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Background Non-objective assessments indicate poor patient adherence to growth hormone (GH) prescribed for growth failure, with sub-optimal growth response. The easypod™ connect device for GH administration enables real-time, objective assessment of adherence. Objective To examine adherence with pediatric GH therapy in Asia-Pacific countries and relationship with growth outcomes. Methods Subjects were children in Indonesia, Singapore, Taiwan enrolled in the multi-national, open-label Easypod Connect Observational Study (ECOS). Adherence during follow-up was the primary endpoint and a relationship with 1-year growth outcomes was assessed by Spearman’s product-moment correlations. Results Over a 1-year time frame, median overall patient adherence was ≥89%; rates were similar for children with GH deficiency (GHD; n=17) and those born small-for-gestational age (SGA; n=5), except that median adherence dropped between 9 months (94%) and 1 year (83%) for SGA subjects. Median initial GH dose was 42.3µg/kg/day for GHD subjects and 31.4µg/kg/day for SGA subjects. Median age (12 years) and bone age (13 years) indicated that most children had entered puberty at treatment onset. Clinically meaningful improvements in growth were observed at 1 year in the GHD group, but not the SGA group. Statistically significant correlations between adherence and height change (P=0.039) as well as height velocity (P=0.004) were observed. Conclusions Children in Asia-Pacific countries show high adherence over the first year of GH therapy with easypod. The easypod study also shows that adherence is correlated to good growth outcomes.

Obese individuals who have little or no metabolic syndrome components are proposed to be "metabolically healthy obese (MHO)". This study aim to evaluate the prevalence of MHO and examine the predictors associated with MHO in a multi-ethnic Asian cohort of severely obese children.This study included a cross-sectional cohort of 406 Chinese, Malay and Indian children aged 5-20 years old with BMI for age ≥ 97th percentile. Metabolic syndrome (MS) and metabolic health (MH) definitions based on the presence or absence of metabolic abnormalities (High triglycerides, low HDL cholesterol, elevated blood pressure and high glucose) were used to define MHO in the cohort.The prevalence of MHO is 63.5% by MS definition and 22.4% by MH definition. Maternal healthy metabolic status (OR: 2.47), age (OR: 0.83, 0.80), paternal obesity (OR: 0.48, 0.53), Malay (OR: 1.97) and Indian ethnicity (OR: 6.38, 3.21) (compared to Chinese ethnicity) are independent predictors for MHO phenotype based on different MHO definitions.Adiposity measures are not associated with MHO phenotype, but instead younger age, maternal healthy metabolic status, absence of paternal obesity, Malay and Indian ethnicity are independent predictors for MHO phenotype in a multi-ethnic Asian cohort of severely obese children.The prevalence of metabolically healthy obese (MHO) in our multi-ethnic Asian cohort of severely obese children is 63.5% and 22.4%, respectively, based on different MHO definitions. Adiposity measures are not associated with the MHO phenotype. There are other factors that contribute to the metabolic phenotype in obese individuals. Younger age, maternal healthy metabolic status, absence of paternal obesity, Malay and Indian ethnicity are independent predictors for MHO phenotype. Parental influence is important in predicting metabolic health in obese individuals.

Objective The mainstay management of hyperphagia and obesity in Prader-Willi syndrome (PWS) relies on dietary restrictions, strict supervision and behavioural modifications, which can be stressful for the patient and caregiver. There is no established pharmacological strategy to manage this aspect of PWS. Theoretically, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP1-RA) used in patients with obesity and type 2 diabetes mellitus (T2DM) may be efficacious in weight and glycaemic control of PWS patients. We conducted a systematic review of the literature to summarize the evidence on the use of GLP1-RA in PWS patients. Design Primary studies were searched in major databases using key concepts 'Prader-Willi syndrome' and 'GLP1 receptor agonist' and outcomes, 'weight control OR glycaemic control OR appetite regulation'. Results Ten studies included, summarizing GLP1-RA use in 23 PWS patients (age, 13-37 years), who had used either exenatide (n = 14) or liraglutide (n = 9) over a duration of 14 weeks to 4 years. Sixteen (70%) of these patients had T2DM. Ten patients experienced improvement in body mass index, ranging from 1.5 to 16.0 kg/m2 , while improvement in HbA1c was seen in 19 of 23 cases, ranging between 0.3% and 7.5%. All five studies reporting appetite or satiety showed improvement in satiety levels. There were no reported serious side effects. Conclusions GLP1-RA appears safe in PWS patients and may have potential benefits for weight, glycaemic and appetite control. Nonetheless, we also highlight a significant gap in the literature on the lack of well-designed studies in this area, which limits the recommendation of GLP1-RA use in PWS patients at present.

The rise in prevalence of childhood obesity is paralleled by an increase in obesity-related metabolic complications, which add significantly to the population burden of cardiovascular morbidity in the long term. Early detection of obesity-related metabolic complications through appropriate screening strategies forms a crucial aspect of obesity management. We performed a scoping review of international and national guidelines on the management of pediatric obesity to evaluate the recommendations on screening for metabolic complications, namely, hypertension, diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Thirty guidelines were included, 23 (76.7%) of which had some guidance on screening for metabolic complications. However, there were significant variations in the extent and details of recommendations for screening for these metabolic complications. There has been no consensus on the body mass index (BMI) thresholds, age of onset, frequency, and screening tests recommended for detecting hypertension, diabetes, dyslipidemia, and non-alcoholic fatty liver disease between guidelines. These variations did not appear to be polarized based on geographical location or population ethnicity. We provide our recommendations on metabolic screening based on the strength of evidence in the guidelines, also incorporating recommendations from key childhood hypertension, diabetes, and lipid guidelines. Appropriate implementation of screening strategies is crucial to improve detection of metabolic complications, to allow for earlier or more intensified interventions for affected children with obesity.

BACKGROUND AND OBJECTIVES Current evidence is lacking on physical activity and nutrition-based interventions focusing on the management of type 1 diabetes mellitus (T1DM) and health-related quality of life among children. To assess the effects of physical activity interventions and nutrition-based interventions for children with T1DM. METHODS Data sources include the Cochrane Central Register of Controlled Trials, Medline, clinicaltrials.gov, the World Health Organization International Clinical Trials Registry Platform, CINAHL through January 2022. Study selection includes randomized controlled trials of children aged 18 years and below with T1DM comparing either a physical activity intervention, a nutrition-based intervention, or hybrid physical activity and nutrition-based intervention with placebo or no-treatment control. Data were pooled using a random-effects model. Primary outcomes were hemoglobin A1c (HbA1c), and health-related quality of life. RESULTS Eighteen trials were included. Physical activity compared with the no-treatment group showed a lack of effect on HbA1c (mean difference = −0.58, 95% confidence interval −1.20 to 0.05; P value = .07). Nutrition-based intervention compared with no-treatment control for HbA1c level revealed a lack of effect (mean difference = −0.61, 95% confidence interval −1.48 to 0.26; P value = .17). Limitations include paucity of studies and low quality of evidence caused by the risk of bias. CONCLUSIONS Despite the lack of significant evidence, the generally favorable results highlight the potential of such interventions in enhancing glycemic control and health-related quality of life. Additionally, promising results from a single physical activity-nutrition-based hybrid intervention in terms of glycemic control indicate the plausible effectiveness of a mixed intervention.

An infant with 46,XY karyotype, and unambiguous female phenotype was found to have testes in the inguinal regions. Capillary sequencing of the androgen receptor (AR) gene identified a hemizygous de novo mutation (NM_000044.6:c.1621G > T) in exon 2 resulting in a termination codon p.(Glu541*) at the DNA binding domain (DBD). This novel nonsense mutation adds to the compendium of AR mutations which result in complete androgen insensitivity syndrome (AIS).

Background Leukocyte telomere length (LTL) is associated with obesity and obesity-related traits, and there are ethnic-specific determinants of LTL. Objective To evaluate LTL associations with obesity and metabolic parameters in Asian children with early-onset obesity. Methods Genomic DNA was extracted from peripheral blood leukocytes of a cohort of children with (N = 371) and without obesity (N = 23), and LTL was measured using quantitative PCR (qPCR). Blood plasma was used for metabolic phenotyping. Statistical analysis was performed using SPSS and STATA. Results Children with obesity had shorter LTL (coefficient = -0.683, PAdj = 1.24 × 10-3 ) as compared to children who were lean. LTL was found to be associated with waist circumference (coefficient = -0.326, PAdj = 0.044) and skin-fold measures (coefficient between 0.267 and 0.301, PAdj between 4.27 × 10-4 and 7.06 × 10-7 ) in children with obesity. However, no significant associations were observed between LTL and metabolic parameters, and between LTL and inflammatory cytokines. LTL also did not significantly mediate the risk of non-alcoholic fatty liver disease (NAFLD) in children with obesity. Conclusions We showed for the first time that Asian children with severe obesity had shorter LTL, and the shortening of LTL was associated with other adiposity measures including waist circumference and skin-fold measurements.

Purpose Consideration of health-related quality of life (HRQoL) and wellbeing outcomes is important to guide healthcare services for youth with obesity, yet youth perspectives may difer from their parents. This study compared youth and parental HRQoL reports and evaluated levels of concordance across HRQoL domains and as a function of youth age, youth gender and parent informant (mother and father). Methods 376 youths with obesity, recruited from community (N=223) and hospital settings (N=153), and their parents (N=190 mothers; N=91 fathers), completed the PedsQL. Parental and youth agreement across subgroup dyads (mother; father; child gender; child age) were evaluated using Wilcoxon signed-rank test, intra-correlations coefcients (ICCs) and Bland–Altman plots. Results Compared to norms, HRQoL levels (youth self-report and parental proxy reports) were lower in all domains. Both mother and fathers’ HRQoL reports were signifcantly lower than youths, most notably in physical HRQoL. Youth–parent concordance ranged from poor to moderate (ICC=0.230–0.618), with lowest agreement for Physical HRQOL. Mothers were better proxies with ICCs being signifcant in all domains. Youth-father ICCs were signifcant only for Social (ICC=0.428) and School (ICC=0.303) domains. Girl–mother agreement was signifcant across all domains, while girl–father agreement was signifcant only in the Social domain (ICC=0.653). Both mothers and fathers were poor raters for boys, and younger youths (aged ≤12), with non-signifcant ICCs in most HRQoL domains. Conclusions Parents are poor surrogates for youth HRQoL. Clinicians should be cognizant that parents are not necessarily accurate proxies for youths, and exercise caution when interpreting parent-proxy scores. National Medical Research Council (NMRC) This study is supported by funding from National Medical Research Council-Clinician Scientist Research Grant (NMRC/ CIRG/1407/2014).

This is the first study to investigate the associations of self-care, illness perceptions and psychological distress with metabolic control in Singaporean adolescents with Type 1 Diabetes Mellitus (T1DM). A cross-sectional sample of 41 adolescents (aged 14–20) completed measures of self-care, illness perceptions and psychological distress. Demographic and medical information were also obtained. Glycated haemoglobin (HbA1c) levels were analysed both as continuous variable to explore dose–effect relationships and as a categorical variable to classify poor versus good metabolic control. A total of 65.9% (n = 27) of the adolescents had poor metabolic control (HbA1c

Context: Five different activating PTH/PTH-related peptide (PTHrP) receptor (PTHR1) mutations have been reported as causes of Jansen metaphyseal chondrodysplasia (JMC), a rare disorder characterized by severe growth plate abnormalities and PTH-independent hypercalcemia.Objectives: Assess the natural history of clinical and laboratory findings in 24 patients with JMC and characterize the disease-causing mutant receptors in vitro.Patients and Methods: The H223R mutation occurred in 18 patients. T410P, I458R and I458K each occurred in single cases; T410R was present in a father and his two sons. Laboratory records were analyzed individually and in aggregate.Results: Postnatal calcium levels were normal in most patients, but elevated between 0.15 and 10 years (11.8 +/- 1.37 mg/dL) and tended to normalize in adults (10.0 +/- 1.03 mg/dL). Mean phosphate levels were at the lower end of the age-specific normal ranges. Urinary calcium/creatinine (mg/mg) were consistently elevated (children, 0.80 +/- 0.40; adults, 0.28 +/- 0.19). Adult heights were well below the 3rd percentile for all patients, except for those with the T410R mutation. Most patients with JMC had undergone orthopedic surgical procedures, most had nephrocalcinosis, and two had advanced chronic kidney disease. The five PTHR1 mutants showed varying degrees of constitutive and PTH-stimulated cAMP signaling activity when expressed in HEK293 reporter cells. The inverse agonist [L-11,dW(12),W-23,Y-36] PTHrP(7-36) reduced basal cAMP signaling for each PTHR1 mutant.Conclusions: Except for T410R, the other PTHR1 mutations were associated with indistinguishable mineral ion abnormalities and cause similarly severe growth impairment. Hypercalciuria persisted into adulthood. An inverse agonist ligand effectively reduced in vitro PTH-independent cAMP formation at all five PTHR1 mutants, suggesting a potential path toward therapy.

Mutations in the MC4R gene are the most common cause of monogenic obesity, and there are few studies on mutations in the promoter region.The objective of the study was to sequence the promoter region of the MC4R gene in a cohort of obese children to identify rare variants.A region 1500 bp upstream of the MC4R gene was sequenced in 267 unrelated local children younger than 10 years, with body weight of at least 150% of ideal. An 891-bp upstream region of the MC4R gene was cloned into a luciferase reporter vector for reporter gene assays.There were no interventions.The basal transcriptional activity of the MC4R promoter was analyzed in human embryonic kidney 293 cells using reporter gene assays.Three rare variants were detected: c.-803AG, c.-105CG, and c.-216CT. The novel c.-803AG variant was found in a 9-year-old severely obese Malay boy. This variant was not found in his severely obese mother but was present in his overweight father, who had type 2 diabetes, and also in his normal-weight brother. The novel c.-105CG variant was found in an obese 9-year-old Malay boy. The c.-216CT variant was found in an obese Chinese girl with Down's syndrome. The transcriptional activities of the c.-803AG and c.-105CG promoters were significantly reduced compared with the wild type but not the c.-216CT promoter.We have described, for the first time, two novel human MC4R gene promoter variants found in obese children that resulted in a decrease in basal transcriptional activity.

Precocious puberty in patients with neurofibromatosis type 1 (NF-1) is predominantly central in origin, with intracranial pathologies like optic glioma. We describe one patient with NF-1 who presented with precocious puberty with the eventual diagnosis of familial male-limited precocious puberty and share the potential pitfalls. He presented at 7 years of age with growth spurt and pubertal genitalia development with enlarged testicular volume of 7 mL, but LHRH stimulation test revealed blunted luteinizing hormone and follicle-stimulating hormone peak suggestive of a peripheral cause, contrary to the expectation due to the background of NF-1. Testosterone level was elevated with bone age advancement by 2 years. Genetic analysis revealed a previously reported heterozygous missense mutation of the luteinizing hormone/choriogonadotropin receptor gene Ala572Val. His father was also heterozygous for the same mutation but was apparently asymptomatic and not short. Conclusion: Our report illustrates two potential pitfalls in the clinical evaluation of patients with familial male-limited precocious puberty (FMPP). Firstly, patients with FMPP will have mild to moderately enlarged testes and should not be wrongly diagnosed as central precocious puberty without the gonadotropin-releasing hormone stimulation test. Secondly, family members with the same mutation may have different phenotypic severities, where some male carriers may have subtle features.

A bstract Nucleobindin 2 (NUCB2) is a precursor of nesfatin-1, a hypothalamic anorectic neuropeptide. The association between variants of the NUCB2 gene and adiposity was examined. 142 severely obese Chinese children in Singapore, and 384 normal weight Chinese children from a longitudinal cohort from Da Qing, China, were studied. NUCB2 was screened using PCR and direct sequencing in 29 severely obese children and 24 non-obese children, then screened for a variant c.1012C>G (Q338E, or rs757081) in the rest of the cohort using TaqMan probe. Five variants, including c.1012C>G (Q338E) were found. Genotyping for c.1012C>G found that the GG genotype was significantly less frequent in the obese group; odds ratio for obese subjects carrying the CC and CG genotypes was 2.29 (95% CI 1.17–4.49) in the dominant model, CC genotype 2.86 (95% CI 1.41–5.81) in the additive model, and C allele 1.57 (95% CI 1.17–2.1). The findings were replicated in an independent cohort of 372 obese and 390 normal weight Chinese children, where the odds ratio of obese subjects with CC and CG genotypes was 1.69 (95% CI 1.12–2.55). Within the Da Qing cohort, subjects with the GG genotype had significantly lower BMI and percentage ideal weight for height (WFH) at 5 and 8 years of age. Subjects with lower birth weights also had more pronounced difference in WFH and BMI at 5 and 10 years of age between GG subjects versus CC/CG subjects. We postulate that GG genotype is protective against excessive weight gain, and factors which predispose to excessive weight gain such as higher birth weights may ameliorate the effect.

Background Visfatin is an adipokine, associated with obesity and possibly glucose regulation. Objective The aim of this study was to examine the association of visfatin and its genetic variants with adiposity, cardiometabolic risk factors and obesity-related morbidities in obese children. Methods Anthropometric measurements, dual energy X-ray absorptiometry scan, fasting blood samples and oral glucose tolerance tests were performed for 243 obese children. We screened the visfatin gene of 24 obese subjects and then performed genotyping of identified genetic variants in other 219 obese children through direct DNA sequencing. Results Fasting serum visfatin correlated with measures of obesity and liver enzymes and was elevated in obese children with abnormal glucose tolerance and non-alcoholic fatty liver disease. The two upstream single nucleotide polymorphisms, -3187G>A (rs11977021) and -1537C>T (rs61330082), were at complete linkage disequilibrium. The AA genotype of -3187G>A was associated with higher serum visfatin (6.17 ± 0.76 ng mL(-1) vs. 3.92 ± 0.44 ng mL(-1)) and higher triglyceride (1.39 ± 0.08 mmol L(-1) vs. 1.19 ± 0.07 mmol L(-1)) as compared with the GG genotype. There was also a significant linear increase in serum visfatin across GG to GA to AA genotype of -3187G>A, indicating possible additive effect of A allele. The dominant GA + AA genotype model of +21426G>A (rs2302559) was associated with lower serum visfatin (3.83 ± 0.56 ng mL(-1) vs. 5.13 ± 0.34 ng mL(-1)) and lower plasma glucose (4.37 ± 0.08 mmol L(-1) vs. 4.77 ± 0.12 mmol L(-1)) as compared with the GG genotype. Conclusion Visfatin and its genetic variants were associated with adiposity, obesity-related morbidities and adverse cardiometabolic parameters. This supported our hypothesis that visfatin plays a significant role in the development of obesity-related morbidities and cardiometabolic risk.

Hyperinsulinaemic hypoglycaemia (HH), which causes persistent neonatal hypoglycaemia, can result in neurological damage and it’s management is challenging. Diazoxide is the first-line treatment, albeit not all patients will fully respond to it, as episodes of hypoglycaemia may persist and it entails unpleasant adverse effects. Sirolimus, an mTOR inhibitor, has reportedly been successful in treating children with severe diffuse HH, thus obviating the need for pancreatectomy. We report a girl with HH, with a novel heterozygous ABCC8 gene missense mutation (c.4154A>T/ p.Lys1385Thr), who was initially responsive to diazoxide therapy. After 11 months of diazoxide treatment, she developed intermittent, unpredictable breakthrough episodes of hypoglycaemia, in addition to generalized hypertrichosis and weight gain from enforced feeding to avoid hypoglycaemia. Sirolimus, which was commenced at 15 months of age, gradually replaced diazoxide, with significant reduction and abolition of hypoglycaemia. The hypertrichosis resolved and there was less weight gain given the reduced need for enforced feeding. Sirolimus, which was administered over the next 15 months, was well tolerated with no significant side effects and was gradually weaned off. After stopping sirolimus, apart from hypoglycaemia developing during an episode of severe viral gastroenteritis, the capillary glucose concentrations were maintained >3.5 mmol/L, even after a 10 h fast. Sirolimus may have a role in the treatment of partially diazoxide-responsive forms of HH who experience breakthrough hypoglycaemia, but the long-term safety and efficacy of sirolimus are not established. Learning points: Conventional treatment of diffuse HH with diazoxide is not always effective in controlling hypoglycaemia and can be associated with unpleasant side effects. Sirolimus was successfully used to abolish recurrent hypoglycaemia in partially diazoxide-responsive HH, with resolution of unacceptable diazoxide-associated side effects. Sirolimus was well tolerated with no clinically significant side effects. Shortly after stopping sirolimus, the capillary glucose levels remained normoglycemic. Background Hyperinsulinaemic hypoglycaemia (HH) from dysregulated insulin secretion of the pancreatic β-cells is an important cause of persistent neonatal hypoglycaemia. Mutations have been reported in the ABCC8 and KCNJ11 genes on chromosome 11p15.1, which encode the sulphonylurea receptor 1 (SUR1) and the inward rectifying potassium channel (Kir6.1) proteins, respectively (1). Both these proteins constitute the ATP-sensitive plasma membrane potassium (KATP) channel, the regulation of which controls cell membrane polarization, which determines insulin release from the pancreatic β-cell. Inactivating mutations of the ABCC8 and KCNJ11 genes result in closure of the KATP channels, leading to depolarization of the cell membrane, opening of the voltage-dependent calcium channels and insulin release. Diazoxide has been the conventional first-line treatment of diffuse HH as it opens the KATP channel and inhibits insulin secretion. However, diazoxide is associated with unpleasant side effects including fluid retention, blood dyscrasias, nausea and hypertrichosis. The use of sirolimus, an inhibitor of mTOR (the mammalian target of rapamycin) as an immunosuppressant in post-renal transplant patients uncovered its association with hyperglycaemia (2). Studies of the pancreas in patients with diffuse HH suggest a pathogenic role in overexpression of the mTOR pathway (3). Research has demonstrated that sirolimus can effectively suppress β-cell proliferation and reduce the severity of HH. Inhibitors of mTOR have already been successfully used to treat adults with pancreatic insulin secreting tumours (4). In recent reports, sirolimus was efficacious and safe in children with HH who were unresponsive to diazoxide therapy and octreotide, thus obviating the need for near total pancreatectomy (5). We report a 3-year 3-month-old girl who demonstrated initial partial response to diazoxide, but then developed intermittent, unpredictable hypoglycaemic episodes and severe hypertrichosis with weight gain. Sirolimus, which replaced diazoxide, was successfully used in abolishing hypoglycaemia and resolving the diazoxide-associated side effects. Shortly after stopping sirolimus, the blood glucose levels remained in the normal range, except during the stress of a viral illness.

The growth trends of Singapore children spanning 5 decades are reviewed, based on 8 anthropometric studies from 1957 till 2002. The heights of pre-school children and school age children appear to have optimised according to their genetic potential, but the weights and body mass indices of children still appear to be increasing from 6 to 18 years for both sexes, probably as a consequence of increasing affluence. This trend is reflected in the increasing obesity prevalence in school children over the past 30 years, and the concomitant increased morbidity associated with the metabolic syndrome, necessitates further research into the causes of obesity. Barker’s hypothesis first suggested that changes in the intra-uterine environment can cause fetal adaptations which persist into adulthood, and are responsible for many chronic diseases of adult life. More recently, intense research in the field of epigenetics suggests that the environment can also influence the phenotype through gene expression, through modification of DNA methylation and histones which, in turn, influences gene expression. The challenge for the future is to determine if there are clear epigenetic changes, which are responsible for the increased prevalence of childhood and adolescent obesity, and whether these changes are transmitted through generations. Unravelling these epigenetic mechanisms may be the key to the prevention of obesity and the metabolic syndrome. Key words: Body mass index, Epigenetics, Height, Weight

Summary Objective Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. The significance of MC4R mutations in Asian obese populations has not been adequately examined. The objective of this study was to determine the role of MC4R mutations in severely obese Asian children. Design We screened 227 obese local children and adolescents for MC4R gene mutations by polymerase chain reaction and direct sequencing. Results We identified three mutations in three subjects: 4 bp deletion from nucleotides 631–634 (c.631–634delCTCT), Tyr157Ser (c.470 A > C) and 1 bp deletion at nucleotide 976 (c.976delT) (1·32% of study subjects). The latter two mutations are novel. The Tyr157Ser mutation was not found in 188 non-obese controls using restriction enzyme digest analysis. In vitro transient transfection studies supported the pathogenic role of both novel mutations Tyr157Ser and c.976delT, where the signalling activities of the mutant receptors were impaired. Heterozygous MC4R mutations were associated with early-onset severe obesity, and homozygosity of the MC4R mutation Tyr157Ser resulted in morbid obesity. Conclusion MC4R mutations result in an autosomal codominant form of obesity with variable expressivity. MC4R deficiency is not as common among the obese children in this study compared to other populations. Family studies revealed that adults heterozygous for the mutations were less obese compared to the children. We hypothesize that this may be due to amelioration of phenotype severity with age, genetic anticipation or difference in exposure to modifying factors at critical stages of childhood such as the environment.

Case Presentation An 8 month-old boy was referred to the endocrinology clinic for concerns of growth failure since 3 months of age. He was born full term with a birth weight of 2.67kg and a length of 45cm. His parents noticed that he was not growing well from 3 months of age. However, his weight gain remained more than satisfactory and he gained 700g in the past month. This infant was otherwise in good health, apart from atopic dermatitis, for which the parents had been applying a daily cream with good effect. He was breast fed until 2 months of age and weaned onto solids at 6 months of age. On examination, the infant had a moon face with hypertrichosis, facial telangiectasia and prominent supraclavicular fat pads. His recumbent length was 62cm (

Aims Mutations in Steroidogenic Acute Regulatory protein (StAR) cause congenital lipoid adrenal hyperplasia (lipoid CAH), characterized by absent steroidogenesis, potentially lethal salt loss, 46,XY sex reversal and massively enlarged adrenals engorged with cholesterol esters. Nonclassic lipoid CAH is a recently recognized disorder caused by StAR mutations that retain partial function. We aim to delineate the clinical and mutational spectrum of StAR mutations in patients with lipoid CAH.

Objective We describe a case of spurious hyperthy-roxinemia secondary to thyroid hormone autoantibodies (THAAbs) in a clinically euthyroid patient with Turner mosaic syndrome. Methods Several commonly available laboratory-based approaches were used, which indicated a disproportionate elevation of free thyroxine (T4) and ultimately led to the diagnosis of THAAbs. A literature review was undertaken to examine the clinical and laboratory associations of THAAbs. Results The free T4 result of the patient was highly discrepant when measured using an Advia Centaur platform (5.89 ng/dL) as compared with the Vitros 5600 and DxI 800 platforms (1.03 and 0.74 ng/dL, respectively). Polyethylene glycol precipitation of the patient’s sample showed reduced free T4 recovery (26%), suggesting the presence of a high-molecular-weight interfering substance. Rheumatoid factor and heterophile blocking tube studies were negative. These results suggested a presumptive diagnosis of THAAbs. Direct detection of THAAbs using a radiobinding method confirmed the diagnosis. A review of the literature showed that THAAbs are prevalent among patients with (autoimmune and nonautoimmune) thyroid disorders and nonthyroid autoimmune disorders but rarely cause spurious measurements. Possible pathogenesis includes molecular mimicry, exposure of the antigenic surfaces of iodinated thyroglobulin molecules to B lymphocytes in injurious or inflammatory conditions involving the thyroid gland. Free thyroid hormone methods using one-step analog and labeled antibody designs are prone to falsely high measurements, whereas two-step analog designs may produce spuriously low results. Conclusion THAAbs are an underrecognized cause of laboratory interference that is best approached by joint clinical-laboratory efforts. The routine laboratory techniques described above can suggest preliminary diagnosis of this rare entity. (Endocr Pract. 2014;20:e134-e139)

A prolonged use of topical corticosteroids can result in Cushing syndrome, though this is less common than with oral or parenteral steroids. Most pediatric cases were due to application of topical steroids for diaper dermatitis. Adverse cardiovascular effects can occur in Cushing syndrome with significant long-term morbidity and mortality, though so far there have been no reports of cardiovascular complications due to excessive usage of topical steroids. We report a 2.5-month-old boy who rapidly developed severe Cushing syndrome induced by the misuse of topical clobetasol, a very potent steroid, without a doctor's prescription as a diaper rash cream, and developed moderate left ventricular hypertrophy and pericardial effusion.

A prospective open study was performed to determine the efficacy and safety of pamidronate in improving bone mineralisation and reducing fracture incidence in osteogenesis imperfecta (OI). Intravenous pamidronate was administered at 1.5 mg/kg bi-monthly to six children with OI, over 12–23 months. The number of fractures decreased from median of 3 (range 1–12) to 0 fractures/year (range 0–4) (P

X-linked congenital adrenal hypoplasia (CAH) presents classically with adrenal insufficiency within the first 6 months of life, as the fetal adrenal cortex progressively involutes. However, there is increasing recognition of delayed presentation after infancy with the need for accurate molecular diagnosis to avoid an erroneous diagnosis of other more common causes of adrenal insufficiency in childhood. We report our genetic studies of a pedigree with two affected boys presenting with late onset X-linked CAH, diagnosed by the presence of a known W171X mutation of the DAX-1 gene, in whom the mother was an obligate heterozygote. Unlike other causes of adrenal insufficiency, the significance of this diagnosis lies in the important association of hypogonadotropic hypogonadism, and the provision of accurate genetic counselling. Conclusion This study demonstrates that genetic analysis for X-linked congenital adrenal hypoplasia is essential to confirm the diagnosis in prepubertal patients presenting with adrenal insufficiency after infancy.

Two heterozygous PTH/PTH-related peptide (PTHrP) receptor missense mutations were previously identified in patients with Jansen’s metaphyseal chondrodysplasia (JMC), a rare form of short limb dwarfism associated with hypercalcemia and normal or undetectable levels of PTH and PTHrP. Both mutations, H223R and T410P, resulted in constitutive activation of the cAMP signaling pathway and provided a plausible explanation for the abnormalities in skeletal development and mineral ion homeostasis. In the present study we analyzed genomic DNA from four additional sporadic cases with JMC to search for novel activating mutations in the PTH/PTHrP receptor, to determine the frequency of the two previously identified missense mutations, H223R and T410P, and to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in three novel JMC patients and is, therefore, to date the most frequent cause of JMC. In the fourth patient, a novel heterozygous missense muta...

We report a rare presentation of mitochondrial disorder in a child with recurrent carpopedal spasms due to hypocalcemia and hypomagnesemia, secondary to renal proximal tubulopathy and possible hypoparathyroidism. At least two mutant mitochondrial DNA species were identified, and abnormal mitochondria were found in the muscle and renal biopsy specimens. The case illustrates the spectrum and diversity of mitochondrial presentations, arising because of heteroplasmy of mutations and the type of organs affected.

Spectacular advances in molecular genetics have enabled the molecular characterisation of many genetic disorders. The clinical applications include: (i) identification of pre-symptomatic and symptomatic affected individuals (monogenic diseases), allowing for early treatment and prevention of complications, (ii) carrier testing for genetic counselling, (iii) pharmacogenetic testing to guide medical treatment, and (iv) susceptibility testing (in polygenic diseases) to determine the risk of developing future disease. Using the model of congenital adrenal hyperplasia (CAH), direct mutational analysis can be applied to: (i) confirm the diagnosis when hormone assays have been equivocal, which would allow for early treatment and prevention of adrenal crisis, (ii) prenatal diagnosis and prenatal treatment in affected females to prevent or reduce prenatal virilisation, (iii) heterozygote carrier identification for genetic counselling, (iv) novel therapeutic applications to optimise treatment, including adjusting the steroid dose based on consistent genotype-phenotype correlations, so as to reduce the incidence of growth-inhibiting effects of steroid excess. However, molecular analysis can occasionally be complicated by multiple mutations on one allele, which may potentially affect genotype-phenotype correlations. Hence, molecular genetic analysis of CAH may eventually be adopted as a second tier confirmation of the disease, but is unlikely to replace the current first tier screening assays of precursor steroid metabolites proximal to the enzyme deficiency.

Introduction: Weight-and-height-based anthropometric indices have long been used for obesity screening among adolescents.However, the ability of their age-and-sex-specific reference values in classifying adolescent as “obese” in different populations was not fully established. Our study aimed to validate the existing international (BMI-for-age charts from WHO, CDC, IOTF) and local cut-offs [percent weight for height (PWH)] for obesity against body fat percentage, as assessed by 4 skinfolds measurement. Materials and Methods: A cross-sectional sample of 6991 adolescents aged 12 to 18 years was measured. All anthropometric measurements were compliant with the internationally accepted protocol. Obesity was defined as percentage body fat greater than or equal to 95 percentile, specific to age and sex. The validity of the existing classification criteria in detecting obesity was evaluated by comparing their respective diagnostic accuracy. Results: Both prevalence of obesity and diagnostic accuracy indices varied by the classification criteria. While all criteria generated very high specificity rates with the lowest being 95%, their sensitivity rates were low ranging from 43% to 71%. Youden’s index suggested that CDC and WHO criteria had optimal sensitivity and specificity. ROC analysis showed that overall performance could be improved by refining the existing cut-offs. Conclusions: Clinical validity of weight-and-height-based classification systems for obesity screening in Asian adolescents is poorer than expected, and this could be improved by refining the existing cut-offs. Key words: BMI-for-age references, Percentage body fat, Singapore, Validity, Weight-for height

OBJECTIVE: To identify factors associated with raised alanine transaminase, aspartate transaminase, and gamma-glutaryl transferase in severely obese children PATIENTS AND METHODS: In all, 201 children with early-onset obesity and greater than 140% ideal weight for height were recruited. Anthropometric and body fat measurements, fasting blood tests, and oral glucose tolerance tests were performed. RESULTS: The mean and standard deviation (SD) for age was 11.1 (3.0) years, for weight for height 170.5% (22.7%), and for percentage body fat was 40.7% (5.2%). Elevated liver transaminases were present in 53 subjects (26.4%), who were therefore at risk for nonalcoholic fatty liver disease, and was associated with male sex (odds ratio [OR] 2.144, 95% confidence interval [CI] 1.033-4.448), Chinese ethnicity (OR 2.062, 95% CI 1.038-4.096), reduced physical activity (OR 2.389, 95% CI 1.163-4.909), insulin resistance (P < 0.05), elevated triglyceride levels (P = 0.029), and increased waist-hip ratio (P = 0.005). Stepwise logistic regression analysis of the main factors as covariates revealed Chinese ethnicity, waist-hip ratio, reduced physical activity, and homeostasis model assessment index were significant predictors. Alanine transaminase/aspartate transaminase were not well correlated with percentage body fat and weight for height. Subjects with type 2 diabetes mellitus and impaired glucose tolerance were more likely to have raised hepatic transaminases (OR 6.176, 95% CI 1.326-28.754). The severity of metabolic syndrome correlated with increasing aspartate transaminase, alanine transaminase, and gamma-glutaryl transferase (P < 0.01). CONCLUSIONS: Insulin resistance, truncal adiposity, and physical inactivity are major determinants potentially modifiable to reduce risk of nonalcoholic fatty liver disease. Increasing physical activity levels were associated with decreasing insulin resistance and transaminases, despite lack of correlation with waist-hip ratio, which supports the direct benefit of regular physical activity in preventing nonalcoholic fatty liver disease.

X-linked adrenal hypoplasia congenita (AHC) is typically associated with DAX-1 mutations and hypogonadotropic hypogonadism. However, atypical cases of X-linked AHC in association with central precocious puberty and even normal puberty have rarely been reported, although the mechanism of action remains unknown.This is a case report of a boy with X-linked AHC associated with Duchenne muscular dystrophy, whose clinical presentation led to analysis of the DAX-1, glycerol kinase (GK1) and dystrophin genes, which were amplified by polymerase chain reaction, with Southern blot analysis of the AHC locus.There was a non-contiguous deletion of the DAX-1 and GK1 genes, with deletion of the dystrophingene from exons 3 to 79.This is the first report of X-linked AHC, central precocious puberty in the absence of the DAX-1 gene. The fact that a 'loss of function' DAX-1 mutation can be associated with hypogonadotropic hypogonadism, precocious and normal puberty, suggests that DAX-1 is but one of several transcription factors which regulate puberty, and provides further evidence that other transcription factors may interact with DAX-1 and influence gonadal regulation in a complex, but hierarchical fashion.

OBJECTIVE—Melanocortin 3 receptor (MC3R) plays a critical role in weight regulation of rodents, but its role in humans remains unclear. The objective of this study was to identify genetic variants of the MC3R gene and determine its association with childhood obesity. RESEARCH DESIGN AND METHODS—We screened 201 obese children for MC3R gene mutations with anthropometric measurements, blood tests, feeding behavior, and body composition assessment. We identified three novel heterozygous mutations (Ile183Asn, Ala70Thr, and Met134Ile) in three unrelated subjects, which were not found in 188 control subjects, and two common polymorphisms Thr6Lys and Val81Ile. RESULTS—In vitro functional studies of the resultant mutant receptors revealed impaired signaling activity but normal ligand binding and cell surface expression. The heterozygotes demonstrated higher leptin levels and adiposity and less hunger compared with obese control subjects, reminiscent of the MC3R knockout mice. Family studies showed that these mutations may be associated with childhood or early-onset obesity. The common variants Thr6Lys and Val81Ile were in complete linkage disequilibrium, and in vitro studies revealed reduced signaling activity compared with wild-type MC3R. Obese subjects with the 6Lys/81Ile haplotype had significantly higher leptin levels, percentage body fat, and insulin sensitivity, and the causative role of the 6Lys/81Ile variants is supported by the presence of an additive effect in which heterozygotes had an intermediate phenotype compared with homozygotes. CONCLUSIONS— MC3R mutations may not result in autosomal dominant forms of obesity but may contribute as a predisposing factor to childhood obesity and exert an effect on the human phenotype. Our report supports the role of MC3R in human weight regulation.

Loss-of-function mutations in the phosphate regulating gene with homologies to endopeptidases on the X-chromosome ( PHEX) have been causally associated with X-linked hypophosphatemic rickets (XLHR). The early diagnosis of XLHR in infants is challenging when it is based solely on clinical features and biochemical findings. We report a 7-month-old boy with a family history of hypophosphatemic rickets., who demonstrated early clinical evidence of rickets, although serial biochemical findings could not definitively confirm rickets. A sequencing assay targeting the PHEX gene was first performed on the mother’s DNA to screen for mutations in the 5′UTR, 22 coding exons, and the exon-intron junctions. Targeted mutation analysis and mRNA studies were subsequently performed on the boys’ DNA to investigate the pathogenicity of the identified mutation. Genetic screening of the PHEX gene revealed a novel mutation, c.1080-2A>C, at the splice acceptor site in intron 9. The detection of an aberrant mRNA transcript with skipped (loss of) exon 10 establishes its pathogenicity and confirms the diagnosis of XLHR in this infant. Genetic testing of the PHEX gene resulted in early diagnosis of XLHR, thus enabling initiation of therapy and prevention of progressive rachitic changes in the infant.

Background Hypercalcemia is a common complication of adult malignancies, but uncommon in childhood cancers. The mechanism leading to hypercalcemia varies with the primary tumour and can include the following: 1) Increased osteoclastic activity at the site of the tumour in the bone marrow 2) A paraneoplastic phenomenon secondary to PTH-related peptide (PTHrP) secretion or 1,25–dihydroxyvitamin D by the tumour. Patients with serum calcium above 3.5 mmol/L tend to be symptomatic and require prompt treatment. The symptoms are generally non-specific and include lethargy, nausea, vomiting, constipation and abdominal pain. Left untreated, hypercalcemia can progress to stupor and coma.

The effect of growth hormone (GH) on subclinical disease activity in a 15-year-old boy with previously quiescent lupus nephritis and chronic renal failure is described. Institution of supraphysiological doses of GH resulted in a rise in erythrocyte sedimentation rate, decrease in serum complement, rise in anti-DNA antibody titers, and increase in T-cell activation markers, all of which improved following cessation of GH treatment.

The short stature homeobox-containing (SHOX) gene, found on the human sex chromosomes, has a role in bone growth and height determination. Haploinsufficiency of the SHOX gene is believed to be responsible for poor growth such as that observed in ther Leri-Weill syndrome (LWS). This is the first report of the study of SHOX gene copy number by the technique of quantitative real-time polymerase chain reaction (RQ-PCR) in 9 patients with LWS. Only 7 patients (78%) of LWS had one copy of the SHOX gene deleted, but 2 patients (12%) have neither a single copy gene deletion nor point mutation after direct sequencing of all 7 exons. Although the majority of patients with LWS in this study have SHOX gene haploinsufficiency, there are some patients with both copies of the SHOX gene intact with absence of any point mutations in the coding region. This may be due to abnormalities in the upstream promoter, or to the effect of other candidate gene mutations. RQ-PCR is a faster and cheaper method of studying SHOX sing-copy deletions compared with the conventional fluorescence in situ hybridization (FISH), and is recommended for the detection of SHOX gene haploinsufficiency.

Use of a third generation TSH assay enabled extremely low values of TSH to be detected through newborn screening. The use of a supplemental free thyroxine improved testing specificity. The hypothyroidism observed is believed to be secondary to suppression of the hypothalamic-pituitary-thyroid axis by placentally transferred maternal thyroxine.

We report an 8-year-old boy with a distinctive form of metaphyseal chondrodysplasia (MCD). He presented with moderate disproportionate short stature and bony swelling of his wrists, knees, and ankles. There were severe metaphyseal abnormalities with a honeycomb appearance affecting the distal tibiae and fibulae, proximal tibiae, distal femurs, distal ulnae and radii, and both hands. His thoracolumbar spine was normal. Radiological examination of the mother's forearms revealed widening of the distal radii and short ulnae with hypoplastic distal ends. Rosenberg and Lohr [1986: Eur J Pediatr 145:40-45] reported a four-generational kindred in which affected members had thickening of the wrist proximal to the styloid process of the ulna and thickening of the dorsum sellae. Although many of the radiographic features of this patient are those of MCD-Rosenberg, the skeletal features of our patient do not appear to represent any known classified forms of MCD.

Circulating antibodies to glutamic acid decarboxylase (GADab) are a major indicator for autoimmune destruction of pancreatic islet cells (type 1 diabetes). Previously reported detection of GADab in oral fluid, however, was assayed by enzyme-linked immunosorbent assay (ELISA) with low diagnostic sensitivity and high non-specific binding. We re-assessed oral fluid GADab detection using a different sampling technique and a more robust assay. Type 1 diabetic subjects (n = 32; mean age +/- SD: 13.9 +/- 3.7 years) provided Orasure oral fluid and venous blood samples. Orasure collections were assayed for total immunoglobulin G (IgG), then concentrated to 1/10 of their volume using mini-centrifugal protein concentrators. All samples were assayed by a GAD65 antibody radio-immunoprecipitation method. Oral fluid antibodies were detected ( > 99th percentile of radio-binding (%counts per min (%cpm)) for seronegatives) in 10/16 seropositive subjects, with %cpm (median: 6.4%; range: 4.6-25.8) significantly greater (P < 0.001) than for seronegatives (median: 4.7%; range: 3.4-5.7). A highly significant correlation (Spearman's rho: 0.85; P