RESUMO
INTRODUCTION: Adolescent polycystic ovary syndrome (PCOS) is characterized by androgen excess and oligo-amenorrhea, and often results from ectopic lipid storage due to a mismatch between early adipogenesis and later lipogenesis. Endogenous HOX transcript antisense RNA (HOTAIR) and exogenous pioglitazone are enhancers of subcutaneous adipogenesis, particularly in the gluteofemoral region. The A allele of HOTAIR rs1443512 is an equivalent of a natural knock-down and is, thus, a candidate to influence the distribution of fat mass, and also the redistribution of fat mass by pioglitazone in adolescent PCOS-without-obesity. SUBJECTS AND METHODS: We performed two post hoc analyses by HOTAIR rs1443512 genotype. In the first, we analyzed the pooled pre-treatment data (auxology; endocrinology; body composition by dual X-ray absorptiometry; abdominal fat distribution by magnetic resonance imaging) of 65 adolescent girls with PCOS-without-obesity in three reported studies (ISRCTN45546616; ISRCTN29234515; ISRCTN11062950). In the second, we analyzed the results of 24 adolescent girls with PCOS-without-obesity, who received pioglitazone (7.5 mg/d for 1 year) as part of a randomized combination treatment (with spironolactone and metformin) in two reported studies (ISRCTN29234515; ISRCTN11062950). All data had been obtained in a blinded-to-genotype way. RESULTS: The pre-treatment data disclosed that the girls-with-A-allele of HOTAIR rs1443512 had developed PCOS with a lower BMI (22.3 ± 2.3 kg/m2; N = 17) than the other girls (24.1 ± 2.7 kg/m2; N = 48), this difference being essentially attributable to a lower fat mass (mean difference 4.6 kg; P < 0.01). On low-dose pioglitazone, girls-with-A-allele (N = 12) raised their fat mass while the other girls (N = 12) did not (total fat mass + 2.2 ± 1.8 kg vs - 0.9 ± 2.2 kg; P < 0.001), particularly in the gynoid area (gluteofemoral fat + 0.6 ± 0.4 kg vs - 0.1 ± 0.5 kg; hip circumference + 2.3 ± 1.9 cm vs - 1.7 ± 3.1 cm; both P < 0.001). CONCLUSION: The present findings suggest that the HOTAIR rs1443512 genotype influences not only the distribution of fat mass in adolescent girls with PCOS-without-obesity but also the redistribution of fat mass during prolonged treatment with low-dose pioglitazone. TRIAL REGISTRATION: ISRCTN45546616 ( https://doi.org/10.1186/ISRCTN45546616 ). ISRCTN29234515 ( https://doi.org/10.1186/ISRCTN29234515 ). ISRCTN11062950 ( https://doi.org/10.1186/ISRCTN11062950 ).
Assuntos
Metformina , Síndrome do Ovário Policístico , Feminino , Adolescente , Humanos , Síndrome do Ovário Policístico/tratamento farmacológico , Pioglitazona/uso terapêutico , Metformina/uso terapêutico , Obesidade/tratamento farmacológico , GenótipoRESUMO
A 3-month-old infant was examined for inconsolable crying with polydipsia, polyuria, and rapid weight gain. Unexpectedly, the symptoms resolved spontaneously during hospitalization but were aggravated 2 weeks after discharge, with the patient presenting a Cushingoid appearance. Investigations ruled out diabetes mellitus and nephrogenic diabetes insipidus but indicated adrenocortical suppression by exogenous glucocorticoids, which were discovered via toxicologic analysis of her previously compounded omeprazole suspension. After discontinuing the omeprazole suspension, the infant recovered fully and the laboratory results normalized. This case shows us that the assumption of appropriate medication intake may conceal unexpected medication errors. Following this case, the current literature on the benefits and risks of compounding and its impact on patient health is discussed.
Assuntos
Síndrome de Cushing , Diabetes Insípido Nefrogênico , Lactente , Feminino , Humanos , Criança , Glucocorticoides/efeitos adversos , Síndrome de Cushing/induzido quimicamente , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/complicações , Diabetes Insípido Nefrogênico/complicações , Diabetes Insípido Nefrogênico/diagnóstico , Polidipsia/diagnóstico , Doença IatrogênicaRESUMO
BACKGROUND: The sequence of prenatal growth restraint and postnatal catch-up growth leads to a thicker intima-media and more pre-peritoneal fat by age 3-6 years. OBJECTIVES: To study whether carotid intima-media thickness (cIMT) and pre-peritoneal fat differ already between catch-up small-for-gestational-age (SGA) infants and appropriate-for-gestational-age (AGA) controls in late infancy (ages 1 and 2 years) and whether such differences - if any - are accompanied by differences in cardiac morphology and function. METHODS: Longitudinal assessments included body height and weight; fasting glucose, insulin, Insulin-like growth factor (IGF-I), high-molecular-weight adiponectin; body composition (by absorptiometry); cIMT, aortic IMT, pre-peritoneal fat partitioning (by ultrasound); cardiac morphometry and function (by echocardiography) in AGA and SGA infants at birth, at age 1 year (N = 87), and again at age 2 years (N = 68). RESULTS: Catch-up SGA infants had already a thicker cIMT than AGA controls at ages 1 and 2 years, and more pre-peritoneal fat by age 2 years (all p values between <0.01 and <0.0001); all cardiac and endocrine-metabolic results were similar in AGA and SGA infants at ages 1 and 2 years. CONCLUSIONS: From late infancy onwards, catch-up SGA infants have a thicker cIMT and more pre-peritoneal fat than AGA controls, but their cardiac morphology and function remain reassuringly similar.
Assuntos
Gordura Abdominal/fisiologia , Espessura Intima-Media Carotídea/estatística & dados numéricos , Desenvolvimento Infantil/fisiologia , Coração/fisiologia , Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Adiponectina/sangue , Glicemia/fisiologia , Composição Corporal/fisiologia , Estatura , Peso Corporal , Pré-Escolar , Ecocardiografia/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Estudos Longitudinais , Masculino , Gravidez , Estudos ProspectivosRESUMO
Low birth weight followed by rapid postnatal weight gain is associated with increased risks for obesity and diabetes in adulthood. Modulation of glucagon-like-peptide 1 (GLP-1) secretion by (epi)genetic mechanisms or nutrition may, in part, influence this risk. Formula-fed infants born small-for-gestational-age (SGA) have higher circulating GLP-1 at age 4 months than breastfed SGA or appropriate-for-gestational-age (AGA) infants. Here we assessed GLP-1 concentrations in healthy AGA (n=149) and SGA (n=107) subjects at age 12 months and their association with endocrine-metabolic and body composition parameters and GLP-1 receptor (GLP-1R) rs6923761 and rs3765467 polymorphisms. At birth, cord GLP-1 concentrations were comparable in AGA and SGA infants. At age 12 months, insulin-like growth factor I (IGF-I) and GLP-1 levels were higher than at birth; SGA infants displayed higher IGF-I and GLP-1 concentrations than AGA infants (both P<0.001) that were unrelated to neonatal nutrition or GLP-1R genotype and that were paralleled by a significant increase in weight Z-score (P<0.001 vs AGA). In conclusion, SGA infants have augmented IGF-I and prefeeding GLP-1 concentrations in late infancy. Increased GLP-1 levels may impair hypothalamic and/or peripheral GLP-1R signaling, exert long-term negative effects on the hypothalamic nuclei regulating energy homeostasis and increase the risks for obesity and diabetes.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Recém-Nascido de Baixo Peso/metabolismo , Fator de Crescimento Insulin-Like I/análise , Estado Nutricional/fisiologia , Adulto , Aleitamento Materno , Feminino , Humanos , Lactente , Recém-Nascido de Baixo Peso/sangue , Recém-Nascido , Estudos Longitudinais , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
BACKGROUND/OBJECTIVES: It is well known that increased abdominal fat is associated with cardiovascular (CV) risk. Perirenal fat has been recently associated with CV risk in adults. However, studies with children are lacking. We investigated the relationship of perirenal fat and other abdominal fat depots (including preperitoneal, intra-abdominal and subcutaneous fat) with carotid intima-media thickness (cIMT-a surrogate marker of CV risk) in prepubertal children, so as to identify novel markers that can be easily assessed and used in the early prevention of cardiovascular disease. SUBJECTS/METHODS: Subjects were 702 asymptomatic prepubertal Caucasian children (418 lean, 142 overweight and 142 obese) who were recruited in a primary care setting. Ultrasound measurements (perirenal, preperitoneal, intra-abdominal and subcutaneous fat and cIMT), clinical (body mass index (BMI) and systolic blood pressure) and metabolic parameters (insulin resistance (HOMA-IR), high molecular weight (HMW) adiponectin and serum lipids) were assessed. RESULTS: Perirenal fat was associated with diverse metabolic and CV risk factors in all the studied subjects. However, in overweight and obese children, perirenal fat was mostly associated with cIMT (P<0.001) and was the only fat depot that showed independent associations with cIMT in multivariate analyses (overweight chidren: ß=0.250, P=0.003, r2=12.8%; obese children: ß=0.254, P=0.002, r2=15.5%) after adjusting for BMI, gender, age and metabolic parameters. Perirenal fat was also the only fat depot that showed independent associations with HMW-adiponectin in obese children (ß=-0.263, P=0.006, r2=22.8%). CONCLUSIONS: Perirenal fat is the main abdominal fat depot associated with cIMT, especially in overweight and obese children, and may thus represent a helpful parameter for assessing CV risk in the pediatric population.
Assuntos
Gordura Abdominal/diagnóstico por imagem , Espessura Intima-Media Carotídea/estatística & dados numéricos , Adiponectina/sangue , Pressão Sanguínea/fisiologia , Criança , Estudos de Coortes , Feminino , Humanos , Masculino , Obesidade/epidemiologia , Sobrepeso/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND AND OBJECTIVE: The sequence of prenatal growth restraint and postnatal catch-up growth may lead to hepato-visceral adiposity, insulin resistance and low-grade inflammation before the onset of puberty. In prepubertal children born appropriate for gestational age (AGA) or small for gestational age (SGA), we assessed potential relationships between the aforementioned sequence and liver volume. SUBJECTS/METHODS: The study population consisted of 86 children (41 AGA and 45 SGA with catch-up growth; age (mean±s.e.m.), 8.5±0.1 years), recruited into two prospective longitudinal studies. Anthropometry, endocrine-metabolic variables and inflammatory and hepatic markers were assessed, along with liver volume, hepatic adiposity and abdominal fat partitioning (by magnetic resonance imaging). RESULTS: AGA and SGA children differed in hepato-visceral adiposity, but had similar liver volumes. Boys had larger livers than girls, and higher sex hormone binding globulin and inflammation markers. Liver volume correlated with height Z-score, body mass index Z-score, HOMA-IR (homeostasis model assessment-insulin resistance) and with subcutaneous and visceral fat, but not with birth weight Z-score or with hepatic adiposity. Height, visceral fat, gender and HOMA-IR were major determinants of liver volume, together explaining 61% of its variance. CONCLUSIONS: The trajectory from prenatal restraint, via postnatal catch-up, to hepato-visceral adiposity and insulin resistance does not appear to be detectably influenced by prepubertal alterations of liver volume. Further follow-up will disclose the potential role of liver volume in the pubertal segment of this trajectory, and whether the augmented fat content and visceral adiposity in SGA subjects is followed by the development of metabolic syndrome and hepatic dysfunction in adulthood.
Assuntos
Fígado Gorduroso/patologia , Recém-Nascido Pequeno para a Idade Gestacional/fisiologia , Gordura Intra-Abdominal/patologia , Fígado/patologia , Obesidade Infantil/epidemiologia , Criança , Feminino , Gráficos de Crescimento , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Análise Multivariada , Sobrepeso/epidemiologia , Sobrepeso/patologia , Obesidade Infantil/patologia , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Telomere length at birth is a major determinant of telomere length in late adulthood. However, the prenatal setting of telomere length is poorly understood. Individuals born large from non-diabetic mothers are at lower risk for later-life disorders than those born small, a feature of their longer health span being a higher lean mass that provides more muscle strength and that is already present in infancy. METHODS: At birth, we studied leukocyte telomere length (by quantitative polymerase chain reaction) in 103 small-for-gestational-age, appropriate-for-gestational-age or large-for-gestational-age (SGA, AGA or LGA) infants born after uncomplicated, term, singleton pregnancies. All infants were breastfed for ≥4 months. At 2 weeks and 12 months, body composition was assessed by dual X-ray absorptiometry. RESULTS: Telomere lengths were shorter in SGA newborns and longer in LGA newborns than in AGA newborns (P < 0.001), also after adjustment for maternal age, pre-gestational body mass index, gestational weight gain and gestational age. Telomere length at birth associated (all P ≤ 0.001) to birthweight (r = 0.50) and to both lean mass (r = 0.43) and fat mass (r = 0.48) at age 2 weeks, but only to lean mass at 12 months (r = 0.51). CONCLUSION: Higher weight and longer telomeres at birth are followed by more lean mass in late infancy. Relatively large, breastfed infants from non-diabetic mothers may become models of how to make a healthy start.
Assuntos
Peso ao Nascer/genética , Composição Corporal/genética , Desenvolvimento Fetal/genética , Telômero/metabolismo , Absorciometria de Fóton , Peso ao Nascer/fisiologia , Composição Corporal/fisiologia , Índice de Massa Corporal , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Aumento de PesoRESUMO
OBJECTIVES: The aim of this paper is to test whether α-defensins and bacterial/permeability-increasing protein were related to obesity and cardiovascular risk factors in prepubertal children. METHODS: Plasma α-defensins and bacterial/permeability-increasing protein, body mass index (BMI), waist circumference, systolic blood pressure (SBP), carotid intima media thickness (cIMT), HOMA-IR and HMW-adiponectin were assessed. RESULTS: In a cross-sectional study (N = 250), higher α-defensins concentrations were positively associated with BMI, waist, SBP, cIMT, HOMA-IR and negative correlated with HMW-adiponectin (all between r = 0.191 and r = 0.377, p ≤ 0.01 and p ≤ 0.0001). Conversely, plasma bacterial/permeability-increasing protein concentrations presented inversed associated with the same parameters (all between r = -0.124 and r = -0.329; p ≤ 0.05 and p ≤ 0.0001). In a longitudinal study (N = 91), α-defensins at age 7 were associated with BMI (ß = 0.189, p = 0.002; model R2 = 0.847) and waist (ß = 0.241, pthinsp;= 0.001; model R2 = 0.754) at age 10. CONCLUSIONS: α-Defensins and bacterial/permeability-increasing protein may be the markers of childhood obesity. Increased concentrations of α-defensins may predict BMI and abdominal fat deposition in children.
Assuntos
Peptídeos Catiônicos Antimicrobianos/sangue , Doenças Cardiovasculares/sangue , Obesidade Infantil/sangue , alfa-Defensinas/sangue , Antropometria , Biomarcadores/sangue , Pressão Sanguínea , Proteínas Sanguíneas , Espessura Intima-Media Carotídea , Criança , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Fatores de RiscoRESUMO
OBJECTIVE: Macrophages are known to be involved in low-grade inflammatory processes such as obesity. soluble cluster of differentiation 163 (sCD163) is shed from the cell surface as specific macrophage activation marker. In prepubertal children, we studied if circulating sCD163 is associated with metabolic and cardiovascular risk markers. METHODS: A population of 236 school-aged Caucasian children (111 girls and 125 boys) aged 8 ± 1 year [81 normal weight (body mass index [BMI]-SDS < 1); 74 overweight (1 ≤ BMI-standard deviation score [SDS] < 2) and 81 with obesity (BMI-SDS ≥ 2)] were studied. BMI, waist circumference, fat mass and visceral fat were measured. Fasting serum sCD163, homeostatic model assessment of insulin resistance, high sensitivity C-reactive protein, gamma-glutamyl transpeptidase and lipids were quantified. RESULTS: Circulating sCD163 concentrations were higher in children with obesity (p < 0.0001). Associations were observed between circulating sCD163 and a less favourable metabolic profile as judged by higher waist circumference, fat mass, visceral fat, epicardial fat, homeostatic model assessment of insulin resistance, high sensitivity C-reactive protein, gamma-glutamyl transpeptidase and triglycerides (all between r = 0.173 and r = 0.363; p < 0.05 to p < 0.0001) and lower high-density lipoprotein-cholesterol (r = -0.285, p < 0.0001). In multiple regression analyses, circulating sCD163 was independently associated with HOMA-IR (ß = 0.162, p = 0.016; model R2 = 0.179) and high density lipoprotein-cholesterol/triglycerides ratio (ß = -0.167, p = 0.012; model R2 = 0.209). CONCLUSIONS: Childhood obesity may increase the risk of developing metabolic diseases later in life through chronic macrophage activation having deleterious effects on metabolism.
Assuntos
Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Ativação de Macrófagos , Metaboloma/fisiologia , Sobrepeso/sangue , Obesidade Infantil/sangue , Receptores de Superfície Celular/sangue , Adolescente , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Criança , Feminino , Humanos , Resistência à Insulina/fisiologia , Lipídeos/sangue , Masculino , Sobrepeso/complicações , Obesidade Infantil/complicações , Fatores de Risco , gama-GlutamiltransferaseRESUMO
BACKGROUND: Infants born small-for-gestational-age (SGA) who develop post-natal weight catch-up are at risk for insulin resistance, central adiposity and cardiovascular disease in later life, even in the absence of overweight. OBJECTIVE: In young (age 3-6 years) non-obese SGA children, we assessed arterial health (as judged by intima-media thickness [IMT]) and abdominal fat distribution (subcutaneous, visceral, preperitoneal and hepatic components by magnetic resonance imaging [MRI] and/or ultrasound [US]) besides a selection of endocrine markers. METHODS: Comparisons of measures in SGA (n = 27) vs. appropriate-for-GA (AGA) children (n = 19) of similar height, weight and body mass index. Longitudinal outcomes (age 3-6 years) were carotid IMT (cIMT); fasting glucose, circulating insulin, IGF-I and high-molecular-weight (HMW) adiponectin; abdominal fat partitioning by US. Cross-sectional outcomes (age 6 years) were aortic IMT (aIMT) and abdominal fat partitioning by MRI. RESULTS: At 3 and 6 years, cIMT and IGF-I results were higher and HMW adiponectin lower in SGA than AGA children; at 6 years, SGA subjects had also a thicker aIMT and more pre-peritoneal and hepatic fat, and were less insulin sensitive (all P values between <0.05 and <0.0001). cIMT correlated positively with pre-peritoneal fat, particularly at 6 years. Post-SGA status and weight gain in early childhood (between 3 and 6 years) were independent predictors of cIMT at 6 years, explaining 48 % of its variance. CONCLUSION: SGA children aged 3-6 years were found to have a thicker intima- media and more pre-peritoneal and hepatic fat than AGA children of comparable size.
Assuntos
Gordura Abdominal/fisiopatologia , Espessura Intima-Media Carotídea , Desenvolvimento Infantil , Obesidade Abdominal/fisiopatologia , Obesidade Infantil/fisiopatologia , Gordura Abdominal/diagnóstico por imagem , Adiponectina/sangue , Biomarcadores/sangue , Glicemia , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Aumento de PesoAssuntos
Acetato de Ciproterona/uso terapêutico , Etinilestradiol/uso terapêutico , Fatores de Crescimento de Fibroblastos/sangue , Flutamida/administração & dosagem , Hiperandrogenismo/tratamento farmacológico , Metformina/administração & dosagem , Tiazolidinedionas/administração & dosagem , Adolescente , Combinação de Medicamentos , Feminino , Hirsutismo/sangue , Hirsutismo/tratamento farmacológico , Hirsutismo/etiologia , Humanos , Hiperandrogenismo/sangue , Hiperandrogenismo/complicações , Hiperinsulinismo/sangue , Hiperinsulinismo/complicações , Hiperinsulinismo/tratamento farmacológico , Estudos Longitudinais , PioglitazonaRESUMO
BACKGROUND: Increased uric acid is an independent biomarker for cardiovascular disease in obese adolescents and adults. OBJECTIVE: We investigated whether uric acid relates to carotid intima-media thickness (cIMT) in prepubertal children, and whether body mass index (BMI) and preperitoneal fat modulate this association. METHODS: 359 asymptomatic prepubertal Caucasian children were stratified according to BMI categories (171 with BMI-SDS < 0; 188 with BMI-SDS ≥ 0) and according to preperitoneal fat levels (180 with preperitoneal fat <50th centile; 179 with preperitoneal fat >50th centile). Uric acid levels, insulin resistance (homeostasis model assessment insulin resistance; HOMA-IR), C-reactive protein (CRP), triacylglycerol (TG), systolic blood pressure (SBP), abdominal fat and cIMT (both by ultrasound) were assessed. RESULTS: Uric acid was associated with several cardiovascular risk factors, namely higher HOMA-IR, CRP, TG, BMI, waist, SBP, preperitoneal fat and cIMT (all P < 0.001 to P < 0.0001). Significant BMI and preperitoneal fat interactions were documented in the relationship between uric acid and cIMT (both P < 0.05), as uric acid was preferentially related to cIMT in heavier children (ß = 0.247, P < 0.001, r(2) = 9.1%) and in children with more preperitoneal fat (ß = 0.263, P < 0.0001, r(2) = 11.9%). CONCLUSIONS: Serum uric acid is associated with cIMT in asymptomatic prepubertal children. Both higher BMI and preperitoneal fat aggravate the potential risk of atherosclerotic disease imposed by higher concentrations of uric acid.
Assuntos
Biomarcadores/sangue , Composição Corporal/fisiologia , Doenças Cardiovasculares/fisiopatologia , Espessura Intima-Media Carotídea , Gordura Intra-Abdominal/fisiopatologia , Ácido Úrico/sangue , Pressão Sanguínea , Índice de Massa Corporal , Proteína C-Reativa , Criança , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Obesidade/fisiopatologia , Fatores de RiscoRESUMO
Prenatal growth restraint associates with the risk for later diabetes, particularly if such restraint is followed by postnatal formula-feeding (FOF) rather than breast-feeding (BRF). Circulating incretins can influence the neonatal programming of hypothalamic setpoints for appetite and energy expenditure, and are thus candidate mediators of the long-term effects exerted by early nutrition. We have tested this concept by measuring (at birth and at age 4 months) the circulating concentrations of glucagon-like peptide-1 (GLP-1) in BRF infants born appropriate-for-gestational-age (AGA; n=63) and in small-for-gestational-age (SGA) infants receiving either BRF (n=28) or FOF (n=26). At birth, concentrations of GLP-1 were similar in AGA and SGA infants. At 4 months, pre-feeding GLP-1 concentrations were higher than at birth; SGA-BRF infants had GLP-1 concentrations similar to those in AGA-BRF infants but SGA-FOF infants had higher concentrations. In conclusion, nutrition appears to influence the circulating GLP-1 concentrations in SGA infants and may thereby modulate long-term diabetes risk.
Assuntos
Aleitamento Materno , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipotálamo/fisiologia , Fórmulas Infantis , Plasticidade Neuronal/fisiologia , Adiponectina/metabolismo , Feminino , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Estudos Longitudinais , MasculinoRESUMO
BACKGROUND: KBG syndrome is a rare disorder characterized by intellectual disability and associated with macrodontia of the upper central incisors, specific craniofacial findings, short stature and skeletal anomalies. Genetic corroboration of a clinical diagnosis has been possible since 2011, upon identification of heterozygous mutations in or a deletion of the ANKRD11 gene. METHODS: We summarized the height data of 14 adults and 18 children (age range 2-16 years) with a genetically confirmed diagnosis of KBG syndrome. Two of these children were treated with growth hormones. RESULTS: Stature below the 3rd centile or -1.88 standard deviation score (SDS) was observed in 72% of KBG children and in 57% of KBG adults. Height below -2.50 SDS was observed in 62% of KBG children and in 36% of KBG adults. The mean SDS of height in KBG children was -2.56 and in KBG adults -2.17. Two KBG children on growth hormone therapy increased their height by 0.6 and 1 SDS within 1 year, respectively. The former also received a gonadotropin-releasing hormone agonist due to medical necessity. CONCLUSION: Short stature is prevalent in KBG syndrome, and spontaneous catch-up growth beyond childhood appears limited. Growth hormone intervention in short KBG children is perceived as promising.
Assuntos
Doenças do Desenvolvimento Ósseo/complicações , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Deficiência Intelectual/complicações , Anormalidades Dentárias/complicações , Anormalidades Múltiplas , Criança , Fácies , Transtornos do Crescimento/complicações , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND/OBJECTIVE: Fibroblast growth factor 19 (FGF19) and 21 (FGF21) have been linked to obesity and type 2 diabetes in adults. We assessed the circulating concentrations of these factors in human neonates and infants, and their association with the endocrine-metabolic changes associated to prenatal growth restraint. SUBJECTS/METHODS: Circulating FGF19 and FGF21, selected hormones (insulin, insulin-like growth factor I and high- molecular-weight (HMW) adiponectin) and body composition (absorptiometry) were assessed longitudinally in 44 infants born appropriate- (AGA) or small-for-gestational-age (SGA). Measurements were performed at 0, 4 and 12 months in AGA infants; at 0 and 4 months in SGA infants; and cross-sectionally in 11 first-week AGA newborns. RESULTS: Circulating FGF19 and FGF21 surged >10-fold in early infancy from infra- to supra-adult concentrations, the FGF19 surge appearing slower and more pronounced than the FGF21 surge. Whereas the FGF21 surge was of similar magnitude in AGA and SGA infants, FGF19 induction was significantly reduced in SGA infants. In AGA and SGA infants, cord-blood FGF21 and serum FGF19 at 4 months showed a positive correlation with HMW adiponectin (r=0.49, P=0.013; r=0.43, P=0.019, respectively). CONCLUSIONS: Our results suggest that these early FGF19 and FGF21 surges are of a physiological relevance that warrants further delineation and that may extend beyond infancy.
Assuntos
Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/sangue , Fatores de Crescimento de Fibroblastos/sangue , Obesidade/sangue , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Adulto , Composição Corporal , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Lactente , Recém-Nascido , Resistência à Insulina , Masculino , Obesidade/etiologia , Obesidade/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: Very low birth weight (VLBW) infants are at an increased risk of long-term cognitive impairment. Early identification and timely interventions are important. We aimed to validate the Dutch version of the revised Parent Report of Children's Abilities (PARCA-R) questionnaire. METHODS: The subjects were survivors from the Belgian participating centers to the NIRTURE trial. As part of a study-related follow-up, PARCA-R was sent out at the age of 2 years. As part of a normal hospital follow-up, these infants were assessed by the Bayley Scales of Infant Development - second edition (BSID-II) at the age of 9, 18 and 36 months. MRI was performed at term in the group of VLBW infants of ZOL Genk as standard care. RESULTS: PARCA-R was sent out to 193 surviving infants. BSID-II was performed in 36% (n=70) at 9 months, in 30% (n=58) at 18 months and in 12% (n=23) at 36 months. MRI was available for 32 infants. We received 86 responses to the PARCA-R. Parent report composite (PRC) scores were significantly correlated with the Mental Development Index (MDI) (p<0.0001 (9 months); p=0.003 (18 months); p=0.01 (36 months)). PRC scores were significantly lower in those with an abnormal MRI (92 vs.124; p=0.04). CONCLUSION: We support the use of the PARCA-R as a time and cost efficient alternative for identifying cognitive delay. PRACTICE IMPLICATIONS: We suggest that the combination of BSID-II, MRI at term and PARCA-R would be the ideal testing method for identifying VLBW infants at risk for cognitive developmental delay by two years of age.
Assuntos
Desenvolvimento Infantil , Deficiências do Desenvolvimento/diagnóstico , Recém-Nascido de muito Baixo Peso/psicologia , Inquéritos e Questionários , Pré-Escolar , Deficiências do Desenvolvimento/epidemiologia , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: The adaptive immune system has emerged as an unexpected modulator of insulin resistance. B lymphocytes accumulate in adipose tissue and produce pathogenic antibodies that cause insulin resistance. OBJECTIVE: We studied whether circulating immunoglobulins (IgG, IgA and IgM) were related to metabolic risk markers in pre-pubertal children with and without overweight. DESIGN AND METHODS: Subjects were 270 asymptomatic pre-pubertal Caucasian children (145 lean, 125 overweight) recruited in a primary care setting. Assessments included serum IgG, IgA and IgM concentrations (nephelometry), insulin resistance (HOMA-IR) and fasting lipids (triacylglycerol and high-density lipoprotein [HDL]-cholesterol). RESULTS: Overweight children had higher IgG and IgA serum levels than lean children (P ≤ 0.01). Increasing serum IgG and IgA, but not IgM, were associated with a less favourable metabolic phenotype, consisting of higher HOMA-IR and triacylglycerol and lower HDL-cholesterol, particularly in obese children, in whom serum IgG and IgA were both independently associated with HOMA-IR (ß = 0.308, P = 0.017, r2 = 9.5% and ß = 0.361, P = 0.005, r2 = 13.0%, respectively) and triacylglycerol (ß = 0.343, P = 0.006, r2 = 11.1% and ß = 0.354, P = 0.003, r2 = 12.2%, respectively). CONCLUSIONS: Increased circulating IgG and IgA in overweight children are associated with a less favourable metabolic phenotype, particularly in obese children. These results suggest a relationship between adaptive immunity and insulin resistance in childhood obesity.
Assuntos
Imunidade Adaptativa/imunologia , HDL-Colesterol/sangue , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Resistência à Insulina , Obesidade Infantil/sangue , Triglicerídeos/sangue , Índice de Massa Corporal , Criança , Feminino , Humanos , Resistência à Insulina/imunologia , Masculino , Obesidade Infantil/imunologia , Obesidade Infantil/prevenção & controle , Fenótipo , Fatores de Risco , EspanhaRESUMO
BACKGROUND: Maternal nutrition is the main source of Poly-Unsaturated Fatty Acids (PUFA) for the fetus. PUFA may influence the accumulation of fat in early life. OBJECTIVES & METHODS: In 33 breastfed infants born appropriate-for-gestational-age, we studied whether body composition (judged by absorptiometry at 2 wk and 4 mo) relates to PUFA levels (assessed by gas chromatography) in the maternal or fetal circulation at birth. RESULTS: Abdominal fat at 2 wk associated negatively to umbilical-cord levels of separate PUFA (linoleic, arachidonic, eicosapentanoic and docosahexaenoic acid; all P between 0.001 and 0.015). Collectively, the assessed n-6â PUFA on one hand and the n-3â PUFA on the other hand associated negatively to the absolute amount of abdominal fat (in grams; P = 0.001 and P = 0.002, respectively) and to the relative amount of abdominal fat (fraction of total fat; P = 0.001 and P = 0.006, respectively). No other significant associations were observed. CONCLUSION: In conclusion, newborns with lower levels of circulating PUFA were found to be abdominally more adipose. The mechanisms underpinning these associations remain to be determined.
Assuntos
Adiposidade , Ácidos Graxos Insaturados/metabolismo , Mães , Obesidade Abdominal/sangue , Efeitos Tardios da Exposição Pré-Natal/sangue , Adulto , Composição Corporal , Aleitamento Materno , Suplementos Nutricionais , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Fenômenos Fisiológicos da Nutrição Pré-NatalRESUMO
Three patients belonging to two families presented with a psychomotor-dysmorphism syndrome including postnatal growth deficiency and major spondylo-, epi-, and metaphyseal skeletal involvement. Other features were muscular hypotrophy, fat excess, partial growth hormone deficiency, and, in two of the three patients, episodes of unexplained fever. Additional investigations showed mild to moderate increases of serum transaminases (particularly of aspartate transaminase (AST)), creatine kinase (CK), and lactate dehydrogenase (LDH), as well as decreased coagulation factors VIII, IX, XI, and protein C. Diagnostic work-up revealed a type 2 serum transferrin isoelectrofocusing (IEF) pattern and a cathodal shift on apolipoprotein C-III IEF pointing to a combined N- and O-glycosylation defect. Known glycosylation disorders with similar N-glycan structures lacking galactose and sialic acid were excluded. Through a combination of homozygosity mapping and expression profiling, a deep intronic homozygous mutation (c.792 + 182G>A) was found in TMEM165 (TPARL) in the three patients. TMEM165 is a gene of unknown function, possibly involved in Golgi proton/calcium transport. Here we present a detailed clinical description of the three patients with this mutation. The TMEM165 deficiency represents a novel type of CDG (TMEM165-CDG). This disorder enlarges the group of CDG caused by deficiencies in proteins that are not specifically involved in glycosylation but that have functions in the organization and homeostasis of the intracellular compartments and the secretory pathway, like COG-CDG and ATP6V0A2-CDG.
RESUMO
OBJECTIVE: Shorter sleep duration predisposes to obesity, but the mechanisms whereby sleep deprivation affects body weight are poorly understood. We tested whether this association is modulated by the obesity genes FTO, TMEM18 and NRXN3. SUBJECTS: Body mass index (BMI), waist circumference, visceral fat (abdominal ultrasound), homeostasis model assessment for insulin resistance (HOMA-IR), systolic blood pressure (SBP) and sleep time per 24 h were assessed in 297 asymptomatic children (151 boys, 146 girls; age range 5-9 years; BMI s.d. score range -2.0-4.0). Associations between sleep duration and the abovementioned outcomes were tested for three common single-nucleotide polymorphisms (SNPs), namely FTO (rs9939609), TMEM 18 (rs4854344) and NRXN3 (rs10146997), as well as for their combination. RESULTS: TT homozygotes (but not A(*) carriers) for the FTO SNP, exhibited nominal associations between decreasing sleep duration and increasing BMI, waist circumference, visceral fat and HOMA-IR (all P<0.05). Similar associations were observed in children with risk alleles (but not in those without risk alleles) for the TMEM18 and NRXN3 SNPs (P<0.05 to P<0.0001). The three SNPs had additive effects on the negative associations between sleep and, respectively, BMI (P<0.001), waist (P<0.005), visceral fat (P<0.001), HOMA-IR (P=0.010) and SBP (P<0.0005). The combined effects on obesity measures and SBP remained significant after correction for multiple testing. On average, 2 h of sleep less per night was associated with an increase in BMI of 1.0 s.d. (95% confidence interval 0.5-1.6 s.d.) and with 8.0 cm (95% confidence interval 3.6-12.2 cm) more waist circumference in genetically susceptible children. CONCLUSION: By age 7, common variations in FTO, TMEM18 and NRXN3 influence the vulnerability to metabolic complications of sleep deprivation. Further genetic studies are warranted to replicate these findings in other populations.