Apolipoprotein M gene polymorphisms in childhood-onset type 1 diabetes in southern Brazil.

Type 1 diabetes mellitus (T1DM), associated with autoimmune destruction of pancreatic ß cells, is observed in children and adolescents. OBJECTIVE: We investigated the potential association of the apolipoprotein M (APOM) polymorphisms rs707921, rs805264, rs805296, rs805297, and rs9404941 in childhood-onset T1DM (n = 144) and compared them to those in healthy (mostly Euro-Brazilian) children (n = 168). METHODS: This project was approved by the Ethics Committee of the Federal University of Parana (CAAE 24676613.6.0000.0102). Genotyping was performed using PCR-restriction fragment length polymorphisms (rs805296 and rs9404941) and TaqMan probes (rs707921, rs805264, and rs805297). RESULTS: All polymorphisms were in Hardy-Weinberg equilibrium. In the codominant model, no significant differences (P > 0.05) were observed in genotype and allele frequencies between healthy controls and children with T1DM. The minor allele frequencies (95% CI) for healthy subjects were rs707921 (A, 10.7%; 7-14%), rs805264 (A, 6.5%; 4-9%), rs805296 (C, 3.6%; 2-6%), rs805297 (A, 22.6%; 22-31%), and rs9404941 (C, 2.7%; 1-4%). The frequencies of the rs805297 A allele and rs805296 C allele were similar to those of other Caucasian populations; both the rs707921 and rs805264 A alleles were similar to American and Latin American populations, whereas that of the rs9404941 C allele was lower than that observed in the Caucasian and Asian populations. CONCLUSIONS: Haplotype analysis suggests that rs805297-C, rs9404941-T, rs805296-T, rs805264-G, and rs707921-C conferred risk (OR: 4.25; 95% CI: 1.81-10.1) to childhood-onset T1DM in the Euro-Brazilian population.

Cerebral Cortical Thickness Morphometry and Neurocognitive Correlations in Adolescents With Congenital Hypothyroidism.

CONTEXT: Subtle cognitive impairments have been described in children with congenital hypothyroidism (CH) detected by neonatal screening (NS), even with early and adequate treatment. Patients with CH may present with brain cortical thickness (CT) abnormalities, which may be associated with neurocognitive impairments. OBJECTIVE: This work aimed to evaluate the CT in adolescents with CH detected by the NS Program (Paraná, Brazil), and to correlate possible abnormalities with cognitive level and variables of neurocognitive prognosis. METHODS: A review was conducted of medical records followed by psychometric evaluation of adolescents with CH. Brain magnetic resonance imaging with analysis of 33 brain areas of each hemisphere was performed in 41 patients (29 girls) and in a control group of 20 healthy adolescents. CT values were correlated with Full-scale Intelligence Quotient (FSIQ) scores, age at start of treatment, pretreatment thyroxine levels, and maternal schooling. RESULTS: No significant difference in CT between patients and controls were found. However, there was a trend toward thinning in the right lateral orbitofrontal cortex among patients and in the right postcentral gyrus cortex among controls. CT correlated significantly with FSIQ scores and with age at start of treatment in 1 area, and with hypothyroidism severity in 5 brain areas. Maternal schooling level did not correlate with CT but was significantly correlated with FSIQ. Cognitive level was within average in 44.7% of patients (13.2% had intellectual deficiency). CONCLUSION: There was a trend toward morphometric alterations in the cerebral cortex of adolescents with CH compared with healthy controls. The correlations between CT and variables of neurocognitive prognosis emphasize the influence of hypothyroidism on cortical development. Socioeconomic status exerts a limiting factor on cognitive outcome.

Cognitive outcome of 458 children over 25 years of neonatal screening for congenital hypothyroidism.

OBJECTIVES: To describe the neurocognitive profile of 458 children with congenital hypothyroidism detected by neonatal screening, followed under the same treatment protocol over 25 years. To correlate estimated full-scale IQ (FSIQ) scores with age at the start of treatment, disease severity, and maternal education. METHODS: Observational, analytical, retrospective, and longitudinal cohort study, that evaluated children detected between 1991 and 2014, who underwent at least one psychometric assessment (WPPSI- R and/or WISC-III). Estimated FSIQ scores are described and correlated with prognosis determinants. RESULTS: Median T4 at diagnosis was 2.8 µg/dL (0.0-16.5), the median age at the start of treatment was 18.5 days (3-309). Maternal education (n = 445): 2.7% of illiteracy, 59.8% with basic education. Estimated FSIQ scores were 88.0 (±11.8) in WPPSI-R (age 5.6 ± 0.5 years) and 84.1 (±13.0) in WISC-III (age 9.1 ± 1.4 years). The intellectual deficit was identified in 11.6%. Correlation between age at the start of treatment and estimated FSIQ was found only in the WPPSI-R test (p = 0.02). Initial T4 and maternal education significantly correlated with estimated FSIQ scores in both tests, with the latter being the most important determining factor. CONCLUSIONS: In this large cohort of mainly low socioeconomic status children, most children achieved normal cognitive levels; however, a significant percentage presented with below-average estimated FSIQ scores and intellectual deficits. Maternal education was the main determining factor in cognitive level followed by hypothyroidism severity.

Cognitive outcome of 458 children over 25 years of neonatal screening for congenital hypothyroidism

Abstract Objectives: To describe the neurocognitive profile of 458 children with congenital hypothyroidism detected by neonatal screening, followed under the same treatment protocol over 25 years. To correlate estimated full-scale IQ (FSIQ) scores with age at the start of treatment, disease severity, and maternal education. Methods: Observational, analytical, retrospective, and longitudinal cohort study, that evaluated children detected between 1991 and 2014, who underwent at least one psychometric assessment (WPPSI- R and/or WISC-III). Estimated FSIQ scores are described and correlated with prognosis determinants. Results: Median T4 at diagnosis was 2.8 µg/dL (0.0-16.5), the median age at the start of treatment was 18.5 days (3-309). Maternal education (n = 445): 2.7% of illiteracy, 59.8% with basic education. Estimated FSIQ scores were 88.0 (±11.8) in WPPSI-R (age 5.6 ± 0.5 years) and 84.1 (±13.0) in WISC-III (age 9.1 ± 1.4 years). The intellectual deficit was identified in 11.6%. Correlation between age at the start of treatment and estimated FSIQ was found only in the WPPSI-R test (p = 0.02). Initial T4 and maternal education significantly correlated with estimated FSIQ scores in both tests, with the latter being the most important determining factor. Conclusions: In this large cohort of mainly low socioeconomic status children, most children achieved normal cognitive levels; however, a significant percentage presented with below-average estimated FSIQ scores and intellectual deficits. Maternal education was the main determining factor in cognitive level followed by hypothyroidism severity.

Vocal Characteristics of Children With Short Stature Before and After Growth Hormone Treatment.

OBJECTIVE: To evaluate the vocal characteristics of children with short stature before and 12 months after growth hormone treatment. MATERIAL AND METHODS: This analytical, observational cohort study included 23 children (age 5-11 years) diagnosed with short stature. Children in the short stature group (SSG) were matched (1:1) for age and sex with children with normal growth (normal stature group; NSG). Participants in the SSG underwent assessments before and 12 months after growth hormone treatment, while those in the NSG underwent the same assessments at baseline and 12 months. The assessments included evaluation of (A) vocal characteristics (history, vocal self-assessment, auditory-perceptual evaluation, and acoustic analysis), (B) anthropometry, (C) bone age, and (D) measurement of insulin-like growth factor-1 (IGF-1) levels. RESULTS: Children in the SSG had more vocal complaints (P = 0.026) than those in the NSG. The groups were similar in terms of vocal self-assessment and auditory-perceptual evaluation (P = nonsignificant). Results of acoustic analysis were also similar for fundamental frequency (F 0) and perturbation measures (P for both = nonsignificant). F 0 and speech frequency decreased significantly at 12 months in both groups. F1 values were higher at 12 months in the NSG, while F2 values were significantly higher in the baseline evaluation in boys in the SSG. Children in the SSG compared with those in the NSG presented a greater increase in height measurements at 12 months, although the anthropometric means were lower in both evaluations (P < 0.001). CONCLUSION: Vocal characteristics in children with short stature before and after treatment with growth hormone are comparable to those in children with normal growth.

Pubertal development and adult height in patients with congenital hypothyroidism detected by neonatal screening in southern Brazil.

Objectives Adequate treatment of congenital hypothyroidism (CH) is required for normal growth and sexual development. To evaluate pubertal development in patients with permanent CH detected by a statewide Neonatal Screening Program of Paraná and, secondly, to evaluate adult height (AH) in a subgroup of patients. Methods Clinical, laboratory, and auxological data obtained from medical records of 174 patients (123 girls). Results Median chronological age (CA) at treatment initiation was 24 days, and mean initial levothyroxine dose was 11.7 ± 1.9 µg/kg/day; mean CA at puberty onset was 11.5 ± 1.3 years (boys) and 9.7 ± 1.2 years (girls); mean CA in girls who underwent menarche (n=81) was 12.1 ± 1.1 years. Thyroid-stimulating hormone (TSH) values above the normal range were observed in 36.4% of the boys and 32.7% of the girls on puberty onset, and in 44.6% around menarche. Among 15 boys and 66 girls who had reached the AH, the median height z-score value was significantly greater than the target height (TH) z-score value in boys (p=0.01) and in girls (p<0.001). Boys with normal TSH values at puberty onset had greater mean AH z-score compared with boys with TSH values above the normal range (p=0.04). Conclusions In this group, pubertal development in girls with CH was not different from that reported in healthy girls in the general Brazilian population. Boys with higher TSH at puberty onset may have an increased risk of not reaching their potential height compared with those with normal TSH during this period. In a subgroup who attained AH, the median AH z-score was greater than the median TH z-score.

Bone mass and dietary intake in children and adolescents with type 1 diabetes mellitus.

OBJECTIVES: To evaluate the bone mineral density (BMD) in children/adolescents with type 1 diabetes mellitus (T1DM) and its association with the nutritional intake, metabolic control, and physical activity level of this population. METHODS: Study including 34 patients with T1DM and 17 controls. Assessments included the participants disease history, intake of macronutrient, calcium, phosphorus and magnesium, physical activity level, total body and lumbar spine BMD and serum levels of glycated hemoglobin, vitamin D, calcium, phosphorus, magnesium, osteocalcin and C-terminal telopeptide. RESULTS: Total body and lumbar spine BMD z-scores were normal in all but two participants in the T1DM group. The T1DM group had significantly lower total body BMD z-score values (p < 0.001) and levels of osteocalcin, C-terminal telopeptide, calcium, phosphorus, and magnesium. Intake of macronutrients and calcium was inadequate in both groups. Participants in the T1DM group were more sedentary (88%) and had inadequate metabolic control (91%) and low vitamin D levels (82%). Bone mass in the T1DM group was influenced by body mass index (BMI), pubertal stage, disease duration, calcium intake, and physical activity level. CONCLUSIONS: Bone mass in patients with T1DM was adequate but lower than controls and was influenced by BMI, pubertal stage, disease duration, calcium consumption, and physical activity level.

Influence of food consumption in the glycemic profile of children and adolescents with type 1 diabetes Mellitus / Influência do consumo alimentar no perfil glicêmico de crianças e adolescentes com diabetes Mellitus tipo 1

ABSTRACT Objective To review the dietary intake of children and adolescents with type 1 diabetes Mellitus and its association with the glycemic profile. Methods Longitudinal observational study. Dietary intake was measured using a three-day dietary record and the glycemic profile with a continuous glucose monitoring (range between 70 and 180mg/dL) and serum glycated hemoglobin levels (ideal <7.5%). Anthropometric data, insulin therapy, and carbohydrate counting were collected. Results The sample included 34 individuals with type 1 diabetes Mellitus aged 13.6±2.1 years. The majority of the population was eutrophic (76.4%). The entire sample used the basal-bolus insulin regimen, with mean insulin dose of 1.0±0.2U/kg/day; for 44.1% of the sample the carbohydrate counting method was used. Macronutrients intake was adequate in only 8.8% of the individuals, the highest frequency of inadequacy was related to carbohydrates (p=0.07). Inadequate glycemic control with hyperglycemia episodes and high mean glycated hemoglobin (9.7%) was observed in all individuals (61.3±18.5%). Carbohydrate counting was responsible for maintaining the percentage of time that the patient had interstitial blood glucose values within the range >40% (p<0.001) and maintaining the percentage of time in hyperglycemia <50% (p<0.001). Conclusion The majority of individuals were eutrophic, but presented inadequate dietary intake and glycemic control. The method of counting carbohydrates positively influenced the glycemic profile.

RESUMO Objetivo Analisar o consumo alimentar de crianças e de adolescentes com diabetes Mellitus tipo 1 e sua associação com o perfil glicêmico. Métodos Estudo observacional longitudinal. O consumo alimentar foi mensurado por meio de um registro alimentar de três dias, e o perfil glicêmico com um monitor contínuo de glicemia (alvo entre 70 e 180mg/dL) e de níveis séricos de hemoglobina glicada (ideal <7,5%). Foram coletados dados antropométricos, terapia insulínica e contagem de carboidratos. Resultados A amostra foi formada por 34 indivíduos com diabetes Mellitus tipo 1 com idade de 13,6±2,1 anos. A maior parte da população era eutrófica (76,4%). Toda a amostra utilizava o esquema de insulina basal-bolus, com dose média de 1,0±0,2U/kg/dia, e 44,1% realizava o método de contagem de carboidratos. O consumo dos macronutrientes estava adequado em apenas 8,8% dos indivíduos, sendo a maior frequência de inadequação nos carboidratos (p=0,07). Foram observados controle glicêmico inadequado com episódios de hiperglicemia em todos os indivíduos (61,3±18,5%) e média elevada de hemoglobina glicada (9,7%). A realização da contagem de carboidratos foi responsável por manter o percentual de tempo em que o paciente obteve valores de glicemia intersticial dentro do alvo >40% (p<0,001) e por manter o percentual de tempo em hiperglicemia <50% (p<0,001). Conclusão A maior parte dos indivíduos era eutrófica, porém apresentava consumo alimentar e controle glicêmico inadequados. O método de contagem de carboidratos influenciou positivamente o perfil glicêmico.

Associação do índice de massa corporal com absortometria de Raio-x de Dupla Energia (DEXA) em diabéticos tipo 1 / Asociación del índice de masa corporal con la absorciometría con rayos X de doble energía (DEXA) en diabéticos tipo 1 / Association of body mass index with dual energy X‐ray absorptiometry (DEXA) in type 1 diabetics

Introdução: Existem várias técnicas para avaliar a composição corporal, dentre elas o DEXA, porém apresenta alto custo. O índice de massa corporal (IMC) se apresenta como método mais utilizado. Entretanto, o mesmo apresenta limitações. Objetivo: Verificar a aplicabilidade de uma nova equação do IMC e associar com o absortometria de Raio-x de Dupla Energia (DEXA) em adolescentes com diabetes mellitus tipo 1. Métodos: Pesquisa intencional composta por 30 adolescentes (15 meninos e 15 meninas), com idades entre 10 e 15 anos. Foi avaliada a estatura e a massa corporal para a obtenção dos IMC2.5 e oIMC2 . O percentual de gordura foi obtido através do DEXA. A hemoglobina glicada foi verificada por meio do teste imunoturbidimétrico TurbiClin. Para análise dos dados foi realizada a média, desvio padrão e percentual de frequência. A correlação entre as variáveis dos IMC, DEXA e hemoglobina glicada, foi avaliada pelo coeficiente de correlação de Pearson. Adotou-se um nível de significância de p < 0,05. Resultados: A nova equação do IMC2.5 apresentou associação com IMC2.5 Escore Z (r=0,68; p=0,001), IMC2 (r=0,99; p=0,001), IMC2 Escore Z (r=0,67; p=0,001) e DEXA (r=0,58; p=0,05). Enquanto, o IMC2.5 Escore Z demonstrou associação positiva com oIMC2 (r=0,70; p=0,001) e IMC2 Escore Z (r=1,0; p=0,001). Conclusão: Para os adolescentes com diabetes mellitus tipo 1 tanto faz a equação utilizada para estimar o estado nutricional, pois a imprecisão de ambos os IMC continua a mesma para determinar percentual de gordura. O mesmo ocorre quando transformado em IMC2.5 escore Z, o nível de correlação continua semelhante(AU)

Introduction: There are several techniques to evaluate body composition, among them DEXA stands out, but presents a high cost. On the other hand, body mass index (BMI) is the most used method. However, it has limitations. Objective: To verify the applicability of a new BMI equation and to associate it with dual energy X‐ray absorptiometry (DXA) in adolescents with DM1. Methods: This research of intentional characteristics was composed of 30 adolescents (15 boys and 15 girls), aged between 10 and 15 years. Stature and body mass were evaluated to obtain BMI2.5and BMI2. The percentage of fat (percentBF) was obtained through DXA. The glycated hemoglobin (HbA1c) was verified by mean soft he TurbiClin immunoturbidimetric test. Descriptive statistics (mean, standard deviation and percentage of frequency) were used to analyze the data. The correlation between the variables (BMI, DXA and HbA1c) was evaluated by the Pearson correlation coefficient. We adopted a significance level of p < 0.05. Results: The new equation of BMI2.5 was associated with BMI2.5 Z score (r= 0.68, p= 0.001), BMI2 (r= 0.99, p= 0.001), BMI2 Z score (r= 0.67, p= 0.001) and DEXA (r= 0.58, p= 0.05). Meanwhile, BMI2.5 Z score showed a positive association with BMI2 (r= 0.70, p= 0.001) and BMI2 Z score (r= 1.0, p= 0.001). Conclusion: We can highlight that for adolescents with DM1, the equation used to estimate the nutritional status is the same, since the imprecision of both BMI remains the same to determine percent G. The same occurs when transformed into BMI2.5 Z score, the level of correlation continues similar(AU)

Introducción: Existen varias técnicas para evaluar la composición corporal, entre ellas destaca el DEXA, pero presenta alto costo. Por otro lado, el índice de masa corporal (IMC) se presenta como método más utilizado. Sin embargo, el mismo presenta limitaciones. Objetivo: Verificar la aplicabilidad de una nueva ecuación del IMC y asociarse con la absorciometría con rayos X de doble energía DEXA en adolescentes con DM1. Métodos: Esta investigación de característica intencional fue compuesta por 30 adolescentes (15 niños y 15 niñas), con edades entre 10 y 15 años. Se evaluó la estatura y la masa corporal para la obtención de los IMC2.5 y el IMC2. El porcentaje de grasa (por cientoG) se obtuvo a través del DEXA. La hemoglobina glucosa (HbA1c) se verificó mediante la prueba inmunoturbidimétrica TurbiClin. Para el análisis de los datos se realizó la estadística descriptiva (media, desviación estándar y porcentaje de frecuencia). La correlación entre las variables (IMC, DEXA y HbA1c) fue evaluada por el coeficiente de correlación de Pearson. Se adoptó un nivel de significancia de p < 0,05. Resultados: La nueva ecuación del IMC2.5 presentó asociación con IMC2.5 Escore Z (r= 0,68; p= 0,001), IMC2 (r= 0,99; p= 0,001), IMC2 Escore Z (r = 0,67; p = 0,001) y DEXA (r = 0,58; p = 0,05). Mientras que el IMC2.5 Escore Z demostró asociación positiva con el IMC2 (r = 0,70; p = 0,001) e IMC2 Escore Z (r = 1,0; p = 0,001). Conclusión: Podemos destacar que para los adolescentes con DM1 tanto hace la ecuación utilizada para estimar el estado nutricional, pues la imprecisión de ambos IMC continúa siendo la misma para determinar por cientoG. Lo mismo ocurre cuando se convierte en IMC2.5.

Impact of Growth Hormone Therapy on Adult Height in Patients with PTPN11 Mutations Related to Noonan Syndrome.

OBJECTIVES: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). MATERIALS AND METHODS: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). RESULTS: The pretreatment chronological age was 10.3 ± 3.5 years. Height-CDC SDS and height-NS SDS were -3.1 ± 0.7 and -0.5 ± 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11- patients. GV SDS increased from -1.2 ± 1.8 to 3.1 ± 2.8 after the first year of therapy in PTPN11+ patients, and from -1.9 ± 2.6 to -0.1 ± 2.6 in PTPN11- patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11- (0.6 ± 0.4 vs. 0.1 ± 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 ± 0.3 vs. 0.2 ± 0.2, respectively, p < 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were -2.1 ± 0.7 and 0.7 ± 0.8, respectively. The total increase in height SDS was 1.3 ± 0.7 and 1.5 ± 0.6 for normal and NS standards, respectively. CONCLUSIONS: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11- patients showed a poor response to rhGH. However, this PTPN11- group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11.

Applicability of the body adiposity index to estimate body fat in adolescents with type-1 diabetes mellitus / Aplicabilidade do índice de adiposidade corporal na estimativa do percentual de gordura de adolescentes com diabetes mellitus tipo 1

ABSTRACT The aim of the present study was to verify the level of concordance between Body Adiposity Index (BAI) and Dual-energy X-ray Absorptiometry (DEXA) in the evaluation of body fat percentage in adolescents with type-1 diabetes mellitus (DM1). The sample consisted of 34 adolescents (16 boys and 18 girls) aged 10-15 years. Height and hip circumference data were collected for BAI calculation, and fat percentage was evaluated using DEXA. The Shapiro Wilk test was used to verify data normality. The Wilcoxon test was performed to compare age, anthropometric and BMI, BAI z score and DEXA between sexes. The correlation of variables (BAI vs DEXA) was evaluated by the Spearman correlation coefficient. For the analysis of residual scores, the Bland-Altman test was applied. The Kappa coefficient (k) was performed to assess the level of concordance between BAI and DEXA. Therefore, weak and non-significant correlation between BAI and DEXA in boys (r= 0.19, p= 0.46), and girls (r= 0.10, p= 0.73) was observed. Thus, weak concordance was observed (k= 0.09) for both sexes. It was concluded that BAI is not recommended to estimate fat percentage in adolescents with DM1.

Resumo O objetivo do presente estudo foi verificar o nível de concordância entre o Absortometria de Raio-x de Dupla Energia (DEXA) na avaliação do percentual de gordura de adolescentes com diabetes mellitus tipo 1 (DM1). A amostra foi constituída por 34 adolescentes (16 meninos e 18 meninas) com idades entre 10 e 15 anos. Coletaram-se os dados de estatura e circunferência do quadril para cálculo do IAC, bem como avaliação do percentual de gordura via DEXA. O teste de Shapiro Wilk foi utilizado para verificar a normalidade dos dados. O teste de Wilcoxon foi realizado para comparar as variáveis de idade, antropométricas e IMC score Z, IAC e DEXA entre sexos. A correlação das variáveis (IAC vs DEXA) foi avaliada pelo coeficiente de correlação de Spearman. Para análise dos escores residuais aplicou-se o teste de Bland-Altman. O coeficiente de Kappa (k) foi realizado para avaliar o nível de concordância entre o IAC e DEXA. Sendo assim, foi encontrada correlação fraca e não significante entre IAC e DEXA tanto nos meninos (r=0,19; p=0,46), quanto nas meninas (r=0,10; p=0,73). Dessa forma, foi possível perceber concordância fraca (k= 0,09) para ambos os sexos. Conclui-se que o IAC não é recomendado para estimar percentual de gordura em adolescentes com DM1.

Phonological acquisition in children with early-treated congenital hypothyroidism: association with clinical and laboratory parameters.

PURPOSE: To evaluate the phonological characteristics of children with congenital hypothyroidism (CH). METHODS: Observational, analytical, cross-sectional, ambispective study including prepubertal children with CH (n=100; study group, SG) and controls without CH ( n=100; control group, CG). Assessments included a speech language pathology interview, the phonological evaluation of the ABFW Child Language Test, medical data, and neuropsychological tests in the first three years of life. RESULTS: On treatment onset of the SG, the median chronological age of the participants was 18.0 days and 48.4% had total T4 <2.5 µg/dL (31.75 nmol/L). At the age of 7 years, children in the SG had higher rates of consonant cluster simplification and lower rates of complete phonological system compared to those in the CG. On analysis of combined age groups (4+5 and 6+7 years), the CG had a higher frequency of complete acquisition versus the SG. On multivariate analysis, thyroid agenesis, abnormal scores on the Clinical Linguistic and Auditory Milestone Scale and developmental quotient tests were associated with the occurrence of phonological disorders. CONCLUSION: Children with CH present delay in phonological acquisition, despite early diagnosis and adequate treatment, especially between the ages of 6-7 years. The etiology of CH and the results of neuropsychological tests in the first years of life seem to be related to this delay.

Assessing the clinical and molecular diagnosis of inherited forms of impaired sensitivity to thyroid hormone from a single tertiary center.

AIM: Resistance to thyroid hormone (RTH), characterized by persistent hyperthyroxinemia with non-suppressed thyrotropin (TSH), is mostly caused by mutations in thyroid hormone receptor beta gene (THRB). Two differential diagnoses should be considered due to similar clinical and laboratory findings: TSH-producing pituitary adenoma (TPA) and Familial Dysalbuminemic Hyperthyroxinemia (FDH). The aim of this study is to describe our single tertiary center experience in the molecular diagnosis of RTH in Brazilian patients, analyzing their clinical and laboratory characteristics and the most common differential diagnosis. SUBJECTS AND METHODS: We enrolled 30 subjects with clinical and laboratory features of RTH. Patient´s evaluations included clinical examination, thyroid hormone profile and imaging tests. Sequencing analysis for THRB hot spot region was conducted on all patients, and those without mutations in beta isoform of the thyroid hormone receptor (TRß) (non-TR-RTH) were investigated for albumin gene (ALB) mutation. RESULTS: Seventeen patients presented mutations in TRß (RTHß); six were non-TR-RTH, three had a diagnosis of FDH with a mutation in ALB, and four were diagnosed with TPA. Two characteristics were different to what is commonly described in the literature: higher serum TSH levels in RTHß patients when compared to the non-TR-RTH group, but this difference did not extend to free T4 (FT4) level; also the percentage of non-TR-RTH was higher than what was reported in other series. CONCLUSION: In the present series, most cases were RTHß with higher levels of TSH. We described three novel mutations in THRB (p.M313V, p.R320G and p.R438P) and the first patients with FDH molecular diagnosis (p.R242H) documented in Brazil.

Resistance exercise alone improves muscle strength in growth hormone deficient males in the transition phase.

Background During the transition phase (TP), patients with growth hormone deficiency (GHD) exhibit decreased muscle strength. Studies assessing the effects of resistance exercise alone on muscle strength in these individuals are scarce. The objective of this study was to evaluate the effects of a program of resistance exercise (PRE) on parameters of muscle strength in subjects in the TP and with childhood-onset GHD treated with recombinant GH (rGH). Methods Sixteen male patients were enrolled and divided into two groups: GHD (n=9) and GH sufficiency (GHS, n=7). Patients with GHD underwent a 12-week PRE followed by another 12-week PRE plus rGH, while GHS patients underwent a 12-week PRE alone. Dynamic knee muscle strength was evaluated using an isokinetic dynamometer. Results Before PRE, there were significant differences between the groups regarding the results of flexor peak torque (FPT) normalized to body weight (BW-FPT) in the dominant (DO, p=0.008) and non-dominant (ND, p=0.01) limbs, and in the agonist/antagonist (A/A) ratio in the DO (p=0.02) and ND (p=0.006) limbs. After PRE in the GHD group, values of FPT and BW-FPT in both limbs increased significantly (p<0.001) and independently of rGH, while the A/A ratio value improved significantly (p<0.001) in the ND limb. Conclusions A short period of PRE alone was sufficient to improve parameters of muscle strength in young male adults with childhood-onset GHD.

Vocal Evaluation of Children with Congenital Hypothyroidism.

OBJECTIVE: To evaluate the vocal characteristics of a group of children with congenital hypothyroidism (CH) and the association of these characteristics with the children's clinical, laboratory, and therapeutic profiles. MATHERIAL AND METHODS: Observational, analytical, cross-sectional study including 200 prepubertal children, of whom 100 had CH (study group [SG]) and 100 had no CH (control group [CG]). The following parameters were evaluated: 1) history (identification, complaints, and interfering variables), 2) auditory-perceptual and acoustic evaluation (samples analyzed by a group of specialists, and objectively by a computer program), 3) self-assessment scores in the Pediatric Voice-Related Quality-of-Life (PVRQoL) survey, 4) laryngological evaluation (presence or absence of laryngeal lesions and data regarding glottal closure), and 5) medical records (CH etiology, age at treatment initiation, disease severity at diagnosis, treatment quality, and thyroid function tests on the day of the examination). RESULTS: In the perceptual assessment, 62.6% of the SG children passed, whereas 37.4% failed in the voice screening, but these results were comparable with those in the CG (P = 0.45). Both groups had mean/median acoustic measurements within the normal limits. The mean PVRQoL in the SG (99.3 ± 2.4) and CG (99.5 ± 1.7) were comparable (P = 1.00). Both SG (16.7%) and CG (15%) presented vocal cord lesions (P = 1.00). There was no association between voice/larynx characteristics and endocrinological data. CONCLUSION: Prepubescent children diagnosed with CH during neonatal screening and who have a lifelong history of adequate treatment of CH showed similar vocal and laryngeal characteristics compared with children without CH.

Phonological acquisition in children with early-treated congenital hypothyroidism: association with clinical and laboratory parameters / Aquisição fonológica em crianças com hipotireoidismo congênito precocemente tratado: associação com dados clínicos e laboratoriais

ABSTRACT Purpose To evaluate the phonological characteristics of children with congenital hypothyroidism (CH). Methods Observational, analytical, cross-sectional, ambispective study including prepubertal children with CH (n=100; study group, SG) and controls without CH ( n=100; control group, CG). Assessments included a speech language pathology interview, the phonological evaluation of the ABFW Child Language Test, medical data, and neuropsychological tests in the first three years of life. Results On treatment onset of the SG, the median chronological age of the participants was 18.0 days and 48.4% had total T4 <2.5 µg/dL (31.75 nmol/L). At the age of 7 years, children in the SG had higher rates of consonant cluster simplification and lower rates of complete phonological system compared to those in the CG. On analysis of combined age groups (4+5 and 6+7 years), the CG had a higher frequency of complete acquisition versus the SG. On multivariate analysis, thyroid agenesis, abnormal scores on the Clinical Linguistic and Auditory Milestone Scale and developmental quotient tests were associated with the occurrence of phonological disorders. Conclusion Children with CH present delay in phonological acquisition, despite early diagnosis and adequate treatment, especially between the ages of 6-7 years. The etiology of CH and the results of neuropsychological tests in the first years of life seem to be related to this delay.

RESUMO Objetivo Avaliar as características fonológicas de crianças com hipotireoidismo congênito (HC). Método Estudo observacional, analítico, transversal e ambispectivo que incluiu crianças pré-púberes com HC (n = 100, Grupo de Estudo, GE) e um grupo controle de crianças pré-púberes sem HC (n = 100, Grupo Controle, GC). As avaliações incluíram uma entrevista fonoaudiológica, avaliação fonológica por meio do teste de linguagem infantil ABFW, e coleta de dados nos prontuários referentes às avaliações médicas e testes neuropsicológicos realizados nos três primeiros anos de vida. Resultados Quanto ao início do tratamento no GE, a idade cronológica mediana dos participantes foi de 18,0 dias e 48,4% apresentaram T4 total <2,5 μg / dL (31,75 nmol / L). Na comparação da avaliação fonológica por idade, aos 7 anos as crianças no GE tiveram maior ocorrência de simplificação de encontros consonantais e menor ocorrência de sistema fonológico completo quando comparadas às crianças do GC. Na análise de grupos etários combinados (4 + 5 e 6 + 7 anos), observou-se que o GC teve aquisição completa do sistema fonológico mais precocemente. Na análise multivariada, agenesia da tireoide, resultados alterados nos testes Clinical Linguistic and Auditory Milestone Scale (CLAMS) e Developmental Quotient Tests (CDC) foram associados à ocorrência de desvios fonológicos. Conclusão Crianças com HC apresentam atraso na aquisição fonológica, mesmo com diagnóstico precoce e tratamento adequado, especialmente entre as idades de 6-7 anos. A etiologia do HC, bem como os resultados obtidos nos testes neuropsicológicos nos primeiros anos de vida, parecem ter relação com este atraso.

DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland.

Context: Thyroid dysgenesis (TD) is the leading cause of congenital hypothyroidism (CH). The etiology of TD remains unknown in ∼90% of cases, the most common form being thyroid ectopia (TE) (48% to 61%). Objective: To search for candidate genes in hypothyroid children with TE. Design, Setting, and Participants: We followed a cohort of 268 children with TD and performed whole-exome sequencing (WES) in three children with CH with TE (CHTE) and compared them with 18 thyroid-healthy controls. We then screened an additional 41 children with CHTE by Sanger sequencing and correlated the WES and Sanger molecular findings with in vitro functional analysis. Main Outcome Measures: Genotyping, mutation prediction analysis, and in vitro functional analysis. Results: We identified seven variants in the DUOX2 gene, namely G201E, L264CfsX57, P609S, M650T, E810X, M822V, and E1017G, and eight known variations. All children carrying DUOX2 variations had high thyroid-stimulating hormone levels at neonatal diagnosis. All mutations were localized in the N-terminal segment, and three of them led to effects on cell surface targeting and reactive oxygen species generation. The DUOX2 mutants also altered the interaction with the maturation factor DUOXA2 and the formation of a stable DUOX2/DUOXA2 complex at the cell surface, thereby impairing functional enzymatic activity. We observed no mutations in the classic genes related to TD or in the DUOX1 gene. Conclusion: Our findings suggest that, in addition to thyroid hormonogenesis, the DUOX2 N-terminal domain may play a role in thyroid development.

Physical exercise in type 1 diabetes: recommendations and care

Abstract - The management of type 1 diabetes mellitus (T1DM) is based on three pillars: insulin therapy, nutrition, and regular practice of physical activity. Physical exercises are associated with metabolic demands that depend on the individual's energy stores and level of physical conditioning, and vary according to environmental conditions and intensity, duration, and type of exercise. All these factors, added to eventual distress with competitions, exert influence on glucose metabolism. The athletic career of diabetic individuals is often hindered by a risk of hypoglycemia during and after the exercise, frequent hyperglycemia before, during, and after certain physical activities, occurrence of ketoacidosis, and presence of chronic microvascular and macrovascular complications. Aerobic exercises reduce the levels of blood glucose while anaerobic exercise may promote transient hyperglycemia. Although diabetic individuals may achieve excellence in sport, their physical performance should be maximized by strict blood glucose control, adequate modifications in insulin dose on the day of the exercise, and appropriate nutritional intake. This review discusses the impact of physical exercise on glucose metabolism, as well as nutritional considerations and strategies appropriate to the practice of physical exercises by patients with T1DM.

An Intron 9 CYP19 Gene Variant (IVS9+5G>A), Present in an Aromatase-Deficient Girl, Affects Normal Splicing and Is Also Present in Normal Human Steroidogenic Tissues.

BACKGROUND/AIMS: Splicing CYP19 gene variants causing aromatase deficiency in 46,XX disorder of sexual development (DSD) patients have been reported in a few cases. A misbalance between normal and aberrant splicing variants was proposed to explain spontaneous pubertal breast development but an incomplete sex maturation progress. The aim of this study was to functionally characterize a novel CYP19A1 intronic homozygote mutation (IVS9+5G>A) in a 46,XX DSD girl presenting spontaneous breast development and primary amenorrhea, and to evaluate similar splicing variant expression in normal steroidogenic tissues. METHODS: Genomic DNA analysis, splicing prediction programs, splicing assays, and in vitro protein expression and enzyme activity analyses were carried out. CYP19A1 mRNA expression in human steroidogenic tissues was also studied. RESULTS: A novel IVS9+5G>A homozygote mutation was found. In silico analysis predicts the disappearance of the splicing donor site in intron 9, confirmed by patient peripheral leukocyte cP450arom and in vitro studies. Protein analysis showed a shorter and inactive protein. The intron 9 transcript variant was also found in human steroidogenic tissues. CONCLUSIONS: The mutation IVS9+5G>A generates a splicing variant that includes intron 9 which is also present in normal human steroidogenic tissues, suggesting that a misbalance between normal and aberrant splicing variants might occur in target tissues, explaining the clinical phenotype in the affected patient.

Alterações fonoaudiológicas em crianças com hipotireoidismo congênito: revisão crítica da literatura / Speech language pathology disorders in children with congenital hypothyroidism: critic review of literature

O Hipotireoidismo Congênito (HC) é a doença endócrina congênita mais comum na infância e corresponde à deficiência de hormônios tireoidianos. Este artigo teve o objetivo de realizar uma revisão crítica da literatura, a respeito das possíveis alterações fonoaudiológicas relacionadas ao HC. Os descritores utilizados para a busca nas bases de dados eletrônicas PUBMED e MEDLINE foram: hypothyroidism OR congenital hypothyroidism AND voice OR hearing OR language. Foram incluídos estudos publicados até julho de 2011. As análises foram realizadas independentemente por dois dos pesquisadores, com posterior discussão e consenso sobre a inclusão. Dos 324 estudos localizados na análise inicial, apenas 20 compuseram a amostra final após o estabelecimento dos critérios de inclusão. Observou-se que há um número considerável de artigos sobre a linguagem de crianças com HC, embora com controvérsias no que se refere aos resultados das avaliações. Quanto à Audiologia, nos últimos anos houve uma redução no número de artigos que descrevem alterações auditivas em crianças com HC. Na área de Voz, foram localizados apenas dois artigos, que se referiram exclusivamente às anormalidades observadas no choro de bebês com HC. Embora com algumas constatações relevantes a respeito do assunto, a grande variabilidade metodológica das pesquisas não permite que se tenha uma conclusão clara sobre as possíveis alterações fonoaudiológicas em crianças portadoras de hipotireoidismo congênito na atualidade.

Congenital Hypothyroidism (CH) is the most common congenital endocrine disorder in childhood which corresponds to a deficiency of thyroid hormones. This article aimed to do a literature review about the Speech Language Pathology disorders that might be associated to HC. The keywords used for searching the electronic databases PUBMED and MEDLINE were: congenital hypothyroidism OR hypothyroidism AND hearing OR voice OR language. It was included studies published up to July 2011. Two researchers did the analyses, independently, with further discussion and consensus about the inclusion. Out of the 324 studies found in the preliminary analysis, only 20 of them were included in the final sample after establishing the criteria for inclusion. We observed that a great number of articles on the children language development on CH, but controversial ones, when it comes to the results of the evaluations. In Audiology, there has been a reduction in the number of articles that describe hearing loss in children who had CH. Only two papers were found about the voice, which referred exclusively to crying abnormalities in babies affected by CH. Although some findings were proven relevant to the subject, the great variability of the research methodology does not allow us to have a clear conclusion on the probable speech language pathology disorders in children with congenital hypothyroidism.