Early onset of primary hypogonadism revealed by serum anti-Mullerian hormone determination during infancy and childhood in trisomy 21

Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2 months-20 year). To compare with an adequate control population, we established reference levels for serum anti-Mullerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6 months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6 months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.

Contribution of ultrasonographic examination to the prenatal detection of trisomy 21: experience from 19 European registers.

The objective of this study was to evaluate the contribution of ultrasound scanning to the prenatal detection of trisomy 21 in a large unselected European population. Data from 19 congenital malformation registers in 11 European countries were included. The prenatal ultrasound screening programs in the countries ranged from no routine screening to three ultrasound investigations per patient. Routine serum screening was offered in four of the 11 countries and routine screening on the basis of maternal age amniocentesis in all. The results show that overall 53% of cases of trisomy 21 were detected prenatally with a range from 3% in Lithuania to 88% in Paris. Ninety-eight percent of women whose babies were diagnosed before 24 weeks gestation chose to terminate the pregnancy. Centres/countries that offer serum screening do not have a significantly higher detection rate of trisomy 21 when compared to those that offer maternal age amniocentesis and anomaly scanning only. Fifty percent of trisomy 21 cases were born to women aged 35 years or more. In conclusions, second trimester ultrasound plays an important role in the prenatal diagnosis of trisomy 21. Of those cases prenatally diagnosed, 64% of cases in women <35 years and 36% of those in women >or=35 years were detected because of an ultrasound finding. Ultrasound soft markers accounted for 84% of the scan diagnoses. There is evidence of increasing maternal age across Europe with 50% of cases of trisomy 21 born to women aged 35 years or more.

An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21

Although approximately 50% of Down Syndrome (DS) patients have heart abnormalities, they exhibit an overprotection against cardiac abnormalities related with the connective tissue, for example a lower risk of coronary artery disease. A recent study reported a case of a person affected by DS who carried mutations in FBN1, the gene causative for a connective tissue disorder called Marfan Syndrome (MFS). The fact that the person did not have any cardiac alterations suggested compensation effects due to DS. This observation is supported by a previous DS meta-analysis at the molecular level where we have found an overall upregulation of FBN1 (which is usually downregulated in MFS). Additionally, that result was cross-validated with independent expression data from DS heart tissue. The aim of this work is to elucidate the role of FBN1 in DS and to establish a molecular link to MFS and MFS-related syndromes using a computational approach. To reach that, we conducted different analytical approaches over two DS studies (our previous meta-analysis and independent expression data from DS heart tissue) and revealed expression alterations in the FBN1 interaction network, in FBN1 co-expressed genes and FBN1-related pathways. After merging the significant results from different datasets with a Bayesian approach, we prioritized 85 genes that were able to distinguish control from DS cases. We further found evidence for several of these genes (47%), such as FBN1, DCN, and COL1A2, being dysregulated in MFS and MFS-related diseases. Consequently, we further encourage the scientific community to take into account FBN1 and its related network for the study of DS cardiovascular characteristics.

An integrative computational analysis provides evidence for FBN1-associated network deregulation in trisomy 21

Although approximately 50% of Down Syndrome (DS) patients have heart abnormalities, they exhibit an overprotection against cardiac abnormalities related with the connective tissue, for example a lower risk of coronary artery disease. A recent study reported a case of a person affected by DS who carried mutations in FBN1, the gene causative for a connective tissue disorder called Marfan Syndrome (MFS). The fact that the person did not have any cardiac alterations suggested compensation effects due to DS. This observation is supported by a previous DS meta-analysis at the molecular level where we have found an overall upregulation of FBN1 (which is usually downregulated in MFS). Additionally, that result was cross-validated with independent expression data from DS heart tissue. The aim of this work is to elucidate the role of FBN1 in DS and to establish a molecular link to MFS and MFS-related syndromes using a computational approach. To reach that, we conducted different analytical approaches over two DS studies (our previous meta-analysis and independent expression data from DS heart tissue) and revealed expression alterations in the FBN1 interaction network, in FBN1 co-expressed genes and FBN1-related pathways. After merging the significant results from different datasets with a Bayesian approach, we prioritized 85 genes that were able to distinguish control from DS cases. We further found evidence for several of these genes (47%), such as FBN1, DCN, and COL1A2, being dysregulated in MFS and MFS-related diseases. Consequently, we further encourage the scientific community to take into account FBN1 and its related network for the study of DS cardiovascular characteristics.

Quantitative analysis of senile plaques in Alzheimer disease: observation of log-normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome).

The discovery that the epsilon 4 allele of the apolipoprotein E (apoE) gene is a putative risk factor for Alzheimer disease (AD) in the general population has highlighted the role of genetic influences in this extremely common and disabling illness. It has long been recognized that another genetic abnormality, trisomy 21 (Down syndrome), is associated with early and severe development of AD neuropathological lesions. It remains a challenge, however, to understand how these facts relate to the pathological changes in the brains of AD patients. We used computerized image analysis to examine the size distribution of one of the characteristic neuropathological lesions in AD, deposits of A beta peptide in senile plaques (SPs). Surprisingly, we find that a log-normal distribution fits the SP size distribution quite well, motivating a porous model of SP morphogenesis. We then analyzed SP size distribution curves in genotypically defined subgroups of AD patients. The data demonstrate that both apoE epsilon 4/AD and trisomy 21/AD lead to increased amyloid deposition, but by apparently different mechanisms. The size distribution curve is shifted toward larger plaques in trisomy 21/AD, probably reflecting increased A beta production. In apoE epsilon 4/AD, the size distribution is unchanged but the number of SP is increased compared to apoE epsilon 3, suggesting increased probability of SP initiation. These results demonstrate that subgroups of AD patients defined on the basis of molecular characteristics have quantitatively different neuropathological phenotypes.

Genotype-phenotype correlation in trisomy 21

Down syndrome (DS) or trisomy 21 (T21) is the most common genetic cause of intellectual disability (ID). Subjects with DS are characterized by complex and variable clinical features including intellectual disability (ID) and craniofacial dysmorphisms. The aim of the thesis is to uncover genotype-phenotype relationships in DS possibly useful to devise therapies based on molecular and cellular mechanisms. In this work, we have investigated different aspects of DS: - we have collected clinical data of children with DS and we have evaluated the cognitive impairment through specific cognitive tests - we have analysed genomics of DS through the study of partial trisomy (PT21) cases. We have described new PT21 cases confirming the hypothesis of the highly restricted DS critical region (HR-DSCR) recently identified as the minimal region whose duplication is shared by all PT21 subjects diagnosed with DS, while it is absent in all PT21 non-DS subjects. Moreover, we have characterized new transcripts included in the HR-DSCR; - we have studied gene expression through RNAseq in blood cells of children with DS; -metabolic alterations in plasma of children with DS were identified through different methods: Nuclear Magnetic resonance, routine blood exams performed during the follow up of the subjects and enzyme-linked immunosorbent assay (ELISA); - to test possible correlations between specific Hsa21 regions and alterations in transcriptomics and metabolomics, we have used trisomic iPSCs and differentiated them into neuronal derivatives. Significant alterations in gene expression and metabolic profiles have been identified, as well as significant correlations with clinical and cognitive aspects. Specific genes and the HR-DSCR may play a role in these alterations: cell models need to be developed to investigate this role. Neural derivatives from trisomic iPSCs are a promising model to better understand genotype-phenotype correlations in DS.

New osseous soft markers for trisomy 13, 18 and 21

INTRODUCTION For ultrasonographic diagnosis of a fetal trisomy so-called "soft markers" (=ultrasonographically detectable morphological variants) are used. Detection of a certain number of them increases the diagnostic certainty of a fetal trisomy. Up to now there are very few diagnostically accepted osseous soft markers for trisomy. Hence potential osseous soft markers applicable for first and second trimester ultrasound screening for trisomy 21, 18 or 13 were studied. METHODS Postmortal fetal X-rays (ap, lateral) of 358 fetuses (trisomy 21: n = 109, trisomy 18: n = 46; trisomy 13: n = 38, control group: n = 165). RESULTS Not yet described but with trisomy 21 statistically associated soft markers were un-timely os sternale ossification, delayed os sacrum ossification, shortened os maxillare, reduced os maxillare-jaw-corner distance, augmented orbita height, premature os calcaneus ossification, bell-shaped thorax, coronal clefts, trend to wider binocular as well as wider intraocular distances; for trisomy 18: elevated clavicula slope, reduced number of ribs, bell-shaped thorax, coronal clefts, reduced os maxillare-jaw-corner distance, shortened ramus mandibulare, shortened os metacarpale IV and V, augmented ratio between biparietal diameter and (osseus and soft-tissue) shoulder width; for trisomy 13: longer os nasale, elevated clavicula slope, premature sternum, delayed os sacrum ossification, delayed/premature cranium ossification, reduced number of ribs, coronal clefts, reduced os maxillare-jaw-corner distance, shortened ramus mandibulare, augmented orbita height, shortened os metacarpale V and a tendency for a shortened os metacarpale IV. CONCLUSION We found several not yet published osseous soft markers statistically associated with trisomy 21, 18 and 13, which can help to ensure sonographically these aneuploidy diagnoses.

Growth hormone binding protein in normal and aneuploid pregnancy: a paradoxical decrease in trisomy 18

Objective To explore whether abnormalities in growth hormone binding protein (GHBP) may underlie the growth restriction associated with fetal aneuploidy. Design A retrospective casecontrol study. Setting Monash Medical Centre, Clayton, Victoria, Australia. Population Twenty-one trisomy 18, and 30 trisomy 21 pregnancies, and 170 chromosomally normal pregnancies at 15-18 weeks of gestation representing three to five controls per case matched for source, gestation and duration of storage. Methods GHBP was measured using a ligand immunofunctional assay. Results In the chromosomally normal pregnancies GHBP levels decreased slightly but significantly across the narrow gestational window studied. Compared with controls, levels of GHBP, expressed as median (95% CI) multiples of the median (MoM), in the trisomy 21 pregnancies were similar, 1.0 (0.92-1.39) MoM and 1.27 (1.04-1.50) MoM, respectively; P = 0.061 (Mann-Whitney CI test) but were significantly reduced in the trisomy 18 pregnancies, 0.68 (0.51-0.84) MoM; P = 0.0014 (Mann-Whitney U test). Conclusions These data suggest that decreased levels of maternal growth hormone binding protein, and by implication growth hormone receptor complement, may underlie the early severe growth restriction that is characteristic of trisomy 18.

As expetativas das mães face à inclusão de crianças com Trissomia 21 no primeiro ano do ensino básico nas escolas da Região Autónoma da Madeira

Partindo da análise do conceito de inclusão de crianças com Síndrome de Down no primeiro ano do ensino básico nas escolas da Região Autónoma da Madeira, após a intervenção da Equipa de Intervenção Precoce, fazendo referência às expetativas das mães, este estudo aborda os principais fatores que poderão influenciar esta temática. Tem como objetivos analisar as expetativas das mães sobre o processo inclusivo de crianças com Trissomia 21 na transição do pré-escolar para o 1.º ciclo e compreender em que medida a Intervenção Precoce contribui para a existência de expetativas positivas ou negativas face à inclusão dos seus filhos. Ao mesmo tempo procura constatar-se quais as principais preocupações em relação à entrada dos seus filhos no primeiro ciclo. Este trabalho assenta numa abordagem qualitativa: os dados foram recolhidos através da realização de sete entrevistas a mães de crianças com Trissomia 21. Para a análise de informação recolhida, utilizou-se a técnica de análise de conteúdo com categorias definidas à posteriori. Concluiu-se que as mães têm expetativas positivas em relação à inclusão dos seus filhos tendo, no entanto, expetativas negativas em relação aos serviços prestados pelas equipas de Intervenção Precoce no que se refere à adequação de serviços, nomeadamente, o tempo destinado ao apoio da Terapia da Fala que foi considerado insuficiente pela maioria das mães. Relativamente à entrada no primeiro ciclo, as principais preocupações prendem-se com a comunicação oral que o(a) seu (sua) filho(a) irá estabelecer com os professores e colegas, com a eventual falta de sensibilização dos docentes face à problemática da T21 e, no que se refere à aprendizagem, as maiores preocupações passam pelo acompanhamento do ritmo de trabalho dos colegas e com a capacidade, ou não, de ler e escrever.

Do down ao up… : contributos do envolvimento familiar na estimulação precoce de uma criança com Trissomia 21

Do Down ao UP… Percurso de sentimentos, emoções, procuras e certezas, por vezes, incertas mas alegre e esperançosamente desafiantes… O itinerário de investigação, e consequente formação, que foi encetado procurou, com o envolvimento familiar, as estratégias e dinâmicas mais eficazes para a promoção de aquisições relevantes e significativas para uma criança, filha do próprio investigador, com necessidades educativas especiais decorrentes do quadro de Trissomia 21. Através da procura objectiva de dados contextualizadores, foi delineado um programa de estimulação precoce aplicado nas rotinas familiares, as quais se constituíram como reais oportunidades/meios de um envolvimento familiar participante e corresponsável, facilitador e promotor de desenvolvimento das potencialidades e capacidades da própria criança. Com esta investigação pretendeu-se destacar a importância da intervenção/estimulação nas rotinas familiares constituídas ou a potencializar, como forma de obtenção de prometedores resultados em todas as áreas de desenvolvimento, veiculando os princípios da normalização, da funcionalidade, da contextualização e do envolvimento convergente de todo o agregado familiar.

Inclusão de crianças com Trissomia 21 no Ensino Regular

A temática da inclusão é uma das mais pertinentes da actualidade educativa. Inserir alunos com necessidades educativas especiais, principalmente os portadores de deficiência, nas turmas regulares e facultar-lhes os recursos humanos e materiais necessários para um pleno desenvolvimento e aproveitamento das suas capacidades, nem sempre é tarefa fácil, pois as escolas muitas vezes não estão ainda preparadas para dar resposta a essa heterogeneidade. Neste estudo pretendemos perceber o tema da inclusão nas necessidades educativas especiais, mais concretamente no Síndrome de Down. Para tal pesquisamos diversos autores para encontrar uma linha de pensamento útil e aplicável na realidade escolar. Algumas estratégias que promovem a inclusão destas crianças no ensino regular irão ser analisadas no presente trabalho.A Presente investigação resulta de uma preocupação pessoal e profissional relativa à integração de crianças com necessidades educativas especiais no ensino regular, partindo da seguinte questão: Como é que a escola pode ser inclusiva para crianças com Trissonomia 21? Segundo a legislação portuguesa, a escola deve ser inclusiva e universal, uma escola para todos, embora por vezes isto não se verifique e continua a existir alguma exclusão. Pretendemos perceber e analisar melhor esta temática colocando como hipóteses de trabalho: A escola está preparada para educar e incluir crianças com síndrome de Down e as metodologias usadas pelos docentes são eficazes nesta inclusão.

A influência da poesia no desenvolvimento da linguagem oral de uma aluna com Trissomia 21

O conceito de poesia é uma forma de arte e traduz-se como um espelho do pensamento do homem realizado na palavra oral e escrita. A poesia poderá ensinar o homem no estudo da palavra, através do seu significado nos valores denotativo e/ou conotativo. A aplicação destes conceitos faz sentido, a partir da ideia de que a palavra no contexto da poesia pode produzir emoções e sensações nas pessoas a quem ela é transmitida. A poesia tem funções multissensoriais que podem definir o input linguístico como forma de desenvolver a linguagem. Vários são os estudos que apontam para as principais competências deficitárias nos indivíduos com Trissomia 21, mas poucas são as investigações que se debruçam sobre a influência da poesia nas várias competências linguísticas. Uma perceção mais ampla e visionária da Arte na voz da poesia pela parte da escola, professores e, em particular, professores de Educação Especial permitirá adotar estratégias de intervenção inovadoras. Pretende este estudo investigar e analisar a forma como a poesia pode influenciar o desenvolvimento da linguagem oral numa aluna com Trissomia 21. Neste projeto, a partir da identificação do caso-problema e da constatação da ausência da poesia no currículo da aluna, procurou-se intervir, no sentido de melhorar as suas competências linguísticas, utilizando para tanto a poesia. A implementação do projeto aconteceu ao longo de seis meses durante quinze sessões de intervenção individuais. Os resultados do projeto mostram que, em todas as competências linguísticas, houve um processo evolutivo, sendo particularmente significativo o desenvolvimento da competência fonológica, aumento de vocabulário e uma maior noção da palavra em contexto. Estes dados levam-nos a crer que a utilização da poesia poderá, também, constituir uma forma de promover a socialização e a autonomia, revelando os efeitos colaterais que poderão decorrer deste tipo de intervenção. - Abstract The concept of poetry is a form of art, showing the man's thought held in the spoken and written word. Poetry can teach man in the study of the word, its meaning through denotative and/or connotative values. The application of these concepts makes sense, from the idea that the word in the context of poetry can stir emotions and feelings in the people to whom it is transmitted. Poetry has multisensory functions that can set the linguistic input as a way to develop language at phonological, lexical, semantics, pragmatic and morfosyntactic skills. There are several studies that point out to the key skills deficit in individuals with Trisomy 21, but there are few investigations that focus on the influence of poetry in various language skills. A broader perception and vision of poetry as art given by school, and teachers, and, particularly teachers of Special Education will allow a more effective intervention strategies. This study aims to investigate and analyze how poetry can influence the development of oral language in a student with Trisomy 21. In this project, we tried to intervene, improving the language skills of the student, using poetry from the identification case-problem and confirmation of the absence of poetry in her curriculum. The implementation of the project took place throughout six months for fifteen individual intervention sessions. The project results show that, in all language skills, there was a progressive process, being particularly significant the development of the phonological skills, increased vocabulary and a greater sense of the word into context. These data lead us to believe that the use of poetry can also be a way to promote socialization and autonomy, revealing the side effects that may result from this type of intervention.

Função Tiroideia em Doentes com Trissomia 21 – Casuística de Duas Consultas num Hospital Pediátrico Central

Em crianças e adolescentes com síndrome de trissomia 21 observa-se uma prevalência aumentada de alterações da função tiroideia. A mais frequentemente encontrada é o hipotiroidismo subclínico, seguida do hipotiroidismo clínico e, mais raramente, doença de Graves. O diagnóstico de hipotiroidismo é, por vezes, tardio pois os sintomas são confundidos com as manifestações características da trissomia 21, sendo portanto fundamental rastrear sistematicamente a função tiroideia nestas crianças. A velocidade de crescimento é um elemento clínico que pode contribuir quer para a valorização do diagnóstico quer da terapêutica apesar de esta não ser totalmente consensual. Descreve-se a casuística de um Hospital Central Pediátrico em foram seguidas quarenta e cinco crianças e adolescentes com trissomia 21, entre Janeiro de 2000 e Maio de 2008. Neste grupo de crianças, foram detectadas alterações da função tiroideia em dezanove; a alteração mais frequente foi o hipotiroidismo subclínico (treze) seguida do hipotiroidismo clínico (cinco); houve apenas um caso de hipertiroidismo. As alterações da função tiroideia aumentaram com a idade dos doentes, foram mais frequentes no sexo feminino e tiveram uma clínica inespecífica.

Nineteen additional unpredicted transcripts from human chromosome 21.

The identification of all human chromosome 21 (HC21) genes is a necessary step in understanding the molecular pathogenesis of trisomy 21 (Down syndrome). The first analysis of the sequence of 21q included 127 previously characterized genes and predicted an additional 98 novel anonymous genes. Recently we evaluated the quality of this annotation by characterizing a set of HC21 open reading frames (C21orfs) identified by mapping spliced expressed sequence tags (ESTs) and predicted genes (PREDs), identified only in silico. This study underscored the limitations of in silico-only gene prediction, as many PREDs were incorrectly predicted. To refine the HC21 annotation, we have developed a reliable algorithm to extract and stringently map sequences that contain bona fide 3' transcript ends to the genome. We then created a specific 21q graphical display allowing an integrated view of the data that incorporates new ESTs as well as features such as CpG islands, repeats, and gene predictions. Using these tools we identified 27 new putative genes. To validate these, we sequenced previously cloned cDNAs and carried out RT-PCR, 5'- and 3'-RACE procedures, and comparative mapping. These approaches substantiated 19 new transcripts, thus increasing the HC21 gene count by 9.5%. These transcripts were likely not previously identified because they are small and encode small proteins. We also identified four transcriptional units that are spliced but contain no obvious open reading frame. The HC21 data presented here further emphasize that current gene prediction algorithms miss a substantial number of transcripts that nevertheless can be identified using a combination of experimental approaches and multiple refined algorithms.

O optimismo na docência e a inclusão de alunos com Trissomia 21

Este projecto tem por objectivo analisar de que forma o optimismo na docência poderá influenciar as práticas educativas, e quais as perspectivas dos docentes em relação à inclusão de crianças portadoras de Trissomia 21 na sala de aula regular. Participaram neste estudo 212 docentes, desde educadores de infância, professores do 1º ciclo, 2º ciclo e 3º ciclo. A amostra é na sua maioria do sexo feminino, e também a maioria dos inquiridos pertencem a um grupo com menos tempo de serviço. Em relação à inclusão, os inquiridos em média não concordam nem discordam da inclusão de alunos com NEE na sala de aula, contudo estão mais concordantes que teriam necessidade de recorrer a um técnico especializado se tivessem uma criança com Trissomia 21 na sala.