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Obstructive sleep apnea (OSA) is a prevalent complication that affects up to 60% of children and adolescents with obesity. It is associated with poorer cardiometabolic outcomes and neurocognitive deficits. Appropriate screening and intervention for OSA are crucial in the management of children with obesity. We performed a scoping review of international and national pediatric obesity (n = 30) and pediatric OSA (n = 10) management guidelines to evaluate the recommendations on OSA screening in pediatric obesity. Sixteen (53%) of the pediatric obesity guidelines had incorporated OSA screening to varying extents, with no consistent recommendations on when and how to screen for OSA, and subsequent management of OSA in children with obesity. We provide our recommendations that are based on the strength and certainty of evidence presented. These include a clinical-based screening for OSA in all children with body mass index (BMI) ≥ 85th percentile or those with rapid BMI gain (upward crossing of 2 BMI percentiles) and the use of overnight polysomnography to confirm the diagnosis of OSA in those with high clinical suspicion. We discuss further management of OSA unique to children with obesity. An appropriate screening strategy for OSA would facilitate timely intervention that has been shown to improve cardiometabolic and neurocognitive outcomes.
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Enfermedades Cardiovasculares , Obesidad Infantil , Apnea Obstructiva del Sueño , Adolescente , Humanos , Niño , Obesidad Infantil/complicaciones , Obesidad Infantil/diagnóstico , Obesidad Infantil/terapia , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/terapia , Apnea Obstructiva del Sueño/complicaciones , Índice de Masa Corporal , Polisomnografía , Enfermedades Cardiovasculares/complicacionesRESUMEN
Hypothalamic obesity does not respond well to conventional interventions for obesity. GLP-1 receptor agonists have mechanisms independent of the hypothalamus which may be potentially beneficial for managing hypothalamic obesity. This systematic review summarizes the efficacy and safety of GLP-1 receptor agonists use in hypothalamic obesity. A PRISMA-compliant systematic review was performed. Data was extracted from included studies and analysed based on change in weight, body mass index, glycaemic control, satiety, and safety profile with GLP-1 receptor agonist use. Ten studies comprising 5 case reports, 4 case series and 1 randomized-controlled trial included 54 patients (24 males, 30 females) with mean age of 25.2 (range 13-71) years with hypothalamic obesity who had received GLP-1 receptor agonists (exenatide = 48, liraglutide = 5 and dulaglutide = 1) over a mean duration of treatment of 12 (range 3-51) months. Mean weight reduction of 7.4 (SD 7.92) kg was observed in patients in whom weight was reported, with 85.7% of patients experiencing weight loss. All patients on liraglutide had weight reduction post-therapy. The sole trial had reported a non-significant reduction in BMI post-exenatide. Glycaemic control had either improved/maintained in all patients in whom this was measured. The main side effects of GLP-1 receptor agonist in individuals with hypothalamic obesity were nausea and vomiting; there were no major safety concerns. Based on limited published experience, GLP-1RA may be effective and safe for weight control in hypothalamic obesity, with the added benefit of improved glycaemic control in those with concurrent diabetes mellitus.
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Exenatida , Receptor del Péptido 1 Similar al Glucagón , Liraglutida , Obesidad , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Índice de Masa Corporal , Exenatida/uso terapéutico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Hipoglucemiantes/uso terapéutico , Enfermedades Hipotalámicas/tratamiento farmacológico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Liraglutida/uso terapéutico , Obesidad/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Resultado del Tratamiento , Pérdida de Peso/efectos de los fármacosRESUMEN
BACKGROUND: Obesity and obesity-related morbidities are associated with poor psychosocial adjustment and health-related quality of life (HRQoL). This study aims to examine HRQoL and psychosocial outcomes in children with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO), and the effects of familial health on these outcomes. METHODS: Four hundred and six children with BMI for age ≥ 97th percentile were classified as having MHO and MUO based on the absence or presence of metabolic abnormalities. HRQoL and psychosocial outcomes were assessed using validated questionnaires such as PedsQL and DASS-21. RESULTS: There were no significant differences in HRQoL and psychosocial outcomes between children with MHO and children with MUO. Children with MUO and prior knowledge of existing metabolic conditions reported significantly lower total HRQoL (71.18 ± 17.42 vs. 75.34 ± 15.33), and higher depression (12.16 ± 11.80 vs. 8.95 ± 8.52) and stress (12.11 ± 8.21 vs. 10.04 ± 7.92) compared to children with MHO. Children with MUO who had fathers with metabolically unhealthy phenotype reported significantly lower total HRQoL (72.41 ± 15.67 vs. 76.82 ± 14.91) compared to children with MUO who had fathers with metabolically healthy phenotype. CONCLUSION: Prior knowledge of existing metabolic abnormalities was associated with poorer HRQoL and mental health in children with obesity. Paternal metabolic health status influenced HRQoL in children with MUO. IMPACT: First study that compared health-related quality of life (HRQoL) and psychosocial outcomes between children with metabolically healthy obesity (MHO) and children with metabolically unhealthy obesity (MUO). No significant differences in HRQoL and psychosocial outcomes between children with metabolically healthy obesity (MHO) and children with metabolically unhealthy obesity (MUO). Children with MUO who had prior knowledge of existing metabolic conditions reported lower HRQoL, higher depression and stress compared to children with MHO. Paternal metabolic health status was found to influence HRQoL in children with MUO. Mental health support intervention with paternal involvement should be provided for children with MUO.
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Síndrome Metabólico , Obesidad Metabólica Benigna , Humanos , Síndrome Metabólico/metabolismo , Calidad de Vida , Obesidad/complicaciones , Estado de Salud , Fenotipo , Índice de Masa Corporal , Factores de RiesgoRESUMEN
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.
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Diabetes Mellitus , Dislipidemias , Hipertensión , Enfermedad del Hígado Graso no Alcohólico , Obesidad Infantil , Niño , Adolescente , Humanos , Obesidad Infantil/complicaciones , Obesidad Infantil/diagnóstico , Obesidad Infantil/epidemiología , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/etiología , Dislipidemias/diagnóstico , Dislipidemias/epidemiología , Dislipidemias/etiología , Factores de RiesgoRESUMEN
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.
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Diabetes Mellitus Tipo 1 , Niño , Diabetes Mellitus Tipo 1/terapia , Ejercicio Físico , Hemoglobina Glucada , Humanos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. IMPACT: 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.
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Síndrome Metabólico , Obesidad Metabólica Benigna , Obesidad Infantil , Estado Epiléptico , Humanos , Obesidad Metabólica Benigna/diagnóstico , Obesidad Metabólica Benigna/epidemiología , Prevalencia , Obesidad Infantil/diagnóstico , Obesidad Infantil/epidemiología , Estudios Transversales , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Índice de Masa Corporal , Fenotipo , Factores de RiesgoRESUMEN
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.
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Diabetes Mellitus Tipo 2 , Síndrome de Prader-Willi , Adolescente , Adulto , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Control Glucémico , Humanos , Liraglutida/uso terapéutico , Síndrome de Prader-Willi/tratamiento farmacológico , Adulto JovenRESUMEN
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).
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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.
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Leucocitos , Obesidad Infantil , Telómero , Edad de Inicio , Asia/epidemiología , Niño , Humanos , Obesidad Infantil/epidemiología , Obesidad Infantil/genéticaRESUMEN
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 differ 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 coefficients (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 significantly 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 significant in all domains. Youth-father ICCs were significant only for Social (ICC = 0.428) and School (ICC = 0.303) domains. Girl-mother agreement was significant across all domains, while girl-father agreement was significant only in the Social domain (ICC = 0.653). Both mothers and fathers were poor raters for boys, and younger youths (aged ≤ 12), with non-significant 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.
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Obesidad/psicología , Padres/psicología , Apoderado/psicología , Calidad de Vida/psicología , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , AutoinformeRESUMEN
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 [L11,dW12,W23,Y36]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.
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Biomineralización/genética , Mutación/genética , Osteocondrodisplasias/genética , Proteína Relacionada con la Hormona Paratiroidea/genética , Receptor de Hormona Paratiroídea Tipo 1/genética , Adulto , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Two sisters with hirsutism presented with mild hirsutism and isolated, grossly elevated (>34.9nmol/L) serum concentrations of androstenedione measured by competitive, homogeneous immunoassay. The clinically discordant laboratory results prompted us to look for assay interference. In this immunoassay, horseradish peroxidase (HRP)-conjugated androstenedione competes with endogenous androstenedione for binding with the solid-phase polyclonal rabbit IgG antibodies. After a wash step, the amount of signal generated by the bound HRP conjugate is inversely proportional to the androstenedione concentration. Alternative analysis by tandem mass spectrometry (a good first line option for troubleshooting) and repeating the competitive immunoassay after polyethylene glycol treatment returned androstenedione concentrations within reference limits. These findings suggested that the original result was spuriously elevated due to assay interference. Additionally, the patient samples were pre-incubated with heterophile blocking reagents, normal rabbit IgG antibodies and HRP-conjugated normal goat IgG antibodies, followed by repeat measurement using the immunoassay. Only samples pre-incubated with HRP-conjugate returned significantly lower androstenedione (9.5 and 12.5nmol/L, respectively), implying neutralisation of the interfering antibodies. Androstenedione remained grossly elevated in the other experiments. This deductive exercise showed that the interference is due to autoantibodies against the HRP label used in the immunoassay. Another immunoassay using HRP label (5α-dihydrotestosterone) also produced gross elevation that was normal by tandem mass spectrometry analysis. Assay interferences, though not uncommon, are frequently overlooked. Laboratory results discordant with clinical features should prompt consideration of assay interference to avoid unnecessary investigations and treatment. This is the first report of autoantibodies against the HRP label used in immunoassay.
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Androstenodiona/aislamiento & purificación , Autoanticuerpos/inmunología , Hirsutismo/diagnóstico , Peroxidasa de Rábano Silvestre/inmunología , Inmunoensayo , Adolescente , Androstenodiona/sangre , Androstenodiona/inmunología , Autoanticuerpos/sangre , Niño , Femenino , Hirsutismo/sangre , Hirsutismo/inmunología , Peroxidasa de Rábano Silvestre/sangre , Peroxidasa de Rábano Silvestre/metabolismo , HumanosAsunto(s)
Absceso/etiología , Inyecciones/efectos adversos , Insulina/administración & dosificación , Infecciones por Mycobacterium no Tuberculosas/etiología , Mycobacterium fortuitum , Enfermedades Cutáneas Bacterianas/etiología , Niño , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Contaminación de Medicamentos , Contaminación de Equipos , Humanos , Masculino , Recurrencia , Factores de Riesgo , Microbiología del AguaRESUMEN
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.
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BACKGROUND: Visfatin is an adipokine associated with glucose and lipid metabolism. We previously reported two visfatin upstream single nucleotide polymorphisms (SNPs), c.-3187G > A (rs11977021) and c.-1537C > T (rs61330082), which were in perfect linkage disequilibrium, in a Singaporean cohort of severely obese children and are associated with visfatin level and adverse cardiometabolic parameters. We aim to functionally characterize the effect of c.-3187G > A and c.-1537C > T SNPs on basal transcriptional activity. METHODS: A 1.6 kb and 3.7 kb upstream promoter region of the visfatin gene was amplified by polymerase chain reaction and separately cloned into luciferase reporter vectors. Successful clones were transfected into human embryonic kidney (HEK293T) and human breast carcinoma (MCF7) cells and in-vitro dual-luciferase assay was performed. Electrophoretic mobility shift assay (EMSA) was also conducted to examine the binding affinity between transcription factors and visfatin promoter sequences. RESULTS: Variant promoter with only c.-1537C > T SNP did not show a change in transcriptional activity as compared to the wild type. However, variant promoter with both c.-3187G > A and c.-1537C > T SNPs showed a statistically significant increase of 1.41 fold (p < 0.01) in transcriptional activity. The longer 3.7kbp visfatin promoter sequence was also shown to have significantly higher transcriptional activity (p < 0.05) as compared to the shorter 1.6kbp visfatin promoter. Both c.-3187G > A and c.-1537C > T variants showed an increased binding with nuclear protein. DISCUSSION AND CONCLUSIONS: We have demonstrated for the first time that visfatin variant promoter with both c.-3187G > A and c.-1537C > T SNPs result in an increase in transcriptional activity. This supports our previous finding and postulation that these SNPs contribute to elevated visfatin levels which may mediate higher triglyceride levels, severe systolic blood pressure and severe hypertension in obese children. These SNPs may co-operatively affect enhancer or silencer function to regulate transcriptional activity. In conclusion, this study shows that upstream visfatin SNPs could potentially affect phenotypic outcome in obese children through alteration of circulating visfatin level.
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Predisposición Genética a la Enfermedad , Nicotinamida Fosforribosiltransferasa/genética , Obesidad/genética , Obesidad/metabolismo , Polimorfismo de Nucleótido Simple , Sitios de Unión , Biomarcadores , Línea Celular , Niño , Humanos , Nicotinamida Fosforribosiltransferasa/metabolismo , Regiones Promotoras Genéticas , Unión Proteica , Factores de Transcripción , Activación TranscripcionalRESUMEN
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.
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A 12-year-old girl presented to the Children's Emergency Department with symptoms of diabetes mellitus. Glutamic acid decarboxylase autoantibodies and anti-Islet cell antibodies were absent. She was also found to have ovarian dysgerminoma with markedly elevated serum ß-human chorionic gonadotropin (ß-HCG). With treatment of her ovarian tumor and normalization of the serum ß-HCG her insulin therapy was quickly discontinued and metformin started. The ovarian dysgerminoma appeared to have accelerated the presentation of severe diabetes. We hypothesized that the elevated ß-HCG and possibly other placental hormones from the germ cell tumor caused her to develop insulin resistance and inadequate ß-cell insulin secretory response.
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Diabetes Mellitus/etiología , Germinoma/complicaciones , Neoplasias Ováricas/complicaciones , Niño , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Femenino , Germinoma/sangre , Humanos , Resistencia a la Insulina , Neoplasias Ováricas/sangreRESUMEN
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.