Non-hermiticity in spintronics: oscillation death in coupled spintronic nano-oscillators through emerging exceptional points.

The emergence of exceptional points (EPs) in the parameter space of a non-hermitian (2D) eigenvalue problem has long been interest in mathematical physics, however, only in the last decade entered the scope of experiments. In coupled systems, EPs give rise to unique physical phenomena, and enable the development of highly sensitive sensors. Here, we demonstrate at room temperature the emergence of EPs in coupled spintronic nanoscale oscillators and exploit the system's non-hermiticity. We observe amplitude death of self-oscillations and other complex dynamics, and develop a linearized non-hermitian model of the coupled spintronic system, which describes the main experimental features. The room temperature operation, and CMOS compatibility of our spintronic nanoscale oscillators means that they are ready to be employed in a variety of applications, such as field, current or rotation sensors, radiofrequeny and wireless devices, and in dedicated neuromorphic computing hardware. Furthermore, their unique and versatile properties, notably their large nonlinear behavior, open up unprecedented perspectives in experiments as well as in theory on the physics of exceptional points expanding to strongly nonlinear systems.

Cytogenomic assessment of the diagnosis of 93 patients with developmental delay and multiple congenital abnormalities: The Brazilian experience.

OBJECTIVE: The human genome contains several types of variations, such as copy number variations, that can generate specific clinical abnormalities. Different techniques are used to detect these changes, and obtaining an unequivocal diagnosis is important to understand the physiopathology of the diseases. The objective of this study was to assess the diagnostic capacity of multiplex ligation-dependent probe amplification and array techniques for etiologic diagnosis of syndromic patients. METHODS: We analyzed 93 patients with developmental delay and multiple congenital abnormalities using multiplex ligation-dependent probe amplifications and arrays. RESULTS: Multiplex ligation-dependent probe amplification using different kits revealed several changes in approximately 33.3% of patients. The use of arrays with different platforms showed an approximately 53.75% detection rate for at least one pathogenic change and a 46.25% detection rate for patients with benign changes. A concomitant assessment of the two techniques showed an approximately 97.8% rate of concordance, although the results were not the same in all cases. In contrast with the array results, the MLPA technique detected ∼70.6% of pathogenic changes. CONCLUSION: The obtained results corroborated data reported in the literature, but the overall detection rate was higher than the rates previously reported, due in part to the criteria used to select patients. Although arrays are the most efficient tool for diagnosis, they are not always suitable as a first-line diagnostic approach because of their high cost for large-scale use in developing countries. Thus, clinical and laboratory interactions with skilled technicians are required to target patients for the most effective and beneficial molecular diagnosis.

Cytogenomic assessment of the diagnosis of 93 patients with developmental delay and multiple congenital abnormalities: The Brazilian experience

OBJECTIVE: The human genome contains several types of variations, such as copy number variations, that can generate specific clinical abnormalities. Different techniques are used to detect these changes, and obtaining an unequivocal diagnosis is important to understand the physiopathology of the diseases. The objective of this study was to assess the diagnostic capacity of multiplex ligation-dependent probe amplification and array techniques for etiologic diagnosis of syndromic patients. METHODS: We analyzed 93 patients with developmental delay and multiple congenital abnormalities using multiplex ligation-dependent probe amplifications and arrays. RESULTS: Multiplex ligation-dependent probe amplification using different kits revealed several changes in approximately 33.3% of patients. The use of arrays with different platforms showed an approximately 53.75% detection rate for at least one pathogenic change and a 46.25% detection rate for patients with benign changes. A concomitant assessment of the two techniques showed an approximately 97.8% rate of concordance, although the results were not the same in all cases. In contrast with the array results, the MLPA technique detected ∼70.6% of pathogenic changes. CONCLUSION: The obtained results corroborated data reported in the literature, but the overall detection rate was higher than the rates previously reported, due in part to the criteria used to select patients. Although arrays are the most efficient tool for diagnosis, they are not always suitable as a first-line diagnostic approach because of their high cost for large-scale use in developing countries. Thus, clinical and laboratory interactions with skilled technicians are required to target patients for the most effective and beneficial molecular diagnosis.

Subtelomeric Copy Number Variations: The Importance of 4p/4q Deletions in Patients with Congenital Anomalies and Developmental Disability.

The most prevalent structural variations in the human genome are copy number variations (CNVs), which appear predominantly in the subtelomeric regions. Variable sizes of 4p/4q CNVs have been associated with several different psychiatric findings and developmental disability (DD). We analyzed 105 patients with congenital anomalies (CA) and developmental and/or intellectual disabilities (DD/ID) using MLPA subtelomeric specific kits (P036 /P070) and 4 of them using microarrays. We found abnormal subtelomeric CNVs in 15 patients (14.3%), including 8 patients with subtelomeric deletions at 4p/4q (53.3%). Additional genomic changes were observed at 1p36, 2q37.3, 5p15.3, 5q35.3, 8p23.3, 13q11, 14q32.3, 15q11.2, and Xq28/Yq12. This indicates the prevalence of independent deletions at 4p/4q, involving PIGG, TRIML2, and FRG1. Furthermore, we identified 15 genes with changes in copy number that contribute to neurological development and/or function, among them CRMP1, SORCS2, SLC25A4, and HELT. Our results highlight the association of genes with changes in copy number at 4p and 4q subtelomeric regions and the DD phenotype. Cytogenomic characterization of additional cases with distal deletions should help clarifying the role of subtelomeric CNVs in neurological diseases.

Post-mortem cytogenomic investigations in patients with congenital malformations.

Congenital anomalies are the second highest cause of infant deaths, and, in most cases, diagnosis is a challenge. In this study, we characterize patterns of DNA copy number aberrations in different samples of post-mortem tissues from patients with congenital malformations. Twenty-eight patients undergoing autopsy were cytogenomically evaluated using several methods, specifically, Multiplex Ligation-dependent Probe Amplification (MLPA), microsatellite marker analysis with a MiniFiler kit, FISH, a cytogenomic array technique and bidirectional Sanger sequencing, which were performed on samples of different tissues (brain, heart, liver, skin and diaphragm) preserved in RNAlater, in formaldehyde or by paraffin-embedding. The results identified 13 patients with pathogenic copy number variations (CNVs). Of these, eight presented aneuploidies involving chromosomes 13, 18, 21, X and Y (two presented inter- and intra-tissue mosaicism). In addition, other abnormalities were found, including duplication of the TYMS gene (18p11.32); deletion of the CHL1 gene (3p26.3); deletion of the HIC1 gene (17p13.3); and deletion of the TOM1L2 gene (17p11.2). One patient had a pathogenic missense mutation of g.8535C>G (c.746C>G) in exon 7 of the FGFR3 gene consistent with Thanatophoric Dysplasia type I. Cytogenomic techniques were reliable for the analysis of autopsy material and allowed the identification of inter- and intra-tissue mosaicism and a better understanding of the pathogenesis of congenital malformations.

Rare genomic rearrangement in a boy with Williams-Beuren syndrome associated to XYY syndrome and intriguing behavior.

Williams-Beuren syndrome (WBS) is caused by a hemizygous contiguous gene microdeletion of 1.55-1.84 Mb at 7q11.23 region. Approximately, 28 genes have been shown to contribute to classical phenotype of SWB with presence of dysmorphic facial features, supravalvular aortic stenosis (SVAS), intellectual disability, and overfriendliness. With the use of Microarray-based comparative genomic hybridization and other molecular cytogenetic techniques, is possible define with more accuracy partial or atypical deletion and refine the genotype-phenotype correlation. Here, we report on a rare genomic structural rearrangement in a boy with atypical deletion in 7q11.23 and XYY syndrome with characteristic clinical signs, but not sufficient for the diagnosis of WBS. Cytogenetic analysis of G-banding showed a karyotype 47,XYY. Analysis of DNA with the technique of MLPA (Multiplex Ligation-dependent Probe Amplification) using kits a combination of kits (P064, P036, P070, and P029) identified an atypical deletion on 7q11.23. In addition, high resolution SNP Oligonucleotide Microarray Analysis (SNP-array) confirmed the alterations found by MLPA and revealed others pathogenic CNVs, in the chromosomes 7 and X. The present report demonstrates an association not yet described in literature, between Williams-Beuren syndrome and 47,XYY. The identification of atypical deletion in 7q11.23 concomitant to additional pathogenic CNVs in others genomic regions allows a better comprehension of clinical consequences of atypical genomic rearrangements.

Cytogenomic delineation and clinical follow-up of 10 Brazilian patients with Pallister-Killian syndrome.

BACKGROUND: Pallister-Killian syndrome (PKS) is a sporadic genetic disorder caused by the presence of a tissue-specific mosaicism for isochromosome 12p - i(12) (p10) and is characterized by facial dysmorphism including coarse facies, upslanting palpebral fissures, bitemporal alopecia, pigmentary skin anomalies, developmental delay, hypotonia and seizures. Although typical clinical features of PKS commonly exist, clinicians often do not raise the possibility of this diagnosis. RESULTS: We reviewed the medical records of 10 patients with confirmed PKS followed in our service (since 1990 to 2015). Age at diagnosis varied from prenatal to 3 years and clinical features were consistent with those described in the literature. In all patients, peripheral blood karyotypes were normal and cytogenomic study was performed in order to confirm the diagnosis. Three of these patients had PKS diagnosis confirmed by buccal smear MLPA. CONCLUSION: An early conclusion from our results demonstrated that MLPA on buccal smears is a good and non-invasive method to detect extra copies of 12p and should be considered as the first exam, before a skin biopsy for a fibroblast karyotype is performed.

Williams-Beuren Syndrome: A Clinical Study of 55 Brazilian Patients and the Diagnostic Use of MLPA.

Williams-Beuren syndrome (WBS) is a genetic disease caused by a microdeletion in the 7q11.23 region. It is characterized by congenital heart disease, mainly supravalvular aortic stenosis, mental retardation, mild short stature, facial dysmorphisms, and variable abnormalities in different systems. Objectives. To report the clinical findings of 55 Brazilian patients confirmed by multiplex ligation-dependent probe amplification (MLPA). Methods. Patients were followed up for 4 years at the Genetics Unit of the Instituto da Criança of the Hospital das Clínicas, FMUSP, Brazil. A kit specific for WBS was used to detect the 7q11.23 microdeletion. Results. Two patients with negative FISH results had positive MLPA results for WBS. The characteristics of the patients with the deletion were as follows: typical WBS facies (98.2%), neuropsychomotor delay (98.2%), hypersocial behavior (94.5%), hyperacusis (94.5%), and congenital heart disease (81.8%). Conclusions. MLPA was effective in detecting the microdeletion in the 7q11.23 region to confirm the diagnosis of WBS. MLPA was also able to confirm the diagnosis of WBS in two patients with typical clinical characteristics but negative FISH results. Thus, MLPA is a promising method in the diagnostic investigation of WBS. WBS is a multisystemic disorder and therefore requires multidisciplinary care and specific follow-up to prevent complications.

Investigation of Copy Number Variation in Children with Conotruncal Heart Defects / Investigação da Variação no Número de Cópias Gênicas em Crianças com Defeito Cardíaco Conotruncal

Background: Congenital heart defects (CHD) are the most prevalent group of structural abnormalities at birth and one of the main causes of infant morbidity and mortality. Studies have shown a contribution of the copy number variation in the genesis of cardiac malformations. Objectives: Investigate gene copy number variation (CNV) in children with conotruncal heart defect. Methods: Multiplex ligation-dependent probe amplification (MLPA) was performed in 39 patients with conotruncal heart defect. Clinical and laboratory assessments were conducted in all patients. The parents of the probands who presented abnormal findings were also investigated. Results: Gene copy number variation was detected in 7/39 patients: 22q11.2 deletion, 22q11.2 duplication, 15q11.2 duplication, 20p12.2 duplication, 19p deletion, 15q and 8p23.2 duplication with 10p12.31 duplication. The clinical characteristics were consistent with those reported in the literature associated with the encountered microdeletion/microduplication. None of these changes was inherited from the parents. Conclusions: Our results demonstrate that the technique of MLPA is useful in the investigation of microdeletions and microduplications in conotruncal congenital heart defects. Early diagnosis of the copy number variation in patients with congenital heart defect assists in the prevention of morbidity and decreased mortality in these patients. .

Fundamento: Os defeitos cardíacos congênitos são o grupo de anormalidades estruturais mais prevalentes ao nascimento e uma das principais causas de morbidade e mortalidade infantil. Estudos têm mostrado a contribuição da variação no número de cópias na gênese das malformações cardíacas. Objetivos: Investigar a variação no número de cópias gênicas em crianças com defeito cardíaco conotruncal. Métodos: Multiplex Ligation-dependent Probe Amplification (MLPA) foi realizado em 39 pacientes com defeito cardíaco conotruncal. Avaliação clínica e laboratorial foi realizada em todos os pacientes. Os pais dos probandos que apresentaram alterações também foram investigados. Resultados: Variação no número de cópias foi detectada em 7/39 pacientes: deleção 22q11.2, duplicação 22q11.2, duplicação 15q11.2, duplicação 20p12.2, deleção 19p, duplicação 15q e 8p23.2 com duplicação 10p12.31. As características clínicas foram compatíveis com o relatado na literatura associadas com microdeleção/microduplicação encontrada. Nenhuma dessas alterações foi herdada dos pais. Conclusões: Nossos resultados demonstram que a técnica de MLPA é útil na investigação de microdeleções e microduplicações em defeitos cardíacos congênitos conotruncais. O diagnóstico precoce das variações no número de cópias em pacientes com defeito cardíaco congênito auxilia na prevenção de morbidade e diminuição da mortalidade nesses pacientes. .

Investigation of copy number variation in children with conotruncal heart defects.

BACKGROUND: Congenital heart defects (CHD) are the most prevalent group of structural abnormalities at birth and one of the main causes of infant morbidity and mortality. Studies have shown a contribution of the copy number variation in the genesis of cardiac malformations. OBJECTIVES: Investigate gene copy number variation (CNV) in children with conotruncal heart defect. METHODS: Multiplex ligation-dependent probe amplification (MLPA) was performed in 39 patients with conotruncal heart defect. Clinical and laboratory assessments were conducted in all patients. The parents of the probands who presented abnormal findings were also investigated. RESULTS: Gene copy number variation was detected in 7/39 patients: 22q11.2 deletion, 22q11.2 duplication, 15q11.2 duplication, 20p12.2 duplication, 19p deletion, 15q and 8p23.2 duplication with 10p12.31 duplication. The clinical characteristics were consistent with those reported in the literature associated with the encountered microdeletion/microduplication. None of these changes was inherited from the parents. CONCLUSIONS: Our results demonstrate that the technique of MLPA is useful in the investigation of microdeletions and microduplications in conotruncal congenital heart defects. Early diagnosis of the copy number variation in patients with congenital heart defect assists in the prevention of morbidity and decreased mortality in these patients.

Congenital Heart Disease as a Warning Sign for the Diagnosis of the 22q11.2 Deletion / Cardiopatias Congênitas como um Sinal de Alerta para o Diagnóstico da Deleção do 22q11.2

Background: To alert for the diagnosis of the 22q11.2 deletion syndrome (22q11.2DS) in patients with congenital heart disease (CHD). Objective: To describe the main CHDs, as well as phenotypic, metabolic and immunological findings in a series of 60 patients diagnosed with 22q11.2DS. Methods: The study included 60 patients with 22q11.2DS evaluated between 2007 and 2013 (M:F=1.3, age range 14 days to 20 years and 3 months) at a pediatric reference center for primary immunodeficiencies. The diagnosis was established by detection of the 22q11.2 microdeletion using FISH (n = 18) and/or MLPA (n = 42), in association with clinical and laboratory information. Associated CHDs, progression of phenotypic facial features, hypocalcemia and immunological changes were analyzed. Results: CHDs were detected in 77% of the patients and the most frequent type was tetralogy of Fallot (38.3%). Surgical correction of CHD was performed in 34 patients. Craniofacial dysmorphisms were detected in 41 patients: elongated face (60%) and/or elongated nose (53.3%), narrow palpebral fissure (50%), dysplastic, overfolded ears (48.3%), thin lips (41.6%), elongated fingers (38.3%) and short stature (36.6%). Hypocalcemia was detected in 64.2% and decreased parathyroid hormone (PTH) level in 25.9%. Decrease in total lymphocytes, CD4 and CD8 counts were present in 40%, 53.3% and 33.3%, respectively. Hypogammaglobulinemia was detected in one patient and decreased concentrations of immunoglobulin M (IgM) in two other patients. Conclusion: Suspicion for 22q11.2DS should be raised in all patients with CHD associated with hypocalcemia and/or facial dysmorphisms, considering that many of these changes may evolve with age. The 22q11.2 microdeletion should be confirmed by molecular testing in all patients. .

Fundamento: Alertar para o diagnóstico da síndrome da deleção 22q11.2 (SD 22q11.2) em pacientes com cardiopatias congênitas. Objetivo: Descrever as principais cardiopatias, alterações fenotípicas, metabólicas e imunológicas em uma série de 60 pacientes com a SD22q11.2. Métodos: Foram incluídos 60 pacientes com SD22q11.2 avaliados entre 2007 e 2013 (M:F = 1,3; idades entre 14 dias a 20 anos e 3 meses) em um centro pediátrico de referência para imunodeficiências primárias. O diagnóstico foi feito pela detecção da microdeleção 22q11.2 através de FISH (n = 18) e/ou MLPA (n = 42), associados a dados clínicos e laboratoriais. Foram analisadas as cardiopatias, aspectos fenotípicos evolutivos da fácies, a hipocalcemia e alterações imunológicas associadas. Resultados: Cardiopatias congênitas ocorreram em 77% dos casos, sendo que a tetralogia de Fallot ocorreu em 38,3%. Correção cirúrgica da cardiopatia foi realizada em 34 pacientes. Os dismorfismos craniofaciais foram detectados em 41 pacientes: face (60%) e/ou nariz alongados (53,3%), fenda palpebral estreita (50%), orelhas displásicas com hiperdobramento (48,3%), lábios finos (41,6%), dedos alongados (38,3%) e baixa estatura (36,6%). Hipocalcemia foi observada em 64,2% com redução do nível de paratormônio (PTH) em 25,9%. Observou-se número reduzido de linfócitos totais, CD4 e CD8 em 40%, 53,3%, e 33,3%, respectivamente. Detectou-se hipogamaglobulinemia em um paciente e redução das concentrações de imunoglobulina M (IgM) em outros dois pacientes. Conclusão: Deve-se suspeitar da SD22q11.2 em todos os portadores de cardiopatia congênita com hipocalcemia e/ou dismorfismos faciais, ressaltando-se que muitas dessas alterações podem ser evolutivas. ...

Congenital Heart Disease as a Warning Sign for the Diagnosis of the 22q11.2 Deletion.

Background: To alert for the diagnosis of the 22q11.2 deletion syndrome (22q11.2DS) in patients with congenital heart disease (CHD). Objective: To describe the main CHDs, as well as phenotypic, metabolic and immunological findings in a series of 60 patients diagnosed with 22q11.2DS. Methods: The study included 60 patients with 22q11.2DS evaluated between 2007 and 2013 (M:F=1.3, age range 14 days to 20 years and 3 months) at a pediatric reference center for primary immunodeficiencies. The diagnosis was established by detection of the 22q11.2 microdeletion using FISH (n = 18) and/or MLPA (n = 42), in association with clinical and laboratory information. Associated CHDs, progression of phenotypic facial features, hypocalcemia and immunological changes were analyzed. Results: CHDs were detected in 77% of the patients and the most frequent type was tetralogy of Fallot (38.3%). Surgical correction of CHD was performed in 34 patients. Craniofacial dysmorphisms were detected in 41 patients: elongated face (60%) and/or elongated nose (53.3%), narrow palpebral fissure (50%), dysplastic, overfolded ears (48.3%), thin lips (41.6%), elongated fingers (38.3%) and short stature (36.6%). Hypocalcemia was detected in 64.2% and decreased parathyroid hormone (PTH) level in 25.9%. Decrease in total lymphocytes, CD4 and CD8 counts were present in 40%, 53.3% and 33.3%, respectively. Hypogammaglobulinemia was detected in one patient and decreased concentrations of immunoglobulin M (IgM) in two other patients. Conclusion: Suspicion for 22q11.2DS should be raised in all patients with CHD associated with hypocalcemia and/or facial dysmorphisms, considering that many of these changes may evolve with age. The 22q11.2 microdeletion should be confirmed by molecular testing in all patients.

Complex structural rearrangement features suggesting chromoanagenesis mechanism in a case of 1p36 deletion syndrome.

Genome rearrangements are caused by the erroneous repair of DNA double-strand breaks, leading to several alterations that result in loss or gain of the structural genomic of a dosage-sensitive genes. However, the mechanisms that promote the complexity of rearrangements of congenital or developmental defects in human disease are unclear. The investigation of complex genomic abnormalities could help to elucidate the mechanisms and causes for the formation and facilitate the understanding of congenital or developmental defects in human disease. We here report one case of a patient with atypical clinical features of the 1p36 syndrome and the use of cytogenomic techniques to characterize the genomic alterations. Analysis by multiplex ligation-dependent probe amplification and array revealed a complex rearrangement in the 1p36.3 region with deletions and duplication interspaced by normal sequences. We also suggest that chromoanagenesis could be a possible mechanism involved in the repair and stabilization of this rearrangement.

Investigação da variação no número de cópias genômicas (CNVs) em pacientes com anomalias congênitas e atraso de desenvolvimento neuropsicomotor (ADNPM) pela técnica de MLPA (Multiplex Ligation-dependent Probe Amplification) / Investigation of the copy number variation (CNVs) in patients with congenital anomalies (CA) and mental retardation (MR) using the MLPA (Multiplex Ligation-dependent Probe Amplification) technique

INTRODUÇÃO: Os desequilíbrios genômicos constituem causa frequente de abortamento, anomalias congênitas (AC) e atraso de desenvolvimento neuropsicomotor (ADNPM). O aprimoramento de novas técnicas de diagnóstico citogenômico, como por exemplo, a MLPA (Multiplex Ligation-dependent Probe Amplification) e a triagem ampla do DNA utilizando arrays, mostraram que a alteração no número normal de cópias genômicas (CNVs) influencia na patogenicidade dos fenótipos em diversas síndromes. OBJETIVOS: Com isso, os objetivos do presente estudo foram identificar CNVs em pacientes com MC e ADNPM utilizando a técnica de MLPA e, a partir dos resultados alterados, aplicar da técnica de array para a identificação de possíveis rearranjos complexos, além de associar as alterações moleculares encontradas com o fenótipo dos pacientes. MÉTODOS: Participaram do estudo 416 pacientes com MC e ADNPM. As amostras de DNA foram analisadas utilizando a técnica de MLPA com kits comerciais para as principais síndromes de microdeleções (P064) e regiões subteloméricas (P036 e P070). Dois kits de MLPA específicos para as regiões 7q11.23 (P029) e 22q11.2 (P250) também foram utilizados para complementar a identificação de CNVs atípicas. Entre os casos que apresentavam alterações pela técnica de MLPA, 15 pacientes foram submetidos à técnica de array, utilizando três diferentes plataformas: Agilent SurePrint G3 Genoma Humano microarray 180 K, HumanCytoSNP-12 BeadChip, CytoScan(TM) HD array 6.0 Affymetrix®. RESULTADOS: A análise molecular pela técnica de MLPA possibilitou a detecção de microdeleções e/ou microduplicações em 97 pacientes sendo que: em 46 pacientes foi possível encontrar alterações utilizando apenas o kit P064 (microdeleções), em 34 pacientes utilizando apenas os kits P036 e P070 (regiões subteloméricas) e em quatro pacientes só foi possível identificar a alteração utilizando outro kit de MLPA (P250), específico para alterações genômicas em 22q11.2. Rearranjos complexos, envolvendo mais...

INTRODUCTION: Genomic imbalances are the most common cause of miscarriage, congenital anomalies (CA) and mental retardation (MR). With the improvement of new cytogenomics diagnostic techniques, such as the MLPA (Multiplex Ligation-dependent Probe Amplification) and the array techniques, it have been shown that changes in the normal gene copy number influence the pathogenic variability of phenotypes in different syndromes. AIMS: The aims of the present study were to identify CNVs in patients with CM and RM using the MLPA technique and, from the abnormalities results, to apply the array methodology for the identification of complex rearrangements. Furthermore, the study aimed to associate the alterations found by molecular techniques with the phenotype of patients. METHODS: 416 patients with CM and RM participated in the study. The samples were analysed by MLPA technique with commercial kits for the main microdeletion syndromes (P064) and subtelomeric regions (P036 and P070). Two more MLPA kits for specific regions 7q11.23 (P029) and 22q11.2 (P250) were used to confirm the altered results and to complement some results with the identification of atypical abnormalities. From the patients who presented abnormalities by MLPA technique, 15 underwent by microarray-based comparative genomic hybridization (CGH-array) technique, using three different platform: Agilent SurePrint G3 Human Genome microarray 180 kb, HumanCytoSNP -12 BeadChip, CytoScan(TM) HD ® and Affymetrix 6.0. RESULTS: The molecular analysis by MLPA technique allowed the detection of microdeletions and/or microduplications in 97 patients. In 46 patients it was possible to find genomic alteration using only MLPA kit P064 and in 34 patients using only the subtelomeric kits P036 and P070. For four patients it was only possible to identify the genomic abnormalities using another specific MLPA kit (P250), involving the 22q11.2 region. Complex rearrangements involving more than three chromosomes were detected...

Estresse em crianças e adolescentes com Síndrome de Williams-Beuren em idade escolar / Stress in children and adolescents with Williams-Beuren syndrome in school age / Estrés en niños y adolescentes con síndrome de Williams-Beuren en edad escolar

Síndrome de Williams-Beuren é uma doença de múltiplos órgãos causada por microdeleção de 25 genes no cromossomo 7 (q11.23), sugerindo uma vulnerabilidade ao estresse. Objetivamos determinar se crianças e adolescentes com síndrome de Williams-Beuren apresentam níveis elevados de estresse. Avaliamos 40 indivíduos em idade escolar, com diagnóstico de síndrome de Williams-Beuren e grupo controle. Os instrumentos utilizados: Escala de Estresse Infantil (ESI), Escala de Inteligência para Crianças (WISC), Escala de Inteligência para Adultos (WAIS) e um questionário semiestruturado. No grupo com o SWB, 50% tinham altos níveis de estresse em comparação com 28,6% no grupo controle, diferença altamente significativa estatisticamente (p <0,001). De escola de inclusão, 40,7% apresentaram maior estresse; de escola especial, 69,2% (p> 0,140). Indivíduos com síndrome de Williams mostram índice elevado de estresse. Este estudo destaca a necessidade de orientação sobre a síndrome a pais e gestão escolar, com foco na redução de possíveis fatores ambientais estressantes.

Williams-Beuren syndrome is a multiorgan disease caused by microdeletion of 25 genes on chromosome 7 (q11.23), suggesting a vulnerability to stress. In this study we aim to determine whether children and adolescents with Williams-Beuren syndrome have high levels of stress. We studied 40 subjects of school age, with confirmed diagnosis of Williams-Beuren syndrome and control group. The instruments used: Child Stress Scale (ESI), Intelligence Scale for Children (WISC), Adult Intelligence Scale (WAIS), and a questionnaire semi-estructured. In the group with SWB, 50% had high levels of stress compared with 28.6% in the control group, statistically highly significant difference (p <0.001). In Inclusion school, 40.7% revealed higher stress; special school 69.2% (p> 0,140) difference was not statistically significant. Individuals with Williams syndrome show high level of stress. This study highlights the need for guidance about the syndrome to parents and school management, with focus on reducing of possible environmental stressors factors.

El Síndrome de Williams-Beuren es una enfermedad de múltiplos órganos causada por microdeleción de 25 genes en el cromosoma 7 (q11.23) sugiriendo una vulnerabilidad al estrés. El objetivo del estudio fue determinar si niños y adolescentes con síndrome de Williams-Beuren presentan niveles elevados de estrés. Evaluamos 40 individuos en edad escolar con diagnóstico de síndrome de Williams-Beuren y grupo control. Los instrumentos utilizados: Escala de Estrés Infantil (ESI), Escala de Inteligencia para niños (WISC), Escala de Inteligencia para Adultos (WAIS) y un cuestionario semi-estructurado. En el grupo con el SWB 50% tenían altos niveles de estrés en comparación con 28,6% en el grupo control, diferencia altamente significativa estadísticamente (p <0,001). De la escuela de inclusión 40,7% presentaron mayor estrés; de la escuela especial 69,2% (p> 0,140). Individuos con Síndrome de Williams muestran índice elevado de estrés. Este estudio destaca la necesidad de orientación sobre el síndrome a padres y gestión escolar con enfoque en la reducción de posibles factores ambientales estresantes.

Estresse em crianças e adolescentes com Síndrome de Williams-Beuren em idade escolar / Stress in children and adolescents with Williams-Beuren syndrome in school age / Estrés en niños y adolescentes con síndrome de Williams-Beuren en edad escolar

Síndrome de Williams-Beuren é uma doença de múltiplos órgãos causada por microdeleção de 25 genes no cromossomo 7 (q11.23), sugerindo uma vulnerabilidade ao estresse. Objetivamos determinar se crianças e adolescentes com síndrome de Williams-Beuren apresentam níveis elevados de estresse. Avaliamos 40 indivíduos em idade escolar, com diagnóstico de síndrome de Williams-Beuren e grupo controle. Os instrumentos utilizados: Escala de Estresse Infantil (ESI), Escala de Inteligência para Crianças (WISC), Escala de Inteligência para Adultos (WAIS) e um questionário semiestruturado. No grupo com o SWB, 50% tinham altos níveis de estresse em comparação com 28,6% no grupo controle, diferença altamente significativa estatisticamente (p <0,001). De escola de inclusão, 40,7% apresentaram maior estresse; de escola especial, 69,2% (p> 0,140). Indivíduos com síndrome de Williams mostram índice elevado de estresse. Este estudo destaca a necessidade de orientação sobre a síndrome a pais e gestão escolar, com foco na redução de possíveis fatores ambientais estressantes.(AU)

Williams-Beuren syndrome is a multiorgan disease caused by microdeletion of 25 genes on chromosome 7 (q11.23), suggesting a vulnerability to stress. In this study we aim to determine whether children and adolescents with Williams-Beuren syndrome have high levels of stress. We studied 40 subjects of school age, with confirmed diagnosis of Williams-Beuren syndrome and control group. The instruments used: Child Stress Scale (ESI), Intelligence Scale for Children (WISC), Adult Intelligence Scale (WAIS), and a questionnaire semi-estructured. In the group with SWB, 50% had high levels of stress compared with 28.6% in the control group, statistically highly significant difference (p <0.001). In Inclusion school, 40.7% revealed higher stress; special school 69.2% (p> 0,140) difference was not statistically significant. Individuals with Williams syndrome show high level of stress. This study highlights the need for guidance about the syndrome to parents and school management, with focus on reducing of possible environmental stressors factors.(AU)

El Síndrome de Williams-Beuren es una enfermedad de múltiplos órganos causada por microdeleción de 25 genes en el cromosoma 7 (q11.23) sugiriendo una vulnerabilidad al estrés. El objetivo del estudio fue determinar si niños y adolescentes con síndrome de Williams-Beuren presentan niveles elevados de estrés. Evaluamos 40 individuos en edad escolar con diagnóstico de síndrome de Williams-Beuren y grupo control. Los instrumentos utilizados: Escala de Estrés Infantil (ESI), Escala de Inteligencia para niños (WISC), Escala de Inteligencia para Adultos (WAIS) y un cuestionario semi-estructurado. En el grupo con el SWB 50% tenían altos niveles de estrés en comparación con 28,6% en el grupo control, diferencia altamente significativa estadísticamente (p <0,001). De la escuela de inclusión 40,7% presentaron mayor estrés; de la escuela especial 69,2% (p> 0,140). Individuos con Síndrome de Williams muestran índice elevado de estrés. Este estudio destaca la necesidad de orientación sobre el síndrome a padres y gestión escolar con enfoque en la reducción de posibles factores ambientales estresantes.(AU)

FGFR4 profile as a prognostic marker in squamous cell carcinoma of the mouth and oropharynx.

BACKGROUND: Fibroblast growth factor receptor 4 (FGFR4) is a member of a receptor tyrosine kinase family of enzymes involved in cell cycle control and proliferation. A common single nucleotide polymorphism (SNP) Gly388Arg variant has been associated with increased tumor cell motility and progression of breast cancer, head and neck cancer and soft tissue sarcomas. The present study evaluated the prognostic significance of FGFR4 in oral and oropharynx carcinomas, finding an association of FGFR4 expression and Gly388Arg genotype with tumor onset and prognosis. PATIENTS AND METHODS: DNA from peripheral blood of 122 patients with oral and oropharyngeal squamous cell carcinomas was used to determine FGFR4 genotype by PCR-RFLP. Protein expression was assessed by immunohistochemistry (IHC) on paraffin-embedded tissue microarrays. RESULTS: Presence of allele Arg388 was associated with lymphatic embolization and with disease related premature death. In addition, FGFR4 low expression was related with lymph node positivity and premature relapse of disease, as well as disease related death. CONCLUSION: Our results propose FGFR4 profile, measured by the Gly388Arg genotype and expression, as a novel marker of prognosis in squamous cell carcinoma of the mouth and oropharynx.