Epistemologia e Currículo: registro do II Workshop de Filosofia e Ensino da UFRGS

O livro reúne textos apresentados no II Workshop de Filosofia e Ensino, realizado na UFRGS em 2015, com a temática "Epistemologia e Currículo

FATORES DE RISCO ENVOLVIDOS NA GÊNESE DO TRANSTORNO DO DÉFICIT DE ATENÇÃO E HIPERATIVIDADE: UMA REVISÃO BIBLIOGRÁFICA

ADHD is a common neuropsychiatric condition that negatively impacts several aspects of the development of affected individuals. The etiology of ADHD involves a complex interaction between genetic, neurobiological, and environmental factors, and understanding these influences is essential for developing more effective prevention and intervention strategies. Objective: This literature review aims to deepen the understanding of the risk factors involved in the genesis of ADHD in children and adolescents, exploring the influence of genetic, neurobiological, and environmental factors, as well as the interaction between them. Methodology: A scientific search was performed in databases such as PubMed/MEDLINE, Scopus, Web of Science and PsycINFO, using search terms related to ADHD, risk factors, etiology, and epidemiology. Original studies and bibliographic reviews published in indexed scientific journals were selected, addressing risk factors associated with ADHD in children and adolescents in the last 20 years. Results and Discussion: The review revealed that genetic factors play a significant role in predisposition to ADHD, with heritability estimates between 70% and 90%. Genomic studies have identified genes related to the dopaminergic system and brain development as important candidates in the etiology of the disorder. Additionally, environmental factors such as maternal smoking during pregnancy and alcohol consumption are associated with an increased risk of ADHD. Conclusion: This literature review reinforces the importance of an integrated approach that considers genetic, neurobiological, and environmental factors in the etiology of ADHD in children and adolescents.  El TDAH es una condición neuropsiquiátrica común que impacta negativamente en varios aspectos del desarrollo de los individuos afectados. La etiología del TDAH implica una interacción compleja entre factores genéticos, neurobiológicos y ambientales, y comprender estas influencias es esencial para desarrollar estrategias de prevención e intervención más eficaces. Objetivo: Esta revisión bibliográfica tiene como objetivo profundizar en la comprensión de los factores de riesgo involucrados en la génesis del TDAH en niños y adolescentes, explorando la influencia de factores genéticos, neurobiológicos y ambientales, así como la interacción entre ellos. Metodología: Se realizó una búsqueda científica en bases de datos como PubMed/MEDLINE, Scopus, Web of Science y PsycINFO, utilizando términos de búsqueda relacionados con TDAH, factores de riesgo, etiología y epidemiología. Se seleccionaron estudios originales y revisiones bibliográficas publicadas en revistas científicas indexadas, que abordaran factores de riesgo asociados al TDAH. Resultados y Discusión: La revisión reveló que los factores genéticos juegan un papel importante en la predisposición al TDAH, con estimaciones de heredabilidad entre 70% y 90%. Los estudios genómicos han identificado genes relacionados con el sistema dopaminérgico y el desarrollo cerebral como candidatos importantes en la etiología del trastorno. Además, los factores ambientales como el tabaquismo materno durante el embarazo y el consumo de alcohol están asociados con un mayor riesgo de TDAH. Conclusión: Esta revisión de la literatura refuerza la importancia de un enfoque integrado que considere factores genéticos, neurobiológicos y ambientales en la etiología del TDAH en niños y adolescentes.O TDAH é uma condição neuropsiquiátrica comum que impacta negativamente diversos aspectos do desenvolvimento dos indivíduos afetados. A etiologia do TDAH envolve uma complexa interação entre fatores genéticos, neurobiológicos e ambientais, e compreender essas influências é essencial para o desenvolvimento de estratégias de prevenção e intervenção mais eficazes. Objetivo: Esta revisão bibliográfica tem como objetivo aprofundar a compreensão dos fatores de risco envolvidos na gênese do TDAH em crianças e adolescentes, explorando a influência dos fatores genéticos, neurobiológicos e ambientais, bem como a interação entre eles. Metodologia: A busca científica foi realizada em bases de dados como PubMed/MEDLINE, Scopus, Web of Science e PsycINFO, usando termos de busca relacionados ao TDAH, fatores de risco, etiologia e epidemiologia. Foram selecionados estudos originais e revisões bibliográficas publicados em periódicos científicos indexados, abordando fatores de risco associados ao TDAH em crianças e adolescentes nos últimos 20 anos. Resultados e Discussão: A revisão revelou que os fatores genéticos têm um papel significativo na predisposição ao TDAH, com estimativas de herdabilidade entre 70% e 90%. Estudos genômicos identificaram genes relacionados ao sistema dopaminérgico e ao desenvolvimento cerebral como candidatos importantes na etiologia do transtorno. Além disso, fatores ambientais, como tabagismo materno durante a gravidez e consumo de álcool, estão associados a um maior risco de TDAH. Conclusão: Esta revisão bibliográfica reforça a importância de uma abordagem integrada que considere os fatores genéticos, neurobiológicos e ambientais na etiologia do TDAH em crianças e adolescentes.O TDAH é uma condição neuropsiquiátrica comum que impacta negativamente diversos aspectos do desenvolvimento dos indivíduos afetados. A etiologia do TDAH envolve uma complexa interação entre fatores genéticos, neurobiológicos e ambientais, e compreender essas influências é essencial para o desenvolvimento de estratégias de prevenção e intervenção mais eficazes. Objetivo: Esta revisão bibliográfica tem como objetivo aprofundar a compreensão dos fatores de risco envolvidos na gênese do TDAH em crianças e adolescentes, explorando a influência dos fatores genéticos, neurobiológicos e ambientais, bem como a interação entre eles. Metodologia: A busca científica foi realizada em bases de dados como PubMed/MEDLINE, Scopus, Web of Science e PsycINFO, usando termos de busca relacionados ao TDAH, fatores de risco, etiologia e epidemiologia. Foram selecionados estudos originais e revisões bibliográficas publicados em periódicos científicos indexados, abordando fatores de risco associados ao TDAH em crianças e adolescentes nos últimos 20 anos. Resultados e Discussão: A revisão revelou que os fatores genéticos têm um papel significativo na predisposição ao TDAH, com estimativas de herdabilidade entre 70% e 90%. Estudos genômicos identificaram genes relacionados ao sistema dopaminérgico e ao desenvolvimento cerebral como candidatos importantes na etiologia do transtorno. Além disso, fatores ambientais, como tabagismo materno durante a gravidez e consumo de álcool, estão associados a um maior risco de TDAH. Conclusão: Esta revisão bibliográfica reforça a importância de uma abordagem integrada que considere os fatores genéticos, neurobiológicos e ambientais na etiologia do TDAH em crianças e adolescentes

The Genetic Basis of Delayed Puberty.

Delayed pubertal onset has many etiologies, but on average two-thirds of patients presenting with late puberty have self-limited (or constitutional) delayed puberty. Self-limited delayed puberty often has a strong familial basis. Segregation analyses from previous studies show complex models of inheritance, most commonly autosomal dominant, but also including autosomal recessive, bilineal, and X-linked. Sporadic cases are also observed. Despite this, the neuroendocrine mechanisms and genetic regulation remain unclear in the majority of patients with self-limited delayed puberty. Only rarely have mutations in genes known to cause aberrations of the hypothalamic-pituitary-gonadal axis been identified in cases of delayed puberty, and the majority of these are in relatives of patients with congenital hypogonadotropic hypogonadism (CHH), for example in the FGFR1 and GNRHR genes. Using next generation sequencing in a large family with isolated self-limited delayed puberty, a pathogenic mutation in the CHH gene HS6ST1 was found as the likely cause for this phenotype. Additionally, a study comparing the frequency of mutations in genes that cause GnRH deficiency between probands with CHH and probands with isolated self-limited delayed puberty identified that a significantly higher proportion of mutations with a greater degree of oligogenicity were seen in the CHH group. Mutations in the gene IGSF10 have been implicated in the pathogenesis of familial late puberty in a large Finnish cohort. IGSF10 disruption represents a fetal origin of delayed puberty, with dysregulation of GnRH neuronal migration during embryonic development presenting for the first time in adolescence as late puberty. Some patients with self-limited delayed puberty have distinct constitutional features of growth and puberty. Deleterious variants in FTO have been found in families with delayed puberty with extremely low BMI and maturational delay in growth in early childhood. Recent exciting evidence highlights the importance of epigenetic up-regulation of GnRH transcription by a network of miRNAs and transcription factors, including EAP1, during puberty. Whilst a fascinating heterogeneity of genetic defects have been shown to result in delayed and disordered puberty, and many are yet to be discovered, genetic testing may become a realistic diagnostic tool for the differentiation of conditions of delayed puberty.SH is funded by the NIHR (CL-2017-19-002), The Rosetrees Trust (M222-F1), and supported by the Academy of Medical sciences, Wellcome Trust, Medical Research Council, British Heart Foundation, Arthritis Research UK and Diabetes UK through the clinical lecturers scheme (SGL019\1043)

Growth hormone secretatogue receptor gene (GHSR) analysis in patients with idiopathic short stature (ISS) and patients with isolated growth hormone deficiency

A ghrelina, hormônio secretado principalmente por células gástricas, liga-se ao seu receptor, o receptor de secretagogo de GH (GHSR - Growth hormone secretagogue receptor), localizado no hipotálamo e na hipófise, estimulando a síntese e secreção do GH. Recentemente foram identificadas mutações no gene GHSR em crianças com baixa estatura idiopática (BEI) e com deficiência isolada de GH (DGH). No presente estudo investigamos a presença de mutações no gene GHSR em crianças com DGH isolada de causa não identificada e crianças com BEI, incluindo um subgrupo de crianças com atraso constitucional de crescimento e desenvolvimento (ACCD). Foram selecionados 14 pacientes com deficiência isolada de GH sem alterações anatômicas da região hipotálamo-hipofisária e 96 pacientes com BEI, destes 31 (32%) apresentavam ACCD. Também foram estudados 150 controles adultos e 197 crianças controle com crescimento e puberdade normais. A região codificadora do GHSR foi amplificada utilizando-se oligonucleotídeos iniciadores específicos, seguida de purificação enzimática e seqüenciamento automático. Encontramos 6 variantes alélicas em heterozigose no GHSR: nenhuma delas presente nos controles estudados, e quatro destas variantes estão localizadas em regiões conservadas do gene. Uma variante foi encontrada em uma paciente do grupo DGH (p.Val249Leu) e as outras cinco (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) foram encontradas em pacientes do subgrupo ACCD do grupo BEI. As variantes missense foram submetidas a estudo funcional que evidenciou que as mutações p.Ser84Ile e p.Val182Ala possuem diminuição na atividade basal associadas à diminuição da expressão do receptor na superfície celular. Adicionalmente, a mutação p.Ser84Ile também apresenta redução na atividade do GHSR induzida pelo ligante. A variante p.Val249Leu foi encontrada em uma paciente do sexo feminino com diagnóstico de DGH isolado. A falta de segregação familiar associada à ausência de déficit funcional da variante nos estudos in vitro sugere que, neste caso, a variante p.Val249Leu não é a causa do fenótipo de DGH nesta família e trata-se de uma variante alélica rara. As 5 variantes alélicas no GHSR (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) encontradas nos pacientes com BEI foram identificadas apenas naqueles com puberdade atrasada, ou seja, pertencentes ao subgrupo ACCD (3 do sexo masculino e 2 do sexo feminino). A freqüência de variantes neste grupo de pacientes foi de 16%, significativamente maior que nos outros grupos, e a ausência de variantes gênicas novas no grupo de crianças obesas com altura normal e mesmo no grupo de crianças com BEI sem ACCD sugere que nosso achado não foi casual e que as alterações descritas podem estar associadas ao fenótipo de ACCD. Os estudos in vitro mostraram prejuízos funcionais em 2 destas variantes (p.Ser84Ile e p.Val182Ala) porém, devido à limitação dos estudos funcionais (celulas heterólogas) não podemos afastar que as demais não tenham algum impacto funcional in vivo. Em conclusão, nossos resultados sugerem um envolvimento dos defeitos no GHSR na etiologia do atraso constitucional do crescimento e desenvolvimento em uma parcela de pacientes com esta condiçãoGhrelin, hormone secreted by gastric cells, stimulates growth hormone secretion by acting on its receptor GHSR, located in the hypothalamus and pituitary. Recently, mutations in the GHSR gene were described in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). In the present study we analyzed the GHSR gene in patients with isolated GHD and patients with ISS, including a subgroup of patients with constitutional delay of growth and puberty (CDGP). We studied 14 GHD patients with normal pituitary magnetic resonance imaging and 96 patients with ISS, 31 of them with CDGP. We also studied 150 adults and in 197 children with normal stature. The entire coding region as well as the exon-intron boundaries of GHSR were PCR amplified in all patients and control group and PCR products were bidirectionally sequenced. Six different heterozygous variants in GHSR were identified: none of them were found in the control group and four of these amino acid substitutions occurred at a conserved position within the GHSR. One variant (p.Val249Leu) was found in a GHD patient and the other five (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were found in patients with CDGP. The missense variants were submitted to functional studies. Two of these variants (p.Ser84Ile and p.Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. The p.Val249Leu variant, found in a female patient with isolated GHD, did not segregate with the phenotype in the family and had no functional impairment in vitro. This suggests that p.Val249Leu is not the cause of the GHD in the family and may be a rare allelic variant. The other variants (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were identified only in patients with CDGP (3 male and 2 female). The frequency of allelic variants observed in this group (16%) was higher than expected by chance in contrast with ISS and GHD children, and the absence of other GHSR mutations in the large group of control children suggests that the association between GHSR mutations and CDGP phenotype is unlikely to be fortuitous. Functional studies revealed that two of the identified missense variants (p.Ser84Ile and p.Val182Ala) are functionally significant. These functional studies were performed in heterologous cell expression systems; therefore it is not possible to completely rule out that the other identified variants might cause some unrevealed impairment on GHSR function or expression in vivo. In conclusion, our data raise the possibility that abnormalities in ghrelin receptor function may be implicated in the ethiology of CDGP in some patient

Novel inactivating mutations in the GH secretagogue receptor gene in patients with constitutional delay of growth and puberty

Background: A limited number of mutations in the GH secretagogue receptor gene (GHSR) have been described in patients with short stature. Objective: To analyze GHSR in idiopathic short stature (ISS) children including a subgroup of constitutional delay of growth and puberty (CDGP) patients. Subjects and methods: The GHSR coding region was directly sequenced in 96 independent patients with ISS, 31 of them with CDGP, in 150 adults, and in 197 children with normal stature. The pharmacological consequences of GHSR non-synonymous variations were established using in vitro cell-based assays. Results: Five different heterozygous point variations in GHSR were identified (c.-6 G>C, c.251G>T (p.Ser84Ile), c.505G>A (p.Ala169Thr), c.545 T>C (p.Val182Ala), and c.1072G>A (p.Ala358Thr)), all in patients with CDGP. Neither these allelic variants nor any other mutations were found in 694 alleles from controls. Functional studies revealed that two of these variations (p.Ser84Ile and p. Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. These mutations were identified in two female patients with CDGP (at the age of 13 years, their height SDS were -2.4 and -2.3). Both patients had normal progression of puberty and reached normal adult height (height SDS of -0.7 and -1.4) without treatment. Conclusion: This is the first report of GHSR mutations in patients with CDGP. Our data raise the intriguing possibility that abnormalities in ghrelin receptor function may influence the phenotype of individuals with CDGP.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP[09/00313-3]Conselho-Nacional de Desenvolvimento Cientifico e Tecnologico CNPq[143524/2008-9]Conselho-Nacional de Desenvolvimento Cientifico e Tecnologico CNPq[300982/2009-7]Conselho-Nacional de Desenvolvimento Cientifico e Tecnologico CNPq[301477/2009-4]Fonds de la Recherche en Sante du QuebecCanadian Institutes of Health ResearchNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/NIH)[R01DK072497

Effectiveness of the Combined Recombinant Human Growth Hormone and Gonadotropin-Releasing Hormone Analog Therapy in Pubertal Patients with Short Stature due to SHOX Deficiency

Context: Isolated heterozygous SHOX defects are the most frequent monogenic cause of short stature, and combined therapy with recombinant human GH (rhGH) and GnRH analog (GnRHa) in pubertal patients has been suggested, but there are no data on final height

A novel STAT5B mutation causing GH insensitivity syndrome associated with hyperprolactinemia and immune dysfunction in two male siblings

Background: GH insensitivity (GHI) syndrome caused by STAT5B mutations was recently reported, and it is characterized by extreme short stature and immune dysfunction. Treatment with recombinant human IGF1 (rhIGF1) is approved for patients with GHI, but the growth response to this therapy in patients with STAT5B mutations has not been reported. Objectives: To report the clinical features, molecular findings, and the short-term growth response to rhIGF1 therapy in patients with STAT5B mutation. Subjects and methods: Hormonal and immunological evaluations were performed in two male siblings with GHI associated with atopic eczema, interstitial lung disease, and thrombocytopenic purpura. STAT5B genes were directly sequenced. The younger sibling was treated with rhIGF1 at a dose of 110 mu g/kg BID. Results: Both siblings had laboratory findings compatible with GHI associated with hyperprolactinemia. Lymphopenia and reduced number of natural killer cells without immunoglobulin abnormalities were observed. STAT5B sequence revealed a homozygous frameshift mutation (p.L142fsX161) in both siblings. The younger sibling (9.9 years of age) was treated with rhIGF1 at appropriate dosage, and he did not present any significant change in his growth velocity (from 2.3 to 3.0 cm/year after 1.5 years of therapy). The presence of a chronic illness could possibly be responsible for the poor result of rhIGF1 treatment. Further studies in patients with STAT5B defects are necessary to define the response to rhIGF1 treatment in this disorder. Conclusion: GHI associated with immune dysfunction, especially interstitial lung disease, and hyperprolactinemia is strongly suggestive of a mutation in STAT5B in both sexes.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo - FAPESP[09/00313-3]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq[143524/2008-9]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq[300982/2009-7]Conselho Nacional de Desenvolvimento Cientifico e Tecnologico - CNPq[301477/2009-4