model of service provision with an established state diabetes network. METHODS The NHS scheme was adapted for use in Australia, and seven trained reviewers were recruited to visit 14 'hub' centres, which in turn covered 29 'spoke' units delivering care to over 95% of all public patients

BACKGROUND: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. METHODS: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. RESULTS: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. CONCLUSIONS: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.

OBJECTIVE: Transition from child to adult status is a crucial stage in young people's lives. It is important that young people continue to receive appropriate endocrine care throughout and following transfer from paediatric to adult services. This study examined indicators of patient loss to follow-up at initial transfer from paediatric care to identify implications for transitional care practice and research. METHODS: A retrospective analysis of patient data following transfer from paediatric services to a young person's transition clinic was conducted. Attendance data from 103 patients transferred to the Young Person's Clinic were analysed to determine factors affecting non-attendance one year post-transfer. RESULTS: We found that overall one quarter of patients did not attend the young person's clinic in the first year after transfer. Those with poor attendance prior to transfer were likely to be poor attenders post-transfer. Further, those without an appointment scheduled in the first six months of their final paediatric transfer appointment were less likely to attend in the first year. CONCLUSIONS: Young people are at risk of losing contact during the transfer from paediatric to the young person's clinic. Measures that promote continuity of contact could reduce the risk of long term disengagement with care. Further development and research is required to identify the best ways to help young people with endocrine conditions in the transition from child to adult status. � 2012 Blackwell Publishing Ltd.

Fat mass predicts bone accrual in prepubertal children, but obese children have increased fracture risk. We hypothesised that bone size and mass would vary according to prior fracture in obese children. One hundred and three children (52 obese) underwent dual-energy X-ray absorptiometry (DXA) scanning of the lumbar spine, total body, and radial metaphysis and diaphysis. We derived body size-adjusted bone mineral density (BMD) estimates for each site using commonly employed procedures. Following adjustment for either age, age(2) and weight, or height and weight based on a reference group of nonobese controls without previous fracture, obese children with prior fracture showed a 0.8 to 1.2 SD reduction in total body areal BMD (aBMD), a 3.0 SD decrease in lumbar (L2-4) aBMD, and a 2.0 SD reduction in radial shaft aBMD. These changes were significant at p < .005. Lumbar volumetric BMD (vBMD) calculated by Carter and Kroger algorithms was significantly reduced in obese children with prior fracture (2.0 to 3.3 SD). Eighteen percent of obese children fulfilled the criteria for osteoporosis. Despite greater lean mass for height in obese children (p < .0001), total body bone mineral content (BMC) for lean mass was reduced (p = .002). Multiple regression models adjusting for height, weight, and gender demonstrated an inverse relationship between total body fat mass and total body, lumbar, and ultradistal radius BMC and aBMD. The data suggest that fat mass substantially inhibits bone accrual in children with prior fracture. These children may require targeted interventions to increase bone mass during adolescence to achieve optimal peak bone mass and reduce the risk of osteoporosis later in life.

A qualitative study nested within a randomized controlled trial explored obese adolescents' experiences of participation in an exercise therapy intervention. Semi-structured interviews were conducted with participants assigned to exercise therapy. Participants' reported feeling more energetic during and after exercise, than before. Many participants reported feeling happy/happier and expressed feeling better about themselves as individuals after the intervention. Most participants felt more confident in their ability to exercise regularly. Greater emphasis needs to be placed upon educating obese adolescents about the wide range of health benefits that exercise can provide, and that weight loss, while important, is only one such benefit.

Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. © 2016 Wiley Periodicals, Inc.

BackgroundMany infants born prematurely experience growth failure following delivery, with subsequent catch-up growth. Traditionally catch-up was thought to be complete in the first few years of life. Most studies have focused on groups of infants defined by birth weight, for example MethodologyThis UK based prospective longitudinal cohort study recruited 204 preterm children born at a tertiary neonatal unit during 1994 and 50 matched controls. Growth parameters have been assessed annually until the completion of growth.ResultsThere was no significant difference in the final height SD score (SDS) of children born at term (n=30) and those born prematurely and AGA (n=70) (0.45 term vs 0.22 preterm). Catch-up growth however, continued throughout the whole of childhood. When the difference between final height SDS and mid-parental height SDS were compared, there were again no significant differences (0.13 term vs 0.03 preterm).ConclusionsThose born prematurely with an AGA achieve a comparable adult height to children born at term, however, catch-up growth continues for much longer than traditionally thought.

Objectives: Kids in Control OF Food (KICk-OFF) is a 5-day structured education program for 11- to 16-year-olds with type 1 diabetes mellitus (T1DM) who are using multiple daily insulin injections. This study evaluates the cost-effectiveness of the KICk-OFF education program compared with the usual care using data from the KICk-OFF trial.Methods: The short-term within-trial analysis covers the 2-year postintervention period. Data on glycated hemoglobin (HbA1c), severe hypoglycemia, and diabetic ketoacidosis (DKA) were collected over a 2-year follow-up period. Sub-group analyses have been defined on the basis of baseline HbA1c being below 7.5 percent (58.5 mmol/mol) (low group), between 7.5 percent and 9.5 percent (80.3 mmol/mol) (medium group), and over 9.5 percent (high group). The long-term cost-effectiveness evaluation has been conducted by using The Sheffield Type 1 Diabetes Policy Model, which is a patient-level simulation model on T1DM. It includes long-term microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular (myocardial infarction, stroke, revascularization, and angina) diabetes-related complications and acute adverse events (severe hypoglycemia and DKA).Results: The most favorable within-trial scenario for the KICk-OFF arm led to an incremental cost-effectiveness ratio (ICER) of £23,688 (base year 2009) with a cost-effectiveness probability of 41.3 percent. Simulating the long-term complications using the full cohort data, the mean ICER for the base case was £28,813 (base year 2011) and the probability of the KICk-OFF intervention being cost-effective at £20,000/QALY threshold was 42.6 percent, with considerable variation due to treatment effect duration. For the high HbA1c sub-group, the KICk-OFF arm was “dominant” (meaning it provided better health gains at lower costs than usual care) over the usual care arm in each scenario considered.Conclusions: For the whole study population, the cost-effectiveness of KICk-OFF depends on the assumption for treatment effect duration. For the high baseline HbA1c sub-group, KICk-OFF arm was estimated to be dominant over the usual care arm regardless of the assumption on the treatment effect duration.

OBJECTIVE. We conducted a proof-of-concept, randomized, controlled trial to investigate the effects of a supervised exercise therapy intervention on psychopathologic outcomes in obese adolescents. METHODS. The participant sample consisted of 81 adolescents (age: 11–16 years) who had been referred to a children's hospital for evaluation of obesity or who responded to a community advertisement. Participants were assigned randomly to exercise therapy, an equal-contact exercise placebo intervention, or usual care. Intervention participants attended 3 one-on-one sessions per week for 8 weeks and then completed a home program for another 6 weeks. Outcomes included self-perceptions (self-esteem), depression, affect, physical activity, aerobic fitness, and BMI. RESULTS. A total of 18 of 81 participants were categorized as morbidly obese (BMI SD score: >3.5; adult equivalent BMI: ≥40). At baseline, 30.3% of participants had a Children's Depression Inventory score of ≥13, and 27% reported recent suicidal ideation. Repeated-measures mixed analysis of covariance (controlling for baseline scores) revealed significant changes in physical self-worth, associated measures of self-esteem, and physical activity over time, consistently favoring exercise therapy. There were no significant changes in BMI. CONCLUSIONS. Findings confirmed psychopathologic conditions as a serious health concern in obese and morbidly obese adolescents. Our study is the first randomized, controlled trial to demonstrate that a brief supervised exercise therapy intervention has the potential to improve psychopathologic outcomes significantly and to increase physical activity in obese adolescents, relative to usual care.

Phytosterolaemia (sitosterolaemia) is a recessively inherited metabolic condition in which the absorption of both cholesterol and plant-derived cholesterol-like molecules at the gut is unselective and unrestricted. In haematology, Mediterranean stomatocytosis or Mediterranean macrothrombocytopenia is a poorly understood haematological condition that combines stomatocytic haemolysis with the presence of very large platelets. Five pedigrees showing this haematology were identified. Gas chromatography mass spectrometry (GC-MS) showed that all of the patients with this highly specific haematology had grossly elevated levels of phytosterols in the blood, diagnostic of phytosterolaemia. All showed mutations in the ABCG5 and ABCG8 previously linked to phytosterolaemia. Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. We draw the following four conclusions: (i) that Mediterranean stomatocytosis/macrothrombocytopenia is caused by an excess of phytosterols in the blood; (ii) that phytosterolaemia, which does not respond to standard statin treatment, can be diagnosed via the distinctive haematology described here, even when the cholesterol is normal; (iii) that phytosterolaemia should be considered in the differential diagnosis of all patients with large platelets; and (iv) that the platelet size should be noted in patients with hypercholesterolaemia.

BACKGROUND/AIM: In childhood an appropriate response to GH treatment is achieved by titration of growth response against dose administered, with careful observation for side-effects. In order to evaluate the potential use of IGF monitoring in children treated with GH, a cross-sectional study has been carried in 215 children and adolescents (134 with GH deficiency (GHD), 54 with Turner syndrome (TS) and 27 with non-GHD growth disorders) treated with GH for 0.2-13.7 years. METHODS: IGF-I and IGF-binding protein-3 (IGFBP-3) were measured in ELISAs, using dried capillary blood collected onto filter papers. Results were expressed as the mean S.D. range (SDS). Values of either analyte < -2 or > +2 SDS were considered abnormal. RESULTS: IGF-I and IGFBP-3 SDS were higher in the TS and non-GHD groups (mean +0.01 and +0.1 respectively) than in those with GHD (mean value -0.6). Nineteen per cent of the IGF-I values (13% low, 6% high) and 12% of IGFBP-3 values were abnormal (10% low, 2% high). Abnormalities, either low or high, were most common in the GHD group. There was a weak but significant relationship between change in height SDS over the Year up to the time of sampling in the whole group and IGF-I SDS. Satisfactory growth performance (+0.5>change in height SDS> -0.5) was found in those with high (7.2%), normal (60%) and low (9.3%) IGF-I levels. Overall, it was estimated that 26% of the tests would indicate that an adjustment to GH dose (up in 18% and down in 8%) could be considered. CONCLUSIONS: From this cross-sectional study of IGF monitoring across a broad range of diagnoses and ages, it can be concluded that the majority of children on GH have normal levels of IGF-I and IGFBP-3, but 26% of tests could suggest that a change of GH dose should be considered. Regular monitoring of IGF-I and IGFBP-3 should be considered in any child on GH treatment.

James, a 13-year-old boy is a tertiary referral for management of long-standing morbid obesity. He has participated in previous attempts at weight loss instigated by the local hospital dietetic department and also attended a 12-week course in the community offering psychological, activity and diet based intervention. Although he briefly slowed his rate of weight gain with the 12-week intervention he has since continued to gain weight inexorably. His current height is 168 cm, weight is 178 kg and he has a body mass index of 63 (Class 3 obesity).

Two of the recognized cranial MRI findings in children with neurofibromatosis type 1 (NF1) are neurofibromatosis bright objects (NBO) and brain glioma. Their differential diagnosis can be problematic. This study aimed to determine the features of these abnormalities on short echo-time in-vivo proton magnetic resonance spectroscopy. Twenty children under the age of 16 with NF1 were studied. A single voxel, short echo-time technique (TE = 20 ms; TR = 5000 ms) was used to obtain proton spectra of typical NBO and any regions suggestive of atypical bright objects or tumor. Nine children without neurofibromatosis with no structural brain abnormality acted as aged-matched comparisons. A semi-quantitative analysis indicated significant increase in choline and myo-inisitol in tumors compared to typical NBO (p < 0.05) and compared to controls (p < 0.05); reduction in the levels of N-acetyl moieties in NBO compared to controls (p < 0.05); reduction in N-acetyl in tumors compared to controls (p < 0.001); and reduction in glutamate/glutamine in tumors compared to controls (p < 0.05). This cross-sectional data suggests that proton spectroscopy can aid differentiating between NBO and brain (non-optic/hypothalamic) glioma. Typical NBO have different short echo-time spectroscopic appearances compared to normal brain.

OBJECTIVE: Serum IGF-I levels are monitored during GH replacement treatment in adults with GH defi- ciency (GHD) to guide GH dose adjustment and to minimize occurrence of GH-related side-effects. This is not routine practice in children treated with GH. The aim of this study was to evaluate changes in (1) serum IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio, and (2) serum leptin, an indirect marker of GH response, during the first year of GH treatment in children with disordered growth. DESIGN: An observational prospective longitudinal study with serial measurements at five time points during the first year of GH treatment was carried out. Each patient served as his/her own control. PATIENTS The study included 31 patients, grouped as (1) GHD (n=20) and (2) non-GHD (Turner syndrome n=7; Noonan syndrome n=4), who had not previously received GH treatment. MEASUREMENTS: Serum IGF-I, IGFBP-3 and leptin levels were measured before treatment and after 6 weeks, 3 months, 6 months and 12 months of GH treatment, with a mean dose of 0.5 IU/kg/wk in GHD and 0.7 IU/kg/wk in non-GHD groups. IGF-I, IGFBP-3 and the calculated IGF-I/IGFBP-3 molar ratio were expressed as SD scores using reference values from the local population. RESULTS: In the GHD group, IGF-I SDS before treatment was lower compared with the non-GHD (-5.4 ± 2.5 vs. -1.8 ± 1.0; P < 0.001). IGF-I (-1.8 SDS ± 2.2) and IGFBP-3 (-1.1 SDS ± 0.6) levels and their molar ratios were highest at 6 weeks and remained relatively constant thereafter. In the non-GHD group, IGF-I levels increased throughout the year and were maximum at 12 months (0.3 SDS ± 1.4) while IGFBP-3 (1.1 SDS ± 0.9) and IGF-I/IGFBP-3 molar ratio peaked at 6 months. In both groups, IGF-I SDS and IGF-I/IGFBP-3 during treatment correlated with the dose of GH expressed as IU/m2/week (r-values 0.77 to 0.89; P = 0.005) but not as IU/kg/week. Serum leptin levels decreased significantly during GH treatment in the GHD (median before treatment 4.0 g/l; median after 12 months treatment 2.4 g/l; P = 0.02) but not the non-GHD (median before treatment 3.0 g/l; median after 12 months treatment 2.6 g/l). In the GHD group, serum leptin before treatment correlated with 12 month change in height SDS (r = 0.70, P = 0.02). CONCLUSIONS: The pattern of IGF-I, IGFBP-3 and their molar ratio during the first year of GH treatment differed between the GHD and non-GHD groups. Calculation of GH dose by surface area may be preferable to calculating by body weight. As a GH dose-dependent increase in serum IGF-I and IGF-I/IGFBP-3 may be associated with adverse effects, serum IGF-I and IGFBP-3 should be monitored routinely during longterm GH treatment. Serum leptin was the only variable that correlated with first year growth response in GHD.

SummaryHuman growth is non-linear and short term changes in height velocity cannot be used to predict future growth. This paper discusses the current knowledge of growth dynamics in the context of a historical review of the subject.

Introduction The Kids In Control OF Food (KICk-OFF) is a cluster-randomised controlled trial, which aims to determine the efficacy of a 5 day structured education course for 11-year-olds to 16-year-olds with type 1 diabetes (T1DM) when compared with standard care, and its cost effectiveness. Less than 15% of children and young people with T1DM in the UK meet the recommended glycaemic target. Self-management education programmes for adults with T1DM improve clinical and psychological outcomes, but none have been evaluated in the paediatric population. KICk-OFF is a 5-day structured education course for 11-year-olds to 16- year-olds with T1DM. It was developed with input from young people, parents, teachers and educationalists. Methods and analysis 36 paediatric diabetes centres across the UK randomised into intervention and control arms. Up to 560 participants were recruited prior to centre randomisation. KICk-OFF courses are delivered in the intervention centres, with standard care continued in the control arm. Primary outcomes are change in glycaemic control (HbA1c) and quality of life between baseline and 6 months postintervention, and the incidence of severe hypoglycaemia. Sustained change in self-management behaviour is assessed by follow-up at 12 and 24 months. Health economic analysis will be undertaken. Data will be reported according to the CONSORT statement for cluster-randomised clinical trials. All analyses will be by intention-to-treat with a two-sided p value of

PURPOSE To determine the effect of cranial irradiation (18 Gy and 24 Gy) on pubertal growth in young adult survivors of childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS Final height (FH) and pubertal growth were retrospectively examined in 142 young adult survivors of childhood ALL. All were in first remission and had received either 18 or 24 Gy of cranial irradiation. Eighty-four children (48 girls) were treated with 24 Gy and 58 (35 girls) with 18 Gy. None had received either testicular or spinal irradiation. Timing and duration of puberty were studied in 110 patients. RESULTS Significant reduction in height standard deviation score (SDS) from diagnosis to FH was seen in both sexes and in both dose groups. In girls, in both dose groups, mean age at peak height velocity (PHV) and mean age at menarche occurred significantly earlier than in the normal population. In boys, there was a normal timing of PHV. The amplitude of PHV was significantly reduced in both sexes and in both dose groups. Parameters of pubertal duration (PHV to menarche, PHV to FH, and menarche to FH) were not significantly different from normal population values. CONCLUSION In conclusion, puberty occurred early in girls, but not in boys. Amplitude of PHV was reduced in both sexes, with no reduction in the duration of puberty. It is likely that disturbances of both timing and quality of growth during puberty contribute to the loss of standing height and body disproportion seen in these children.

Growth hormone (GH) stimulates linear growth and improves nitrogen balance in many catabolic states, including sepsis, and in malnutrition associated with chronic obstructive pulmonary disease. In children with cystic fibrosis (CF), these anabolic effects could aid survival and enhance suitability for transplantation. We assessed response to 0.49 IU/kg/week of recombinant human growth hormone (hGH) for 6–12 months in seven children with cystic fibrosis. All showed an initial increase in height velocity (0.33-4.14 cm/year) and height standard deviation score (P

Context: Childhood obesity is increasingly associated with type 2 diabetes (T2D). Metformin reduces the risk for T2D in adult obese nondiabetic patients, but the evidence in obese children and young people is inconclusive. Objective: The objective of the study was to assess the effect of metformin on body mass index sd score (BMI-SDS), metabolic risk factors, and adipokines. Design: This was a prospective, randomized, double-blind, placebo-controlled trial. Setting: The study was conducted at six pediatric endocrine centers in the United Kingdom. Participants: One hundred fifty-one obese children and young people with hyperinsulinemia and/or impaired fasting glucose or impaired glucose tolerance (metformin: 74, placebo: 77). The study was comprised of 67.5% females, 65.6% postpubertal individuals, and 23.8% British Asian or Afro-Caribbean participants. The age range was 8–18 yr, the mean age was 13.7 (sd 2.3) yr, and the mean BMI-SDS was +3.4 (sd 0.5). Interventions: The intervention included metformin 1 g in the morning and 500 mg in the evening vs. placebo for 6 months. Main Outcome Measure: The main outcome measure was a reduction in BMI-SDS at 6 months. Secondary outcomes included insulin and glucose levels from oral glucose tolerance tests, alanine aminotransferase (ALT), and adiponectin to leptin ratio (ALR) at 3 and 6 months. Results: Metformin was associated with a significant reduction in BMI-SDS compared with placebo at 6 months [mean difference −0.1 sd (95% confidence interval −0.18 to −0.02), P = 0.02]. Significant improvements at 3 months were found in the metformin group: fasting glucose, −0.16 mmol/liter (−0.31 to −0.00), P = 0.047; ALT, 19% (5–36%), P = 0.008; and ALR, 32% (4–67%), P = 0.02. Conclusions: Metformin therapy has a beneficial treatment effect over placebo for BMI-SDS, fasting glucose, ALT, and ALR ratio at 3 months, with changes in BMI-SDS sustained at 6 months.

Splenogonadal fusion is a rare congenital malformation where an abnormal union occurs between the spleen and gonad or mesonephric derivatives. Although it occurs in females it is much less prevalent than in males (male:female ratio, 16:1), but this may partly be because of the inaccessibility of the female gonads leading to under-diagnosis. To our knowledge this is the first case of splenogonadal fusion associated with sex reversal reported in the literature.

Summary Context Increasing numbers of very low birth weight (VLBW) infants are surviving into adulthood because of improvements in neonatal intensive care. Adverse events in early life can have long-term effects through reprogramming of metabolic systems. Objective To determine whether young adult VLBW survivors have abnormalities of skeletal development or endocrine function. Design Cross-sectional, observational, case-control study. Participants Thirty-seven VLBW subjects and 27 healthy controls at peak bone mass (mean age 23). Measurements Differences between cases and controls in body size, body composition, bone mass and bone geometry [assessed by dual-energy X-ray absorptiometry (DXA), hip structure analysis and peripheral quantitative computed tomography (pQCT)], bone turnover [urine N-terminal telopeptide of type I collagen (NTX), serum C-terminal telopeptide of type I collagen (CTX)], aminoterminal propeptide of type I procollagen (PINP) and bone alkaline phosphatase), hormones (sex steroids, IGF-1, PTH and 25-OH vitamin D) and insulin sensitivity (HOMA-IR and oral glucose tolerance testing). Results VLBW subjects had lower bone density at the lumbar spine (5.7%) and femoral neck (8.6%), which persisted after correction for bone size by the estimation of volumetric density (bone mineral apparent density). Urine NTX was higher in VLBW subjects than in controls, but there were no significant differences in other bone turnover markers. VLBW survivors had lower insulin sensitivity (mean INS-30 controls = 57.0, VLBW subjects = 94.3, P

Puberty is the physiological sequence of events when secondary sexual characteristics develop and reproductive capacity is achieved. The start of puberty is characterised by the appearance of a palpable breast bud (stage B2) in girls and testicular volumes of >3.5 ml in boys. These changes are brought about in response to the pulsatile secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus stimulating the release of follicle stimulating hormone (FSH) and luteinising hormone (LH) from the anterior pituitary. It is still unclear why the GnRH neurons are usually inhibited after infancy until the start of puberty, although fat mass (via leptin signalling) and kisspeptin secreting neurons stimulating the GnRH system certainly play a role. LH acts on the gonads to increase the secretion of oestrogen in the female or nocturnal testosterone in the male that then promote growth in target tissues. FSH acts on the gonads to produce ovum or sperm, respectively. Androgens in particular promote other secondary sexual characteristics such as smelly feet and axillae, acne, body odour and mood swings – often most noticeable to the parents. The timing of puberty is very variable and is dependent on socioeconomic status, ethnicity, nutritional and genetic factors. There has been an apparent secular trend in the onset of female puberty, although the mean age of menarche has remained fairly stable during the last 2 decades, implying that the duration of puberty may be increasing in girls.1 Hence, the definition of early or late puberty is fairly arbitrary. In the UK, the ranges for normal onset of puberty are shown on the growth charts,2 with the 98th centile for start of testicular enlargement just less than 9 years in a boy and just over 8 years for B2 in a girl. Similarly, only 2% of boys have not started …

Knemometry has been used to measure lower leg growth during 32 nine day courses of dexamethasone in 26 babies ranging from 24 to 32 weeks' gestation at birth. Mean leg length velocity was 0.37 mm/day in the 10 days before steroids. Administration of dexamethasone was associated with a decrease in velocity in all babies, and in 15 leg shortening was documented. Mean leg length velocity during steroid treatment was -0.003 mm/day. After the course of dexamethasone was completed there was an immediate increase in leg length velocity to a mean of 0.52 mm/day over the first 10 days then falling to a value similar to the growth velocity observed before treatment. Leg length had reached the value predicted by growth before steroids about 30 days after dexamethasone. The reduction in leg length velocity occurred despite a significant increase in energy intake and decrease in oxygen requirements.

The characteristics of a knemometer designed for accurate lower leg measurement in babies were assessed. Repeated measurement of a 100 mm Perspex rod gave a mean length of 99.993 mm and a mean SD of 0.058. When used to measure leg length, technical error of the measurement technique was 0.31 with a mean leg length of 98.49 mm (coefficient of variation 0.31%). Leg lengths measured at birth in 324 babies from 23 to 42 weeks' gestation gave an estimated in utero leg length velocity of 0.43 mm/day (95% confidence interval 0.41 to 0.45). Assessment of interobserver variation showed poor agreement in absolute values of leg length, although similar estimates of leg length velocity could be obtained. The neonatal knemometer allows measurements to be made in situations where conventional growth measurements are not possible. It is believed that knemometry has an important role in accurate evaluation of factors that can influence short term bone growth.

IntroductionMutations in the GLI-similar 3 (GLIS3) gene encoding the transcription factor GLIS3 are a rare cause of neonatal diabetes and congenital hypothyroidism with six affected cases from three families reported to date. Additional features, described previously, include congenital glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay and facial dysmorphism.SubjectsWe report two new cases from unrelated families with distinct novel homozygous partial GLIS3 deletions. Both patients presented with neonatal diabetes mellitus, severe resistant hypothyroidism in the presence of elevated thyroglobulin and normal thyroid anatomy, degenerative liver disease, cystic renal dysplasia, recurrent infections and facial dysmorphism. These novel mutations have also resulted in osteopenia, bilateral sensorineural deafness and pancreatic exocrine insufficiency, features that have not previously been associated with GLIS3 mutations. Gene dosage analysis showed that the parents were carriers of a deletion encompassing exons 1–2 (case 1) or exons 1–4 (case 2) of the 11 exon gene. Genome-wide SNP analysis did not reveal a common ancestral GLIS3 haplotype in patient 2.ConclusionsOur results confirm partial gene deletions as the most common type of GLIS3 mutations, accounting for four of five families identified to date. We propose that mutations in GLIS3 lead to a wider clinical phenotype than previously recognised. We also report the first case of a recessive GLIS3 mutation causing neonatal diabetes and congenital hypothyroidism in a child from a non-consanguineous pedigree, highlighting the importance of molecular genetic testing in any patient with this phenotype.

Obese children, particularly those who have fractured, have reduced body size-adjusted total body and regional bone mass. We performed an observational cross-sectional cohort study to determine the relationship between adipokines (leptin and adiponectin), bone-derived cytokines and bone turnover in children which may explain this observation. Participants aged 5–16 years were recruited into obese (BMI SDS 3.3 ± 0.6) and lean (BMI SDS 0.2 ± 1.0) groups and further subdivided into groups by fracture history. Free leptin (leptin/leptin soluble receptor) and adiponectin; RANK-ligand (RANKL), osteoprotegerin (OPG); Dickkopf-1 (DKK1); and the bone turnover markers procollagen type I amino propeptide (P1NP) and carboxy-terminal telopeptide of type I collagen (CTx). Total body and truncal fat mass were measured by DXA. Results: Free leptin (p > 0.0001) and adiponectin (p = 0.0002) were higher and lower in obese children respectively. OPG was lower in obese children (p = 0.01), being inversely related to free leptin (p = 0.009), total body and truncal fat mass (both p = 0.01). RANKL was inversely related to free leptin in children with prior fracture (p = 0.03). CTx was higher in obese children (p = 0.003). Free leptin was positively associated with both CTx (p = 0.03) and P1NP (p = 0.02). DKK1 was inversely related to adiponectin (p = 0.02). Conclusion: Bone formation relative to resorption was reduced in obese children; this difference was accentuated in those with prior fracture. Adipokines may regulate these changes. Osteoprotegerin may play a fundamental role in the failure of obese children to accrue bone mass appropriately.

Background: There are few data in the paediatric literature on the normal cortisol response to stimulation during the low dose synacthen test (LDST) (1 μg). Aim: To examine the cortisol responses in children, subsequently presumed to be normal, who had an LDST during anterior pituitary function tests (APFTs). Methods: A retrospective review of results in children with short stature and normal growth hormone levels. Results: Of 33 children tested, seven had suboptimal cortisol responses based on accepted criteria (peak

OBJECTIVE—Mutations in the human HNF4A gene encoding the hepatocyte nuclear factor (HNF)-4α are known to cause maturity-onset diabetes of the young (MODY), which is characterized by autosomal-dominant inheritance and impaired glucose-stimulated insulin secretion from pancreatic β-cells. HNF-4α has a key role in regulating the multiple transcriptional factor networks in the islet. Recently, heterozygous mutations in the HNF4A gene were reported to cause transient hyperinsulinemic hypoglycemia associated with macrosomia. RESEARCH DESIGN AND METHODS—Three infants presented with macrosomia and severe hypoglycemia with a positive family history of MODY. The hypoglycemia was confirmed to be due to hyperinsulinism, and all three patients required diazoxide therapy to maintain normoglycemia. Two of the three infants are still requiring diazoxide therapy at 8 and 18 months, whereas one of them had resolution of hyperinsulinemic hypoglycemia at 32 months of age. RESULTS—Sequencing of the HNF4A gene identified heterozygous mutations in all three families. In family 1, a frameshift mutation L330fsdel17ins9 (c.987 1003del17ins9; p.Leu330fs) was present in the proband; a mutation affecting the conserved A nucleotide of the intron 2 branch site (c.264–21A>G) was identified in the proband of family 2; and finally a nonsense mutation, Y16X (c.48C>G, p.Tyr16X), was found in the proband of family 3. CONCLUSIONS—Heterozygous HNF4A mutations can therefore cause both transient and persistent hyperinsulinemic hypoglycemia associated with macrosomia. We recommend that macrosomic infants with transient or persistent hyperinsulinemic hypoglycemia should be screened for HNF4A mutations if there is a family history of youth-onset diabetes.

Background: Phytosterolaemia (sitosterolaemia) is a rare autosomal recessive condition caused by mutations on the ABCG5 and ABCG8 gut transporter proteins. This leads to accumulation of plant-derived cholesterol-like molecules in blood and tissues.Case: We describe a family of Bangladesh origin, where three siblings (two males and one female) have homozygous mutations for phytosterolaemia, and exhibit short stature and adrenal failure with the female having ovarian failure.Findings: The index case (18-year-old female) and her sibling (16 years) have adrenal insufficiency with hyperpigmentation and raised levels of ACTH, at 367 and 690 ng/l respectively. The youngest child at 7 years has normal adrenal function. In addition, the index case has ovarian failure and sibling 2 has partial growth hormone deficiency.Conclusion: Although short stature is a recognised phenomenon, no previous association has been made between phytosterolaemia and other endocrine abnormalities. We postulate that the elevated plant sterol levels in phytosterolaemia may interfere with endocrine hormone synthesis; in particular, we present evidence that adrenal cholesterol metabolism may be preferentially affected, accounting for the adrenal insufficiency.

Objective Maize and soy flour mixes are often used in the treatment of moderate malnutrition in Malawi. Their efficacy has not been formally evaluated. A recently developed ready-to-use food (RTUF) effectively promotes growth among severely malnourished children. The authors compared the effect of maize and soy flour with that of RTUF in the home treatment of moderately malnourished children. Methods Sixty-one underweight, stunted children 42 to 60 months of age were recruited in rural Malawi, in southeastern Africa. They received either RTUF or maize and soy flour for 12 weeks. Both supplements provided 2 MJ (500Kcal) of energy daily but had different energy and nutrient densities. Outcome variables were weight and height gain and dietary intake. Results Before intervention, the mean dietary intake and weight and height gain were similar in the two groups. During the supplementation phase, the consumption of staple food fell among children receiving maize and soy flour but not among those receiving RTUF. There was thus higher intake of energy, fat, iron, and zinc in the RTUF group. Both supplements resulted in modest weight gain, but the effect lasted longer after RTUF supplementation. Height gain was not affected in either group. Periodic 24-hour dietary recalls suggested that the children received only 30% and 43%, respectively, of the supplementary RTUF and maize and soy flour provided. Conclusions RTUF is an acceptable alternative to maize and soy flour for dietary supplementation of moderately malnourished children. Approaches aimed at increasing the consumption of supplementary food by the selected recipients are needed.