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Context Ectopic posterior pituitary (EPP), a condition in which the posterior pituitary gland is displaced due to defective neuronal migration, is frequently associated with hypopituitarism. Genetic variants play a role, but many cases remain unexplained. Objective A large EPP cohort was studied to explore the importance of genetic variants and how they correlate with clinical findings. Methods Whole exome sequencing was performed on a discovery sample of 27 cases to identify rare variants. The variants that met the criteria for rarity and biological relevance, or that were previously associated with EPP (ROBO1 and HESX1), were then resequenced in the 27 cases plus a replication sample of 51 cases. Results We identified 16 different variants in 12 genes in 15 of the 78 cases (19.2%). Complete anterior pituitary deficiency was twice as common in cases with variants of interest compared to cases without variants (9/15 [60%] vs 19/63 [30.1%], respectively; Z test, P = 0.06). Breech presentation was more frequent in the variant positive group (5/15 vs 1/63; Z test, P = 0.003). Four cases had variants in ROBO1 and 1 in HESX1, genes previously associated with EPP. The ROBO1 p.S18* variant has not been reported previously; ROBO1 p.Q1227H has not been associated with EPP previously. Conclusion EPP cases with variants of interest identified in this study were more likely to present with severe clinical disease. Several variants were identified in genes not previously associated with EPP. Our findings confirm that EPP is a multigenic disorder. Future studies are needed to identify additional genes.

Background Childhood overweight and obesity are a global concern, with prevalence rising dramatically over the last decades. The condition is caused by an increase in energy intake and reduction of physical activity, leading to excessive fat accumulation, followed by systemic chronic inflammation and altered function of immune cell responses. This study aimed at providing new insights regarding sex-specificity on the inflammatory response to obesity in the young patient. Design Forty-three Brazilian obese adolescents (Female = 22 and Male=21, BMI (body mass index) Z-score average = 2.78 ± 0.51) and forty-nine eutrophic adolescents (Female = 24 and Male = 25, BMI Z-score average = −0.35 ± 0.88) were enrolled in the study. Anthropometrical analyses and blood cell counts were carried out. Using Luminex®xMAP™ technology, circulating serum cytokines, chemokines, and inflammatory biomarkers were analyzed. Two-way ANOVA test, Tukey’s test, and Spearman’s correlation coefficient were employed, with a significance threshold set at p Results We identified increased levels of serum amyloid A (SAA), platelets, and leukocytes solely in male obese patients. We found a noteworthy sex-dependent pattern in regard to inflammatory response: obese boys showed higher TNFβ, IL15, and IL2 and lower IL10 and IL13, while obese girls showed increased TNFα, CCL3, CCL4, and IP10 content in the circulation. BMI Z-score was significantly linearly correlated with neutrophils, leukocytes, platelets, SAA, TNFα, CCL3, CCL4, IP10, and IL13 levels within the entire cohort (non-sex-dependent). Conclusions Our data support a complex relationship between adiposity, blood cell count, and circulating inflammatory cytokine content. High SAA levels suggest that this factor may play a critical role in local and systemic inflammation. In the eutrophic group, females presented a lower status of inflammation, as compared to males. Both obese boys and girls showed an increased inflammatory response in relation to eutrophic counterparts. Taken together, results point out to clear sex dimorphism in the inflammatory profile of obese adolescents.

Background The intima-media thickness of the carotid artery (cIMT) and endothelial dysfunction are associated with cardiovascular (CV) disease. Objectives To evaluate the correlation between cIMT, brachial intraluminal diameter and flow-mediated vasodilation on the reactive hyperemia phase in adolescents with obesity with predictors of CV risk. Methods Seventy-three pubertal patients with overweight or obesity were evaluated (45 girls) with a mean (standard deviation [SD]) age of 12.9 (2.5) years. Patients underwent anthropometric measurements and had the lipid profile, oral glucose tolerance test (oGTT) and serum intercellular adhesion molecule-1 (sICAM-1) levels analyzed. The ratios of the waist circumference (WC)/height (WHtR) and triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C), homeostatic model assessment of insulin resistance (HOMA-IR), the Matsuda index and insulin area under the curve (AUC) were calculated. All patients were evaluated for cIMT and arterial blood flow velocity of the brachial artery. Results 75.3% of the patients had high cIMT values. We found a positive correlation between WHtR and cIMT (r = 0.233; p = 0.050). There was a positive correlation between sICAM-1 and insulin AUC (r = 0.323; p = 0.012) and WHtR (r = 0.258; p = 0.047). Patients with abnormal arterial dilation had higher sICAM-1 values (p = 0.02) despite having smaller WHtR (p = 0.046). Conclusions These adolescents with obesity had high cIMT values. Insulin resistance was associated with sICAM-1. Endothelial dysfunction was positively correlated with sICAM-1. There is no consensus about what the best laboratorial approach to evaluate insulin resistance in adolescents is, and the cutoff values of each method are arbitrary. So, as we saw earlier, the association between anthropometric data (WHtR) and ultrasound findings could be useful to evaluate the CV risk of these adolescents with obesity, because of its practical, direct and low-cost value.

Background: Ataxia-telangiectasia (A-T) is a DNA repair disorder characterized by changes in several organs and systems. Advances in clinical protocols have resulted in increased survival of A-T patients, however disease progression is evident, mainly through metabolic and liver changes. We aimed to identify the frequency of significant hepatic fibrosis in A-T patients and to verify association with metabolic alterations and degree of ataxia. Results: Dyslipidemia was observed in 16/25 (64%), diabetes in 4/22 (18%), insulin resistance in 5/17 (29%), hepatic steatosis in 13/20 (65%) and suggestive of significant hepatic fibrosis in 5/25 (20%). Patients in the group with significant hepatic fibrosis were older (pConclusions: A suggestive diagnosis of significant hepatic fibrosis was observed in 20% of A-T patients which was associated with changes in liver enzymes, ferritin, increased HOMA-AD and with severity of ataxia compared to patients without hepatic fibrosis.

To evaluate the effect of high-intensity interval training (HIT) on the cardiorespiratory performance and substrate oxidation pattern in insulin-resistant and insulin-sensitive obese adolescents. Methods: We recruited 25 obese adolescents in three schools, and trained them in six HIT sessions, comprising of six series at 100% and recovery at 50% peak velocity (Vpeak). For the evaluation, the participants were divided into two groups: insulin-resistant (IR, n = 12; HOMA index ≥3.16) and insulin-sensitive (IS, n = 13). All participants underwent cardiopulmonary and indirect calorimetry testing. We compared the effects of HIT before and after the intervention among the two groups. The data were analyzed using Student’s t and Mann–Whitney (intergroup comparisons) and Student’s t and Wilcoxon (pre- and post-training comparisons) tests; and Cohen’s d (influence of HIT). Results: There was a significant post-training increase in Vpeak, oxygen consumption (VO2), velocity (V), and heart rate (HR) at the exertion intensity at the first ventilatory anaerobic threshold (VAT1) in both groups (p < 0.05; d < 0.02). The exercise promoted changes in substrate oxidation rates of the groups, with an increase in carbohydrate oxidation (CHOox) for both IR (p = 0.064) and IS (p = 0.034). Conclusion: Six HIT sessions improved cardiorespiratory performance in both groups and increased CHOox in insulin-sensitive obese adolescents, suggesting its utility for increasing physical fitness and controlling glycemia in these population groups.

Objective: To describe the participation of the environment in the childhood obesity epidemic, since childhood obesity currently represents a great challenge, with high prevalence worldwide, including in Brazil. Data source: Survey of articles published in the last 10 years in PubMed, evaluating the interface between the environment and childhood obesity. Data synthesis: Recent studies show that the environment is very important in the etiopathogenesis of obesity and its comorbidities. Therefore, factors such as air pollution, exposure to chemical substances that interfere with the metabolism, excessive consumption of ultra-processed foods, changes in the intestinal microbiota, and sedentary lifestyle are associated with increased obesity, insulin resistance, type 2 diabetes, and changes in lipid metabolism. These factors have a greater impact on some stages of life, such as the first thousand days, as they affect the expression of genes that control the adipogenesis, energy expenditure, and the mechanisms for hunger/satiety control. Conclusions: Environmental aspects must be taken into account in the prevention and treatment of childhood obesity, both from the individual and the population point of view, with adequate and comprehensive public health policies.

Introduction: Ectopic posterior pituitary (EPP) is a malformation of the hypothalamic-pituitary region presented as a spectrum from isolated growth hormone deficiency (GHD) to multiple pituitary hormone deficiencies (MPHDs). Our goal was to establish whether the FAST1.2 protocol, which combines the FAST1 protocol with 3D-T2 DRIVE images, could identify the pituitary stalk (PS) and the regional anatomy more accurately. Methods: A retrospective study of 36 individuals with EPP and hypopituitarism and a control group of 78 individuals with eutopic posterior pituitary was conducted. All individuals were submitted to FAST1.2. The position and size of the pituitary lobes were described, and the presence/absence of the PS was confirmed. Results: FAST1 identified the PS in 19% of individuals with EPP, while FAST1.2 identified the PS in 67% (p < 0.001). In the FAST1.2 protocol, the PS was visible in all control individuals. All EPP patients with isolated GHD had visible PS in FAST1.2, while only 58.6% of MPHD cases had visible PS. The size of the anterior lobe and the anteroposterior length of the posterior pituitary were smaller in the EPP group versus controls (p < 0.001). We noticed a reduced anterior pituitary lobe in both diameters in MPHD patients (p < 0.05). Six patients acquired new pituitary hormone deficiencies not recognized at the time of MRI; in this group, only 1 patient had a PS not visible in FAST1.2. Discussion/Conclusion: The FAST1.2 protocol could prevent the misdiagnosis of idiopathic GHD in patients with short stature and could also be important in the progression to MPHD. The PS could be considered a predictor of hypopituitarism, but its use as an isolated indicator for the progression to MPHD is not recommended. Our results reinforce the use of the size of the anterior lobe as a predictor of hypopituitarism and a possible predictor of the degree of pituitary insufficiency. The FAST1.2 protocol could be used as an alternative to gadolinium administration, as a cheaper and faster method, while eliminating the potential risks associated with the administration of contrast media.

Approximately 10% of adolescents worldwide are overweight or obese, hence the urgent and universal need to elucidate possible mechanisms that lead to obesity in the adolescent population.We examined the hypothalamic metabolism and its relationship with physical development in obese and eutrophic adolescents.We performed a case-control study with 115 adolescents between 11 and 18 years of age, to compare obese (BMI z-score ≥ 2) and nonobese individuals (eutrophic controls; BMI z-score ≤ 1). The following hypothalamic metabolite ratios were examined as primary outcomes: glutamate/creatine (Cr), the sum of glutamate and glutamine/Cr, N-acetylaspartate (NAA)/Cr, myoinositol/Cr, and total choline/Cr (glycerophosphocholine + phosphocholine/Cr), quantified by magnetic resonance spectroscopy. BMI z-scores, pubertal status, and scores on the Yale Food Addiction Scale, the Binge Eating Scale, and the Child Depression Inventory were assessed as secondary outcomes. Pearson coefficients (r) or nonparametric Spearman correlation (rho) analyses were performed between hypothalamic metabolite ratios and other parameters, such as BMI z-scores, physical development, food habits, depression symptoms, and serum protein concentrations (cytokines, hormones, and neuropeptides).Adolescents with obesity showed a lower hypothalamic NAA/Cr ratio (0.70 ± 0.19) compared to their eutrophic counterparts (0.84 ± 0.20; P = 0.004). The NAA/Cr ratio was negatively correlated with BMI z-scores (r = -0.25; P = 0.03) and serum insulin (rho = -0.27; P = 0.04), C-peptide (rho = -0.26; P = 0.04), amylin (r = -0.27; P = 0.04), ghrelin (rho = -0.30; P = 0.02), and neuropeptide Y (r = -0.27; P = 0.04). Also, the NAA/Cr ratio was positively correlated with circulating IL-8 levels (rho = 0.26; P = 0.04).High BMI z-scores are associated with lower hypothalamic NAA/Cr ratios. The negative correlations found between the NAA/Cr ratio and serum cytokines, hormones, and neuropeptides suggest a broad cross-talk linking hormonal imbalances, neurohumoral alterations, and hypothalamic functions in adolescents with obesity.

Objective: Weight and height growth impairment is one of the most frequent manifestations in HIV‐infected children and may be the first sign of disease, being considered a marker of disease progression and an independent risk factor for death. The aim of this review is to evaluate the influence of antiretroviral therapy on the growth pattern of children and adolescents living with HIV/AIDS. Source of data: A non‐systematic review was carried out in the PubMed database, with the terms “HIV”, “Weight and height growth”, “ART” and “children”. The most relevant publications were selected. Data Synthesis: Antiretroviral therapy has significantly reduced morbidity and mortality in HIV‐infected children and is clearly associated with recovery of weight and height‐for‐age Z‐scores, especially when started early, in the asymptomatic child still without weight–height impairment. Therapeutic strategies involving the GH/IGF‐1 axis, especially for children with growth impairment, are still being studied. Conclusions: HIV‐infected children show early weight–height impairment; antiretroviral therapy improves the anthropometric profile of these children. Resumo: Objetivo: O acometimento do desenvolvimento pondero‐estatural é uma das manifestações mais frequentes nas crianças infectadas pelo HIV e pode ser o primeiro sinal de doença, é considerado um marcador de progressão para doença e um fator de risco independente para morte. O objetivo desta revisão é avaliar a influência da terapia antirretroviral no padrão de crescimento em crianças e adolescentes vivendo com HIV/Aids. Fonte dos dados: Foi feita uma revisão não sistemática na base de dados PubMed, com os termos “HIV”, “desenvolvimento pondero estatural”, “TARV” e “crianças”. Foram selecionadas as publicações mais relevantes. Síntese dos dados: A terapia antirretroviral reduziu substancialmente a morbimortalidade em crianças infectadas pelo HIV e está claramente associada à recuperação do escore‐z de peso e de estatura para idade, principalmente quando iniciada precocemente, na criança assintomática e ainda sem comprometimento pondero‐estatural. Estratégias terapêuticas que envolvem o eixo GH/IGF‐1, principalmente para crianças com comprometimento do crescimento, ainda estão em estudo. Conclusões: As crianças infectadas pelo HIV apresentam comprometimento pondero‐estatural precoce e a terapia antirretroviral melhora o perfil antropométrico dessas crianças. Keywords: HIV, Child, Growth, Antiretroviral therapy, Palavras‐chave: HIV, Criança, Crescimento, Terapia antirretroviral

Background Ectopic posterior pituitary (EPP) is a malformation of the hypothalamic-pituitary region. Our goal was to describe midline structural brain abnormalities in patients with EPP using a dedicated protocol (FAST1.2 protocol) of magnetic resonance imaging (MRI) to evaluate the hypothalamus and pituitary gland, highlighting their clinical-laboratory correlations. Methods A cross-sectional study of patients diagnosed with EPP, and a control group. All individuals were submitted to a dedicated MRI protocol called FAST1.2, which combines the FAST1 protocol developed by our group with 3D T2DRIVE imaging. Results We evaluated 36 individuals with EPP and 78 individuals as a control group. One patient had two posterior pituitary lobes, one inside the sella turcica and the other along the pituitary stalk; in five patients, the EPP was along the pituitary stalk; in 28 the EPP was at the infundibular recess of the third ventricle, and in two the EPP was hypothalamic. In the EPP group, eleven individuals had interhypothalamic adhesion (IHA), three septo-optic dysplasia, one a cerebellar malformation, and one a pineal cyst. We did not observe a higher frequency of severe hormonal deficiency or developmental delay in patients with IHA. In the control group, eleven patients had a pineal cyst, three pars intermedia cysts, one hydrocephalus, and one hypothalamic hamartoma. Conclusion FAST1.2 acquisition allows confident recognition of regional anatomy and recognition of midline structural abnormalities on T2DRIVE, particularly including the pituitary stalk and IHA, thereby making MRI acquisition faster with no need for intravenous contrast administration. We suggest that IHA could be associated with defects in neuronal migration, as might occur in patients with EPP.

Introdução: A obesidade infantil, além de fator de risco para outras doenças metabólicas, pode também alterar o crescimento e os padrões de puberdade. Objetivos: No sexo feminino, a obesidade é associada à antecipação da puberdade. No sexo masculino, existem poucos estudos e há divergências. Este estudo, assim, busca avaliar o crescimento e puberdade em crianças e adolescentes acima do peso. Métodos: Estudo retrospectivo, com análise de prontuários médicos de pacientes em idade pré puberal e puberal com sobrepeso ou obesidade. Os dados obtidos foram: peso, estatura (E), índice de massa corporal (IMC), circunferência abdominal (CA), e estadiamento puberal. Resultados: Não houve impacto da gravidade da obesidade na idade cronológica (IC) de entrada na puberdade ou na estatura. A estatura final média das pacientes do sexo feminino permaneceu dentro do alvo familiar, e a estatura final dos pacientes do sexo masculino permaneceu acima do padrão genético. Discussão: As pacientes do sexo feminino apresentam maior crescimento no período pré-púbere e menor crescimento durante a puberdade, fato consistente com estudos anteriores. Porém, essas pacientes não apresentam ganho de peso após a menarca, contrariando a literatura. Nos pacientes do sexo masculino, a gravidade do IMC não impactou a IC de entrada na puberdade, tendo este reduzido ao longo da puberdade. Em nenhum dos grupos houve perda de estatura final.

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified 7 variants, 4 of which are putatively damaging, in FAT2 and DCHS2 in 6 patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency, and 2 presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2–/– mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4–/– and Dchs1–/– mouse mutants, but all animal models displayed normal commitment to anterior pituitary cell types. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption., FAT and DCHS protocadherins are necessary for correct hypothalamic-pituitary development in mice and humans.

Objective: Childhood obesity is a growing concern as the World Health Organization (WHO) states that ~10% of adolescents worldwide are overweight or obese. This condition is the reflex of energy imbalance between the calories consumed and those expended. Sex-related responses associated with dyslipidemia, hormonal alterations, and neuro-humoral disruptions in childhood obesity are the focus of the present investigation.Methods: Ninety-two Brazilian adolescents were enrolled and divided between obese and eutrophic groups. Obesity was assessed using body mass index Z-score according to age and weight. Anthropometrical analyses, blood pressure, blood lipids, metabolism-regulating hormones, and neuropeptides were carried out.Results: Systolic blood pressure was higher in female and male patients with obesity. Obese females presented alterations in lipid profile and an augment of cardiovascular disease prediction ratios TC/HDL, TG/HDL, LDL/HDL, and VLDL/HDL. The levels of leptin, GIP, and neuropeptide showed sex-dimorphism in obesity. The obese adolescents presented increased levels of circulating insulin, c-peptide, amylin, glucagon, and GLP-1. Correlation analysis showed significant linearity between body mass index, blood pressure, lipids, lipoproteins, hormones, and neuropeptides content.Conclusions: Our data support an existing link associating hypertension, dyslipidemia, and neuro-hormonal imbalance in childhood obesity. We also described a sex-dependent pattern in childhood obesity-associated dyslipidemia and blood pressure in female patients with obesity solely.

Introduction: Childhood obesity is one of the main public health problems in Brazil and worldwide and is a risk factor for many other metabolic diseases. Furthermore, studies show that being overweight influences growth and puberty. Objectives: In females, being overweight is associated with the anticipation of puberty. However, in males, few studies have been done and they are controversial. Therefore, this study aimed to evaluate growth and puberty in overweight boys and girls. Methods: In this retrospective study, we analyzed the medical records of patients aged 5 to 19 years, overweight or obese, from the pediatric endocrinology clinic of the Irmandade de Misericórdia, Santa Casa de São Paulo. The data collected were: height (H) and weight, body mass index (BMI), expressed as z-scores (height SDS and BMI SDS, respectively). Pubertal staging was evaluated according to Tanner's criteria. Final height was considered when the growth rate was less than 2 cm/year and/or bone age was over 15 years. Results: Ninety girls were evaluated, with mean (SD) chronological age (CA) at puberty onset of 9.8 (1.2) years. Girls had higher stature compared to the family pattern, but their final height was equal to the genetic target. Eighty-two boys were evaluated, with a mean (SD) CA at puberty at 11.7 (1.2) years. Boys were above family height at the onset of puberty, but reduced height SDS during puberty evolution. There was a reduction in BMI SDS from beginning to end of puberty, different from what was observed in girls. Discussion: In this group evaluation, the onset of puberty occurred within the expected average age for a general population, in both genders, with no pubertal anticipation or delay being observed. Both groups showed taller stature compared to the familiar target at the beginning of puberty, however, they reached the end within the genetic pattern, suggesting that growth is accelerated in the prepubertal phase and then lowered during puberty. Furthermore, in girls, there was no difference between BMI SDS at the beginning and at the end of puberty, indicating that these patients do not show any worsening in weight after menarche. Boys, on the other hand, reduced BMI SDS during puberty, suggesting, therefore, that treatment should be individualized, since body composition is different according to gender.

Aromatase inhibitors (AIs) have been used to recover height loss due to their capacity to delay growth plate closure. Long-term studies describing final heights are needed to determine the efficacy and safety profiles of these drugs for the treatment of impaired growth. This study aims to identify the therapeutic efficiency of AIs in improve growth and to describe potential adverse effects during treatment. Retrospective data analysis of 96 adolescents, among which 22 patients already attained near-final height, were followed at outpatient clinics of two referral centers. Patients were all in puberty and present idiopathic decrease in predicted adult height. Patients were treated with Anastrozole (ANZ: 1 mg/day) or Letrozole (LTZ: 2.5 mg/day) with/without recombinant human growth hormone (0.05 mg/kg/day) for 1.0 to 3.5 years (2.1±1.2 years). Height gain, body mass index, lipid, liver enzyme, gonadotropins and testosterone levels were described before and at the end of treatment. Predicted adult height (PAH) and NF height were compared with the TH. The height SDS (adjusted to bone age) significantly increased (p

Objective: To evaluate the usefulness of elastography (using manual compression) as an additional diagnostic tool for children and adolescents with thyroid nodules. Materials and Methods: This was a prospective study conducted between September 2012 and August 2013 at a hospital in Brazil. We performed elastography, ultrasound, and fine-needle aspiration biopsy in 32 patients between 6 and 18 years of age who had, in total, 38 thyroid nodules. Results: The elastography findings correlated with the histopathological diagnosis in 78.5% of cases. In three patients, an unnecessary thyroidectomy could have been avoided if the elastography results had been prioritized. Only one malignant thyroid nodule was found to show high elasticity. Conclusion: Our results suggest that high elasticity of a nodule on elastography is associated with a low risk of thyroid cancer. If further confirmed in other studies, elastography may prove useful as a complementary test for screening thyroid nodules in children. Resumo Objetivo: Avaliar a utilidade da elastografia (usando compressão manual) como uma ferramenta adicional de diagnóstico em crianças e adolescentes com nódulos da tireoide. Materiais e Métodos: Este foi um estudo prospectivo realizado entre setembro de 2012 e agosto de 2013 em um hospital no Brasil. Realizamos elastografia, ultrassonografia e biópsia por aspiração com agulha fina em 32 pacientes com idade entre 6 e 18 anos que tinham, no total, 38 nódulos tireoidianos. Resultados: Os achados da elastografia em relação ao histopatológico foram corretos em 78,5% dos casos. A elastografia poderia ter evitado a tireoidectomia desnecessária de três pacientes. Apenas um nódulo maligno da tireoide foi classificado como E1. Conclusão: Nossos resultados sugeriram que a alta elasticidade de um nódulo na elastografia está associada a um baixo risco de câncer de tireoide. Caso se confirme em outros estudos, a elastografia pode ser útil como teste de triagem complementar de nódulos tireoidianos em crianças.

Clinical and laboratory diagnosis and treatment of central precocious puberty (CPP) remain challenging due to lack of standardization. The aim of this revision was to address the diagnostic and therapeutic features of CPP in Brazil based on relevant international literature and availability of the existing therapies in the country. The diagnosis of CPP is based mainly on clinical and biochemical parameters, and a period of follow-up is desirable to define the “progressive” form of sexual precocity. This occurs due to the broad spectrum of pubertal development, including isolated premature thelarche, constitutional growth and puberty acceleration, progressive and nonprogressive CPP, and early puberty. Measurement of basal and stimulated LH levels remains challenging, considering that the levels are not always in the pubertal range at baseline, short-acting GnRH is not readily available in Brazil, and the cutoff values differ according to the laboratory assay. When CPP is suspected but basal LH values are at prepubertal range, a stimulation test with short-acting or long-acting monthly GnRH is a diagnostic option. In Brazil, the treatment of choice for progressive CPP and early puberty is a long-acting GnRH analog (GnRHa) administered once a month or every 3 months. In Brazil, formulations of GnRHa (leuprorelin and triptorelin) are available and commonly administered, including 1-month depot leuprorelin 3.75 mg and 7.5 mg, 1-month depot triptorelin 3.75 mg, and 3-month depot leuprorelin 11.25 mg. Monthly or 3-month depot GnRHa are effective and safe to treat CPP. Arch Endocrinol Metab. 2016;60(2):163-72

Background: In 21-hydroxylase deficiency (21-OHD), there is an influence of genotype on the severity of external genitalia virilization. However, females carrying mutations predicting a similar impairment of enzymatic activity present a wide variability of genital phenotypes. In such cases, interindividual variability in genes related to the sex steroid hormone pathway could play a role. Objective: To evaluate the influence of POR, HSD17B5 and SRD5A2 variants on the severity of external genitalia virilization in 21-OHD females. Design and Patients: Prader stages were evaluated in 178 females with 21-OHD from a multicenter study. The 21-OHD genotypes were divided into two groups according to their severity: severe and moderate. The influences of the POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants on the degree of external genitalia virilization were analyzed. Results: The POR p.A503V, HSD17B5 c.-71A>G, HSD17B5 c.-210A>C, and SRD5A2 p.A49T and p.V89L variants were found in 25, 33, 17, 1, and 31% of the alleles, respectively. In uni- and multilinear regression, HSD17B5 c.-210A>C has a significant influence on the degree of external genitalia virilization. This variant was also identified with a higher frequency in the most severely virilized females. Conclusion: We demonstrated that a variant in the promoter region of HSD17B5 related to fetal androgen synthesis influences the genital phenotype in 21-OHD females.

Aims: To report false-negative normal growth hormone (GH) peak response in patients with ectopic posterior pituitary gland (EPP) identified with a simplified magnetic resonance imaging (FAST1-MRI). Methods: We analyzed 75 EPP patients with short stature and reduced growth velocity. Sagittal-T1 imaging (thickness: 2 mm and gap: 0.2 mm) without gadolinium administration was used. A GH peak of ≥5 ng/ml after clonidine or insulin stimulation was considered normal. Results: Normal GH response was observed in 15 of 75 (20%) patients [mean (SDS) peak = 8.2 (4.1) ng/ml]. Age at diagnosis [6.5 (3.0) years vs. 7.8 (4.1) years], gender (10 males/5 females vs. 44 males/16 females), pubertal stage (14 prepubertal/1 pubertal vs. 51 prepubertal/7 pubertal), and target height [-0.4 (0.6) vs. -0.4 (0.9)] were recorded. The perinatal history did not differ between responsive and nonresponsive patients. There was a trend to more frequent multiple hormone deficiency in nonresponsive when compared with responsive patients [3/15 (20%) and 31/60 (51.7%), respectively (p = 0.055)]. Height at diagnosis was lower in nonresponsive patients (p = 0.042). No significant difference in the IGF1 levels (p = 0.598) was observed between the groups. Conclusion: Normal GH values after stimulation tests do not exclude EPP-associated GH deficiency. A simplified fast acquisition sagittal-T1 MRI protocol investigation included at the initial diagnostic approach is able to prevent misdiagnosis of GH deficiency in patients with short stature.

The use of clinical cases in Medicine courses is traditionally tied to a complex, cumbersome manual process which usually requires time and effort to be carried on. Aiming to the optimization of such process, this paper presents a study of the applicability of a clinical cases-based computational evaluation system for Medicine courses. Such system includes the design, implementation and experimental application of evaluation tests for postgraduate students from healthcare area. It will be shown that the adoption of this computational system allowed the addition of new learning tools and features, and significantly reduced the work load required by the manual process, with satisfactory rates of acceptance by students and professors.

This paper presents the definition and validation of a set of 22 usability heuristics for electronic systems for the clinical cases-based learning assessment. They aims to contribute to improve the development of systems interfaces, always them to be used both in the definition of design as in usability inspection.

Background and Aims: Evaluate the nutritional status, plasma concentration of vitamin E and markers of cardiovascular risk in ataxia telangiectasia (AT) patients. Methods: Cross-sectional study with 13 patients with AT and 22 healthy controls, evaluating the following factors: nutritional status, food intake, lipid profile, plasma concentration of vitamin E, malondialdehyde and high sensitivity C-reactive protein, linking them with atherosclerosis risk in AT patients. Results: Average age was 14.6 in the AT group, 30.8% were malnourished and 23.1% had stunting. A greater impairment of lean body mass was found in these patients. Concentrations of triglycerides (TG), total cholesterol (CT), LDL-c, non-HDL cholesterol (NHDL-c) were significantly higher in patients and HDL-c, lower. Vitamin E/total lipids and vitamin E/TG ratios were lower in the AT group, and significant inverse correlation between these ratios and NHDL-c, CT/HDL-c, and LDL-c/HDL-c, log TG/HDL-c was observed in the AT group. Alanine aminotransferase correlated directly and significantly with NHDL-c, CT/HDL-c and LDL-c/HDL-c, in patients. Conclusion: The alterations of lipid metabolism biomarkers suggestive of atherosclerotic risk of male AT patients coupled with lower vitamin E/total lipids ratio and low lean body mass may complicate the clinical course of the disease and emphasizes the importance of multidisciplinary care, routine monitoring of cardiovascular biomarkers and appropriate nutritional guidance.

CAPES Foundation, Ministry of Education of Brazil, Brasilia DF, Brazil Background: Ataxia telangiectasia (A-T) is a neurodegenerative disease that leads to mitochondrial dysfunction and oxidative stress. Insulin resistance (IR), type 2 diabetes and the risk for development of cardiovascular disease was recently associated as an extended phenotype of the disease. We aimed to assess IR liver involvement carotid intima-media thickness (cIMT) and metabolic alterations associated to cardiovascular risk in A-T patients, and relate them with age. Results: Glucose metabolism alterations were found in 54.6% of the patients. Hepatic steatosis was diagnosed in 11/17 (64.7%) A-T patients. AST/ALT ratio > 1 was observed in 10/17 (58.8%). A strong positive correlation was observed between insulin sum concentrations with ALT (r = 0.782, p < 0.004) and age (r = 0.818, p = 0.002). Dyslipidemia was observed in 55.5% of the patients. The apolipoprotein (Apo-B)/ApoA-I ratio (r = 0.619 p < 0.01), LDL/HDL-c (r = 0.490 p < 0.05) and the Apo-B levels (r = 0.545 p < 0.05) were positively correlated to cIMT. Conclusions: Metabolic disorders implicated in cardiovascular and liver diseases are frequently observed in adolescent A-T patients and those tend to get worse as they become older. Therefore, nutritional intervention and the use of drugs may be necessary. Fed Univ São Paulo UNIFESP, Escola Paulista Med, Dept Pediat, Rua Otonis 725, BR-04025002 São Paulo, SP, Brazil ABC Fdn FMABC, Fac Med ABC, Dept Morphol & Physiol, Santo Andre, SP, Brazil Fed Univ São Paulo UNIFESP, Escola Paulista Med, Dept Diagnost Imaging, São Paulo, SP, Brazil Santa Casa São Paulo Sch Med Sci FCMSCSP, São Paulo, SP, Brazil Fed Univ Alfenas UNIFAL, Sch Nutr, Alfenas, MG, Brazil Fed Univ São Paulo UNIFESP, Escola Paulista Med, Dept Pediat, Rua Otonis 725, BR-04025002 São Paulo, SP, Brazil Fed Univ São Paulo UNIFESP, Escola Paulista Med, Dept Diagnost Imaging, São Paulo, SP, Brazil Web of Science

Purpose: The purpose of this study was to verify the correlation between neck circumference (NC) and body mass index (BMI) in children, and to determine NC percentiles for Brazilian children. Methods: The subjects of this cross-sectional study were students between the ages of 6 and 19 years from five schools in São Paulo, Brazil. Clinical and anthropometric data were collected from the students from April 2011 to June 2012. NC was measured at the level of the cricoid cartilage. We calculated Pearson correlation coefficients between NC and other indices of obesity with Sigma Stat 3.5. NC percentiles were produced using the LMS (lambda, mu, and sigma) method (STATA 12.0). Results: Among 2,794 students, 49.9% were male. NC was significantly correlated with age, BMI, waist circumference (WC), and body fat percentage (%BF). The NC of boys was greater than that of girls. The NC curves of smoothed 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles were constructed by age and sex. Conclusions: NC can be used in the assessment of obesity in childhood. There was a positive correlation between NC and BMI, WC and %BF. This study was the first to provide NC percentiles for children in Brazil.

Objectives: To correlate birth weight and current metabolic condition in overweight pubertals. Methods: A retrospective cross-sectional study of 125 pubertal patients (85 females / 40 males) with overweight, categorized into three groups according to birth weight (4000g). The following data were evaluated: chronological age, zBMI, Waist circumference (WC)/H, zHeight and lipid profile. Results: Low birth weight was observed in 16 patients (12.8%) and high birth weight in 15 (12.0%). At the time of the evaluation, the mean (SD) of the chronological age was 13.3 years (2.3), Body Mass Index z score (zBMI) + 2.60 (0.6), WC/height 0.59 (0.09), height z score + 0.44 (1.15) and HOMA-IR 4.37 (3.07), Glycemia 85.3 mg/dL(8.4), Insulin Sum 500.4 (306.4), Total Cholesterol 166 mg/dL (37.3), Low Density Lipoprotein (LDL) 100.5 mg/dL (28.9), High Density Lipoprotein (HDL) 41.4 mg/dL (8.8), triglycerides (TG) 119.8 (63.3) mg/dL and TG /HDL ratio 3.1 (1.97). There was only difference of the zBMI (p

Background: The onset of puberty is first detected as an increase in pulsatile secretion of gonado-tropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. Methods: We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. Results: We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. Conclusions: Deficiency of MKRN3 causes central precocious puberty in humans. Copyright © 2013 Massachusetts Medical Society.

Normal testosterone levels are frequently observed in women with androgenetic alopecia (AGA), suggesting the involvement of androgen sensitivity in this condition. Androgen sensitivity is related to androgen receptor (AR) messenger RNA (mRNA) production in hair follicles and is negatively related to the number of CAG repeats present in exon 1 of the AR gene. The aim of this study was to compare AR expression in AGA women with normal controls and to correlate this expression with the number of CAG repeats. Hair follicles were obtained from 27 women with AGA and 21 controls for AR gene expression analysis. AR expression was evaluated through AR mRNA quantification using real-time polymerase chain reaction and the number of CAG repeats in the AR gene was determined in complementary DNA samples obtained from hair follicles and analyzed with the Gene Scan software. AR mRNA in the frontal-parietal region was significantly higher than in the occipital region of AGA patients (paired t-test, P = 0.046). No significant difference was identified in controls (P = 0.67). Both regions in the same individual showed a significant positive correlation in AGA patients (r = 0.77; P < 0.05) and in controls (r = 0.91; P < 0.05). A negative correlation was identified between AR expression and the number of CAG repeats only in AGA patients (r = 0.510; P = 0.013). The identification of elevated AR mRNA quantitation in hair follicles is a useful tool for identifying potentially abnormal androgen sensitivity in AGA patients.

Background/aims Treatments for Graves' disease (GD) in children and adolescents include oral antithyroid drugs (ATDs), near total thyroidectomy, and radioactive iodine (RAI). ATDs remain the preferred choice in this age group, but because persistent remission occurs in 30% of cases, RAI is becoming a common option for definitive therapy. Methods We performed a review of 65 medical records of GD patients under age 19 years who were followed between 1985 and 2005. Results The prevalence of GD was higher in females (3:1) and during puberty (for both genders). If no remission was detected during ATD treatment, RAI was indicated when the following criteria were present: non-compliance, relapse, or side effects that were related to ATDs, large goiter, and long-term use of ATDs. The majority of patients developed hypothyroidism within 6 months after RAI. A progressive higher dose regimen was implemented in the last 10 years of the study period. A second RAI dose was necessary in eight cases. During the follow-up period, three pregnancies occurred. One patient with a thyroid nodule and benign cytology was detected. Conclusions RAI therapy is effective and safe in the treatment of GD in children and adolescents.

Turner syndrome (TS) is the complete or partial loss of the second sex chromosome, occurring in 1:5 000 girls. Early recognition allows appropriate therapy for short stature and puberty. Neonatal diagnosis of TS permits detection of associated malformations, minimizing sequels. Aiming to develop a molecular method for the diagnosis of TS we employed blood samples stored on filter paper. We evaluated 78 female controls, 25 TS girls with 45,X karyotype, and 32 TS patients with other karyotypes. After DNA extraction, samples were submitted to real-time PCR, using primers and probes directed to the study gene ARSE and to the control gene GAPDH. A ROC curve established the ARSE:GAPDH ratio with a cutoff value of 0.7. Low ARSE:GAPDH ratio of

Background/Aim: Healthy individuals present variable responses of the hypothalamic-pituitary-adrenal (HPA) axis induced by different patterns of physical training. The aim of this study was to evaluate whether prolonged low-grade physical training influences the HPA axis and also glucocorticoid receptor-α (GRα) mRNA levels in mononuclear cells of obese adolescents. Methods: We studied 19 patients with BMI above the 95th percentile (male:female ratio 7:12) aged from 9.5 to 15.5 years. Patients underwent a 12-week physical exercise program. Before and after exercise, in vivo glucocorticoid sensitivity was determined by employing a very-low-dose intravenous dexamethasone suppression test, and in vitro GRα mRNA levels were evaluated by quantitative real-time PCR. Results: After exercise there was a trend to reduce the in vivo glucocorticoid sensitivity (p = 0.071) and a significant increase in GRα mRNA levels (p = 0.025). Conclusion: For this subset of obese adolescents, prolonged low-grade physical training tended to reduce glucocorticoid sensitivity. The discrepancy of cortisol response to dexamethasone and the GRα mRNA measurement suggest a post-receptor phenomenon or should be related to target tissue-specific differences in glucocorticoid sensitivity. Future studies should address the adaptive GRα mRNA during different exercise protocols, and also the correlation of pituitary sensitivity with glucocorticoid target tissue sensitivity.

O tratamento da hiperplasia adrenal congênita (HAC) por deficiência da 21-hidroxilase forma clássica é habitualmente realizado com acetato de hidrocortisona. A hidrocortisona oral, em nosso meio, só está disponível em farmácias de manipulação. A prednisolona possui solução oral estável, comercialmente disponível, e tem como vantagem poder ser utilizada em dose única diária. O objetivo desse estudo foi comparar a eficácia da prednisolona aos resultados obtidos com o acetato de hidrocortisona. Foram estudados 15 pacientes, idade cronológica média (DP) de 7,2 anos (3,6), em dois períodos consecutivos de um ano, inicialmente utilizando a hidrocortisona (17,5 mg/m²/dia, divididos em três doses), seguida do uso de prednisolona (3 mg/m²/dia, dose única matinal). A avaliação dos tratamentos foi realizada por meio das variações do escore Z de estatura para idade cronológica (deltaZE), do escore Z de estatura para a idade óssea (deltaZEIO) e do escore Z do Índice de massa corporal (IMC) (deltaZIMC), bem como os valores da androstenediona em cada período. Não houve diferença na deltaZE, na deltaZEIO e na deltaZIMC entre os dois períodos, assim como nos valores de androstenediona. Concluiu-se que a prednisolona em dose única diária apresenta eficácia semelhante à obtida com a hidrocortisona utilizada três vezes ao dia, podendo ser considerada uma opção terapêutica nos pacientes com HAC por deficiência da 21-hidroxilase. Hydrocortisone acetate is usually employed in the treatment of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. In Brazil, however, oral hydrocortisone acetate is only available from manipulation pharmacies. Prednisolone has stable oral pharmaceutical formulations commercially available, with the advantage of a single daily dose. The aim of this study was to compare the efficacy of oral prednisolone and oral hydrocortisone in the treatment of CAH due to 21-hydroxylase deficiency. Fifteen patients with mean (SD) chronological age of 7.2 (3.6) years, were evaluated in two consecutive 1-year periods. In the first year, hydrocortisone (17.5mg/m²/day, divided in three doses) was used in the treatment, followed by the use of prednisolone (3 mg/m²/day, once in the morning) in the second year. The comparison between the two treatments was assessed after a one-year treatment period by: variation of height standard deviation score (SDS) (delta Height SDS), variation of height SDS according to bone age (delta BA SDS), variation of body mass SDS (delta BMI SDS) and serum levels of androstenedione. No significant difference was observed in relation to the delta Height SDS, delta BA SDS and delta BMI SDS. No significant difference was observed in the serum levels of androstenedione. We conclude that the efficacy of prednisolone administered once a day orally is comparable to the oral use of hydrocortisone three times a day. Oral prednisolone may be an option for patients with CAH due to 21-hydroxylase deficiency.

Background/Aim: In several populations, major histocompatibility complex and CTLA-4 (cytotoxic T lymphocyte antigen-4) gene polymorphisms are related to adult subjects with Graves’ disease (GD). Our aim was to study the association of +49A>G polymorphism of the CTLA-4 gene in Brazilian children and adults with GD and its correlation with clinical and laboratory markers of disease severity. Methods: CTLA-4 +49A>G polymorphism was established by polymerase chain reaction-restriction fragment length polymorphism analysis in 44 children and 72 adults with GD and compared to a stringent control group consisting of octogenarians with no history of thyroid disease; free T4 and T3 levels and T3/T4 ratio, antithyroid antibodies, and Graves’ ophthalmopathy were also evaluated according to genotype. Results: No significant difference was found in the frequency of CTLA-4 +49A>G polymorphism among children and adults with GD compared to controls and within groups. There was no significant correlation between the presence of G allele and Graves’ ophthalmopathy, gender, age at diagnosis, and biochemical markers of disease severity. Conclusion: The frequency of CTLA-4 +49A>G polymorphism is not different in children and adults with GD compared to the normal control population and does not seem to contribute independently to the severity of the clinical presentation of GD.

Approximately 10% of thyroid cancers are present in patients less than 21 years of age, representing 3% of all cancers of children and adolescents, with predominance in females 2:1 in relation to males. Thyroid cancers in this age group are usually papillary (90%), bilateral, multifocal and bigger in size compared to adults. Capsule invasion and lymphatic and pulmonary metastases are more frequent in children. Radiation sensitivity seems to represent an important factor in prepubertal patients. Familial history is reported in 5% of the cases. Genes such as RET/PTC, RAS and BRAF are usually involved in thyroid carcinogenesis in this age group. Cervical adenomegaly is a common clinical presentation, but does not represent a poor prognostic factor in children. Ultrasound and fine needle aspiration biopsy are valuable diagnostic procedures. Surgery is the preferred treatment including thyroidectomy and ganglionary excision, followed by ablative radioiodine therapy. L-thyroxine replacement with suppressive dosage should be employed targeting chronic TSH suppression. Long-term prognosis is usually better in children when compared with adults. Plasma thyroglobulin measurement is also useful to detect residual thyroid cancer disease.

Relative antiinflammatory and immunosuppressive potencies of glucocorticoids (GC) were previously well defined. Nonetheless, GC also regulate cell proliferation and programmed death (apoptosis). The aim of this study was to determine the relative potency of different GC on the modulation of cell survival. The GC-sensitive lymphoblast cell line CEM-c7/14 was submitted to 48h-exposure to GC (dose-response curve from 10-8 to 10-5M). Cell survival was analyzed employing the DimethylTiazol-Tetrazolium (MTT) test. For each GC at least 4 experiments were performed in quadruplicate. Responses to different GC at the same molarity were analyzed by ANOVA on Ranks. Cell responses to the same GC in different concentrations were tested by repeated measures ANOVA. The EC50 for each GC was calculated with the GraphPad Prism 3.0 software. The use of low concentrations (10-8 and 10-7M) of hydrocortisone and methylprednisolone determined a similar effects on cell survival, which was less prominent than that observed with betamethasone, budesonide or momethasone. Momethasone was the most potent GC, inducing the most intense dexamethasone reduction on cell survival at the lowest concentration (10-8M). Momethasone and methylprednisolone were the two GC with the strongest impact on cell survival. Our findings suggest that antiproliferative and apoptotic potencies of GC are different from those previously reported antiinflammatory and immunosuppressive actions. As potências antiinflamatória e imunossupressora dos glicocorticóides (GC) já foram bem estabelecidas previamente. No entanto, os GC também possuem atividade reguladora da proliferação celular e da morte celular programada (apoptose). O objetivo deste estudo foi determinar a potência relativa de diferentes GC na modulação da sobrevida celular. Linfoblastos cortico-sensíveis (linhagem celular CEM-C7/14) foram mantidos em cultura prolongada e submetidos ao tratamento com GC por 48h, em doses variando entre 10-8 e 10-5 molar. O índice de sobrevida celular foi quantificado pelo teste MTT (DimetilTiazol-Tetrezolium). Para cada GC avaliado, foram realizados pelo menos quatro experimentos em quadruplicata. A resposta celular aos diferentes GC foi analisada através do teste estatístico ANOVA on Ranks, enquanto a resposta ao mesmo GC em concentrações diferentes foi analisada pelo teste ANOVA for repeated measures. O EC50 de cada GC foi calculado utilizando-se o software GraphPad Prism 3.0. Durante o uso de concentrações baixas (10-8 e 10-7 molar), observou-se sobrevida semelhante dos linfoblastos após tratamento com hidrocortisona ou metilprednisolona. Nestas mesmas concentrações baixas, a sobrevida celular foi menor quando utilizou-se dexametasona, betametasona, budesonida ou mometasona. A mometasona e a metilprednisolona foram os dois GC que determinaram maior redução da sobrevida linfoblástica. Nossos resultados sugerem que as potências antiproliferativa e pró-apoptótica dos GC sejam diferentes dos efeitos antiinflamatórios e imunossupressores previamente estabelecidos para estes GC.

OBJETIVO: Avaliar a evolução antropométrica, terapia nutricional e mortalidade de crianças desnutridas hospitalizadas em centro de referência. MÉTODOS: Em estudo retrospectivo, avaliou-se 98 prontuários de crianças desnutridas (ZPIAIM:To study anthropometric development, nutritional support and mortality rate of malnourished children hospitalized in a referral center METHODS: In a retrospective study we surveyed 98 hospitalized malnourished children (ZW