A simulation study assessing the accuracy and reliability of orchidometer estimation of testicular volume.

CONTEXT: 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. OBJECTIVE: Prosthetic testicular models were engineered to investigate accuracy and reliability of TV estimation. DESIGN: Simulation study. SETTING: Conducted over three-day 2015 British Society for Paediatric Endocrinology and Diabetes (BSPED) meeting. PARTICIPANTS: Two hundred fifteen meeting delegates (161F, 54M): 50% consultants, 30% trainees, 9% clinical nurse specialists, 11% other professionals. INTERVENTION: Three child-sized mannequins displayed latex scrotum containing prosthetic testicles of 3, 4, 5, 10 and 20 mL. 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. MAIN OUTCOME MEASURES: Accuracy by variance from the simulated TV. Inter- and intra-observer variability. RESULTS: One thousand two hundred eighty four individual estimations were obtained. Eighty-five participants repeated measurements. Delegates measured TV accurately on 33.4% (±2.6) of occasions: overestimations 37% (±2.3), underestimations 28% (±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 3 mL testis 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. CONCLUSIONS: Overall TV estimation accuracy was poor. Considerable variation exists between and within subjects. Seniority slightly improved measurement estimation.

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans.

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.

The Australasian Diabetes Data Network: first national audit of children and adolescents with type 1 diabetes.

OBJECTIVES: To assess glycaemic control, anthropometry and insulin regimens in a national sample of Australian children and adolescents with type 1 diabetes. DESIGN: Cross-sectional analysis of de-identified, prospectively collected data from the Australasian Diabetes Data Network (ADDN) registry. SETTING: Five paediatric diabetes centres in New South Wales, Queensland, South Australia, Victoria and Western Australia. PARTICIPANTS: Children and adolescents (aged 18 years or under) with type 1 diabetes of at least 12 months' duration for whom data were added to the ADDN registry during 2015. MAIN OUTCOME MEASURES: Glycaemic control was assessed by measuring haemoglobin A1c (HbA1c) levels. Body mass index standard deviation scores (BMI-SDS) were calculated according to the CDC-2000 reference; overweight and obesity were defined by International Obesity Task Force guidelines. Insulin regimens were classified as twice-daily injections (BD), multiple daily injections (MDI; at least three injection times per day), or continuous subcutaneous insulin infusion (CSII). RESULTS: The mean age of the 3279 participants was 12.8 years (SD, 3.7), mean diabetes duration was 5.7 years (SD, 3.7), and mean HbA1c level 67 mmol/mol (SD, 15); only 27% achieved the national HbA1c target of less than 58 mmol/mol. The mean HbA1c level was lower in children under 6 (63 mmol/mol) than in adolescents (14-18 years; 69 mmol/mol). Mean BMI-SDS for all participants was 0.6 (SD, 0.9); 33% of the participants were overweight or obese. 44% were treated with CSII, 38% with MDI, 18% with BD. CONCLUSIONS: Most Australian children and adolescents with type 1 diabetes are not meeting the recognised HbA1c target. The prevalence of overweight and obesity is high. There is an urgent need to identify barriers to achieving optimal glycaemic control in this population.

An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3).

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.

Bariatric surgery in severely obese adolescents: a single-centre experience.

BACKGROUND: Increasing numbers of severely obese young people undergo bariatric surgery in the USA with reports of substantial weight loss after 1 year. National Institute for Clinical Excellence 2006 suggests considering surgery for young people in 'exceptional circumstances'. We present six patients operated upon 2004-2012 at our centre in the UK. CASE SERIES: Six patients (4 male) aged 14-16 years (mean age 15.10) underwent surgery. Mean preoperative body mass index (BMI) was 62.7 kg/m(2) and BMI SDS +4.4. Comorbidities included hypertension, insulin resistance, obstructive sleep apnoea, limited mobility, benign intracranial hypertension and psychosocial issues. All six patients had prior involvement with local lifestyle weight management services and had pharmacological intervention. Four laparoscopic gastric bypass procedures, one laparoscopic gastric banding (patient had a gastric balloon prior to band) and one laparoscopic sleeve gastrectomy were performed. RESULTS: There were no major postoperative procedural complications (one patient had a port rotation). Mean percentage of weight loss, as a percentage of total body weight at 6 and 12 months, was 22 and 27%, respectively. Average absolute weight loss at current follow-up is 54 kg. Mean BMI at 12 months postprocedure was 46.5 kg/m(2)-a mean fall of 16.2 kg/m(2). Mean BMI SDS fell from +4.4 to +3.8 at 12 months and +3.1 at 2 years. Resolution of hypertension, improved school attendance and no progression to T2DM were the benefits noted. CONCLUSIONS: Recent systematic reviews and meta-analyses suggest that bariatric surgery results in sustained and clinically significant weight loss in paediatric populations. The surgical option should continue to be exercised with extreme caution only in severely obese adolescents and done so in appropriate case results in positive outcomes.

Transition in endocrinology: the challenge of maintaining continuity.

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 the factors affecting nonattendance 1-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 6 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.

Fat and bone in children: differential effects of obesity on bone size and mass according to fracture history.

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 Kröger 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.

'I can actually exercise if I want to; it isn't as hard as I thought': a qualitative study of the experiences and views of obese adolescents participating in an exercise therapy intervention.

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.

Exercise therapy as a treatment for psychopathologic conditions in obese and morbidly obese adolescents: a randomized, controlled trial.

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: > or = 40). At baseline, 30.3% of participants had a Children's Depression Inventory score of > or = 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.

Thiamine-responsive megaloblastic anaemia syndrome: long-term follow-up and mutation analysis of seven families.

AIM: Thiamine-responsive megaloblastic anaemia syndrome (TRMA) is the association of diabetes mellitus, anaemia and deafness, due to mutations in SLC19A2, encoding a thiamine transporter protein. This is a unique monogenic form of vitamin-dependent diabetes for which there is limited long-term data. We aimed to study genotype-phenotype relationships and long-term follow-up in our cohort. METHODS: We have studied 13 patients from seven families and have follow-up data for a median of 9 y (2-30 y). RESULTS: All patients originated from Kashmir or Punjab, and presented with non-immune, insulin-deficient diabetes mellitus, sensorineural deafness and a variable anaemia in the first 5 y of life, the anaemia progressing to megaloblastic and sideroblastic changes in the bone marrow. The anaemia and diabetes mellitus responded to oral thiamine hydrochloride 25 mg/d, but during puberty thiamine supplements became ineffective, and almost all patients require insulin therapy and regular blood transfusions in adulthood. All patients are homozygous for mutations in the SLC19A2 gene. We have identified a novel missense mutation (T158R) that was excluded in 100 control alleles. CONCLUSION: Diabetes in this syndrome is due to an insulin insufficiency that initially responds to thiamine supplements; however, most patients become fully insulin dependent after puberty. A mutation screening strategy is feasible and likely to identify mutations in almost all cases.

Protocol for: Sheffield Obesity Trial (SHOT): a randomised controlled trial of exercise therapy and mental health outcomes in obese adolescents [ISRCNT83888112].

BACKGROUND: While obesity is known to have many physiological consequences, the psychopathology of this condition has not featured prominently in the literature. Cross-sectional studies have indicated that obese children have increased odds of experiencing poor quality of life and mental health. However, very limited trial evidence has examined the efficacy of exercise therapy for enhancing mental health outcomes in obese children, and the Sheffield Obesity Trial (SHOT) will provide evidence of the efficacy of supervised exercise therapy in obese young people aged 11-16 years versus usual care and an attention-control intervention. METHOD/DESIGN: SHOT is a randomised controlled trial where obese young people are randomised to receive; (1) exercise therapy, (2) attention-control intervention (involving body-conditioning exercises and games that do not involve aerobic activity), or (3) usual care. The exercise therapy and attention-control sessions will take place three times per week for eight weeks and a six-week home programme will follow this. Ninety adolescents aged between 11-16 years referred from a children's hospital for evaluation of obesity or via community advertisements will need to complete the study. Participants will be recruited according to the following criteria: (1) clinically obese and aged 11-16 years (Body Mass Index Centile > 98th UK standard) (2) no medical condition that would restrict ability to be active three times per week for eight weeks and (3) not diagnosed with insulin dependent diabetes or receiving oral steroids. Assessments of outcomes will take place at baseline, as well as four (intervention midpoint) and eight weeks (end of intervention) from baseline. Participants will be reassessed on outcome measures five and seven months from baseline. The primary endpoint is physical self-perceptions. Secondary outcomes include physical activity, self-perceptions, depression, affect, aerobic fitness and BMI.

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

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.