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OBJECTIVE: In children born small for gestational age (SGA), the relationship between growth hormone (GH) treatment and insulin resistance (IR) has only been investigated for a short period, necessitating a longer observation period. This study aimed to evaluate the long-term (10 years) effect of GH to SGA-children on IR and safety during treatment. DESIGN: This was a multicenter observational study. PATIENTS: SGA-children who received GH treatment in Spain (stratified by Tanner-stage and age at GH onset [two groups: ≤6 years old or >6 years old]). MEASUREMENTS: The analysed variables (yearly measures) included auxologic, metabolic (insulin-like growth factor-1 (IGF-1), height velocity [HV], weight and homeostatic model assessment-IR [HOMA-IR]) and safety data. Data were collected prospectively (since the study approval: 2007) and retrospectively (since the initiation of GH treatment: 2005-2007). RESULTS: A total of 389 SGA children (369 Tanner-I) were recruited from 27 centres. The mean age (standard deviation) of the children at GH treatment onset was 7.2 (2.8) years old. IGF-1 (standard deviation score [SDS]) and HOMA-IR values tended to increase until the sixth year of GH-treatment, with significant differences being observed only during the first year, while these remained stable in the later years (within normal ranges). Height (SDS) increased significantly (basal: -3.0; tenth year: -1.13), and the maximum HV (SDS) occurred during the first year (2.75 ± 2.39). CONCLUSIONS: HOMA-IR values increased significantly in SGA-children during the first year of GH-treatment, remained stable and were within normal ranges in all cases. Our 10-year data suggests that long-term GH treatment does not promote IR and is well-tolerated, safe and effective.
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Estatura , Hormônio do Crescimento Humano , Resistência à Insulina , Fator de Crescimento Insulin-Like I , Criança , Pré-Escolar , Idade Gestacional , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional , Fator de Crescimento Insulin-Like I/metabolismo , Estudos RetrospectivosRESUMO
Early childhood is a critical period for obesity prevention. This randomized controlled study evaluated the effectiveness of an educational intervention preventing obesity in preschool-age children. A nutritional education intervention, with a follow-up session one year later, was conducted with parents of children aged 3 to 4 years of public schools in the province of Málaga. The main outcome variable was the body mass index z-score (zBMI). The prevalence of overweight or obesity was the secondary outcome variable. The sample comprised 261 students (control group = 139). Initial BMI, weight, height-for-age and prevalence of overweight and obesity were similar for both groups. After the first year of the intervention, the zBMI of the intervention group decreased significantly from 0.23 to 0.10 (p = 0.002), and the subgroup of patients with baseline zBMI above the median decreased from 1 to 0.72 (p = 0.001), and in the second year from 1.01 to 0.73 (p = 0.002). The joint prevalence of overweight and obesity increased in the control group (12.2% to 20.1%; p = 0.027), while in the intervention group, there were no significant changes. This preschool educational intervention with parents improved their children's BMI, especially those with a higher BMI for their age, and favored the prevention of overweight or obesity.
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Obesidade Infantil , Índice de Massa Corporal , Criança , Pré-Escolar , Educação em Saúde , Humanos , Sobrepeso/epidemiologia , Sobrepeso/prevenção & controle , Obesidade Infantil/epidemiologia , Obesidade Infantil/prevenção & controle , Instituições AcadêmicasRESUMO
Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; P < 0.0001). Seventeen individuals harbored a second heterozygous rare disruptive variant in CYP11A1 and two had very rare synonymous changes in trans (c.990G>A, Thr330 = ; c.1173C>T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an Escherichia coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G>A variant, plus the c.990G>A and c.1173C>T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted "benign" variant in CYP11A1 is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.
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BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is caused by NR0B1 (DAX1) gene mutations. Affected male children suffer from adrenal insufficiency, leading to a salt-wasting crisis in early infancy and hypogonadotropic hypogonadism in adulthood. OBJECTIVE: To characterize clinically and at the molecular level a cohort of Spanish patients with AHC. PATIENTS AND METHODS: Nine boys (from five families) with AHC were screened for NR0B1 mutations. Clinical and endocrine evaluations were recorded. RESULTS: NR0B1 gene mutations were found in all analyzed patients, one of them being novel (p.Gln305*). One patient presented with preserved hypothalamic-pituitary-gonadal axis. Salt-wasting episodes, delayed puberty, and hypogonadotropic hypogonadism were common, although no association was observed between AHC phenotype and genetic mutations. None of the patients has had descendants. CONCLUSIONS: AHC phenotype cannot be predicted based on genetic results as there is no definite genotype-phenotype relationship, including intrafamilial variability. Nevertheless, genetic testing for NR0B1 mutations is indicated if there is a suspicion of an X-linked adrenal insufficiency in order to proceed with the appropriate therapy and genetic counseling.
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Insuficiência Adrenal/genética , Receptor Nuclear Órfão DAX-1/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Adolescente , Insuficiência Adrenal/sangue , Hormônio Adrenocorticotrópico/sangue , Aldosterona/sangue , Criança , Pré-Escolar , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Testes Genéticos , Humanos , Hidrocortisona/sangue , Hipoadrenocorticismo Familiar , Lactente , Recém-Nascido , Masculino , LinhagemRESUMO
BACKGROUND: Recombinant human growth hormone (rhGH) availability has allowed the treatment of a greater number of growth disorders. It is important to get an insight into the clinical characteristics of the paediatric population before rhGH treatment. METHODS: An observational, retrospective and multicentre study was conducted to evaluate the patients' baseline characteristics prior to rhGH therapy. RESULTS: A total of 1404 patients (53.8% males) aged 0.5-17.3 years were included. Clinical conditions were as follows: GH deficiency (GHD), 66.0%; small for gestational age (SGA), 29.7%; and Turner syndrome (TS), 4.3%. Male gender was predominant in most growth disorders; age at diagnosis was higher in GHD patients; therapy with rhGH started at lower chronological age in SGA and TS groups. CONCLUSION: The baseline characteristics of the population to be treated with rhGH were similar to those reported in other growth databases. Delayed age at treatment initiation should increase the awareness of these disorders among general paediatricians and entice them to refer children suspected of having these disorders to a specialist.
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Atitude Frente a Saúde , Bases de Dados Factuais , Nanismo/tratamento farmacológico , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Síndrome de Turner/tratamento farmacológico , Adolescente , Estatura , Criança , Pré-Escolar , Nanismo/diagnóstico , Nanismo/epidemiologia , Feminino , Seguimentos , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/epidemiologia , Humanos , Lactente , Masculino , Prognóstico , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Espanha/epidemiologia , Síndrome de Turner/diagnóstico , Síndrome de Turner/epidemiologiaRESUMO
BACKGROUND: Childhood obesity has grown very fast over recent decades and now it represents a serious public health problem. The number of adipocytes is set in childhood and adolescence and then, an effective understanding of the development of adipose tissue during these periods will help in the prevention of this pathology. OBJECTIVES: The current study aimed to determine which adipose tissue characteristics are related to a high weight Z-score in childhood. PATIENTS AND METHODS: The current study included 82 children aged 5-130 months who underwent inguinal hernia surgery. Anthropometric variables were measured, and a nutritional and physical activity questionnaire was completed. Subcutaneous adipose tissue samples, taken during the operation, were analyzed for preadipocyte number, adipocyte volume, fatty acid composition (gas chromatography of FAME), and relative gene expression of various genes (real time PCR). RESULTS: The results showed that children with a higher weight Z-score spend more time in sedentary activities and less time running or involved in active games. SCD-1 activity index, arachidonic/linoleic index, and adipocyte volume were significantly higher in children with a weight Z-score greater than 0. The preadipocyte number and the genetic expression of the studied genes did not differ between the groups. A multiple regression analysis was done to determine which variables were related to the weight Z-score. R2 values indicated that the model which included adipocyte volume, SREBP-1c, SCD-1 expression, and activity index, predicted 59% of the variability in the weight Z-score among the children. The main variables associated with adipocyte volume were PPARγ, Adiponectin, CB1R expressions, as well as the SCD-1 activity and normalized weight. CONCLUSIONS: It was concluded that in childhood, the weight Z-score is related to adipocyte volume and adipose tissue gene expression.
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CONTEXT: Oestrogen induction of pubertal changes in Turner girls may reinforce their psychological well-being and may also optimise final height; however, oestrogen type, dose, and route are not well established. OBJECTIVE: To induce normal pubertal development in Turner girls and ovarian insufficiency with oral 17ß-oestradiol (E(2)), either as individualised dose (ID) or as fixed dose (FD), and to determine whether growth is affected. DESIGN: Open-label randomised, parallel groups, multicentre clinical trial in 48 GH-treated Turner girls. Oral E(2) was given in tablets, either as an ID of 5-15 µg/kg per day during 2 years or as a FD of 0.2 mg daily during the first year followed by 0.5 mg daily during the second year. Main outcome measures were the event of attaining a Tanner breast staging ≥4 (primary), FSH, and auxological variables (secondary). RESULTS: Shorter median time to Tanner staging ≥ B4 in the FD group (733 days) compared with the ID group (818 days) (P=0.046). Higher proportion of girls with Tanner staging ≥ B4 (65%) in the FD group compared with the ID group (42%) (P=0.068). Bone age did not show inadequate acceleration and adult height prediction was maintained in both groups. No oestrogen-related adverse events were reported. CONCLUSIONS: Two-year treatment with oral E(2) can progressively induce normal pubertal development in Turner syndrome. Low-dose oral E(2) given as a FD produces a satisfactory pubertal development not inferior to ID. Treatment was well tolerated and did not interfere with the growth-promoting effect of GH.
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Estradiol/administração & dosagem , Indução da Ovulação/métodos , Medicina de Precisão , Puberdade/efeitos dos fármacos , Síndrome de Turner/tratamento farmacológico , Administração Oral , Adolescente , Desenvolvimento do Adolescente/efeitos dos fármacos , Desenvolvimento do Adolescente/fisiologia , Estatura/efeitos dos fármacos , Estatura/fisiologia , Criança , Relação Dose-Resposta a Droga , Estradiol/efeitos adversos , Feminino , Humanos , Medicina de Precisão/métodos , Puberdade/fisiologia , Fatores de Tempo , Síndrome de Turner/fisiopatologiaRESUMO
OBJECTIVE: Couples at risk of severe congenital adrenal hyperplasia (CAH) may be offered prenatal treatment or preimplantation diagnosis. However, proper genetic counselling requires the accurate identification of apparently 'mild alleles' in partners of CAH-carriers/patients. METHODS: CYP21A2 gene analyses were performed in 255 patients with severe 21-hydroxylase deficiency (21-OHD), 94 with mild 21-OHD, 752 parental samples, 233 clinically unaffected partners and 253 historic DNA samples. GENSCAN and ClustalX2.0 software were used for in silico analyses, and Epidat 3.1 software for statistical calculations. RESULTS: Twenty-seven partners were carriers of p.Val282Leu (alias p.Val281Leu, allele frequency 11.7%, 7.4-16.1). 'Val282Leu alleles' were detected in 30 patients with salt-wasting (SW) disease, 21 with other pseudogene-derived and rare coding cis severe mutations, and 9 without. These CYP21A2 genes were compared to those of 94 fully characterized patients with mild deficiency carrying p.Val282Leu in compound heterozygosity with a severe allele. A rare intronic variant, c.292+5G>A, was detected in the nine 'severe Val282Leu alleles' and that was not seen in mild p.Val282Leu alleles, in other deficient alleles or in normal chromosomes. The in silico documented effect on splicing and the clinical association (p < 0.0001) confirmed p.Val282Leu; c.292+5G>A as a severe allele. CONCLUSION: As only severe alleles require clinical intervention, CAH-carrier detection of p.Val282Leu should be followed by the analysis of c.292+5G>A.
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Hiperplasia Suprarrenal Congênita/enzimologia , Heterozigoto , Diagnóstico Pré-Natal/métodos , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Alelos , DNA/química , DNA/genética , Feminino , Aconselhamento Genético , Variação Genética , Humanos , Recém-Nascido , Masculino , Repetições de Microssatélites , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy.