Abstract Characterization of specific birth defects is essential for conducting scientific investigations, care and therapeutic strategies. This article describes demographic, clinical and genetic aspects, risk factors and access to treatment of Brazilian patients with orofacial clefts registered in a specialized collaborative center of the Brazilian Database on Craniofacial Anomalies (BDCA). We interviewed 70 individuals with typical orofacial clefts using a standard instrument from the database and subjected them to genetic testing. The patients were grouped as syndromic and non-syndromic. The majority of individuals were of lower middle class, native ancestry and syndromic. There was a significant difference in the type of clefts regarding gender. There was no significant difference between bilateral and unilateral, between the side affected, right and left, or familial recurrence related to type of oral cleft. The risk factor familial recurrence was significantly higher among non-syndromic cases. Etiological factors were identified or suggested in 62.5% of the syndromic cases. There was a delay in diagnosis and in access to treatment in most cases. We concluded that gender, native ancestry and low family income represent risk factors. Furthermore, the distribution by cleft types and gender is similar to previous studies. The results can guide scientific investigations and care policies.

Abstract Birth defects (BDs) are functional and structural alterations in embryonic or fetal development. With an incidence of approximately 3-5%, BDs are a leading cause of infant mortality and lifelong disability. A population-based prospective case-control study was conducted for one year with 5204 infants, between March 1st, 2011 and February 29th, 2012 in the city of São José do Rio Preto, State of São Paulo, Brazil. The incidence of BDs was 3.2% [95% confidence interval (95%CI): 2.8-3.8%]. The most common congenital anomalies were heart diseases in isolation (11.2%; 95%CI: 7.3-16.9%) followed by Down syndrome (9.5%; 95%CI: 5.9-14.8%), neural tube defects (8.9%; 95%CI: 5.4-14.1), urinary tract anomalies (7.7%; 95%CI: 4.4-12.7%), and polydactyly (7.0%; 95%CI: 4.0-12.0%). The majority of mothers with Down syndrome babies had advanced age. Family members with the same BD, maternal alcohol consumption, gestational diabetes, and previous miscarriages were the most frequent risk factors. The results were similar to published data from other countries except for the incidence of Down syndrome, which was twice as high as reported by other authors and is probably due to the high sociocultural level of the region where the current study was performed, leading to pregnancies at older maternal age.

Resumo Objetivo: Identificar desequilíbrios genômicos patogênicos em pacientes que apresentam cardiopatias congênitas (CC) e anomalias extracardíacas e exclusão da síndrome de deleção 22q11.2 (SD22q11.2). Métodos: Foram avaliados por microarray cromossômico (CMA) 78 pacientes negativos para a deleção 22q11.2, previamente testados por hibridação in situ com fluorescência (FISH) e/ou amplificação de múltiplas sondas dependentes de ligação (MLPA). Resultados: Foram identificadas variações do número de cópias de DNA (CNVs) clinicamente significativas (≥ 300 kb) em 10% (8/78) dos casos, além de CNVs potencialmente relevantes em dois casos (duplicação de 993 kb em 15q21.1 e duplicação de 706 kb em 2p22.3). Genes envolvidos como IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1 e LTPB1 são conhecidos por atuar no desenvolvimento cardíaco e podem ser genes candidatos a CC. Conclusão: Esses dados mostram que pacientes que apresentam CC, com anomalias extracardíacas e exclusão da SD22q11.2, devem ser investigados por CMA. Ainda, este estudo enfatiza a possível função das CNVs nas CC.

Abstract Objective: To identify pathogenic genomic imbalances in patients presenting congenital heart disease (CHD) with extra cardiac anomalies and exclusion of 22q11.2 deletion syndrome (22q11.2 DS). Methods: 78 patients negative for the 22q11.2 deletion, previously screened by fluorescence in situ hybridization (FISH) and/or multiplex ligation probe amplification (MLPA) were tested by chromosomal microarray analysis (CMA). Results: Clinically significant copy number variations (CNVs ≥300 kb) were identified in 10% (8/78) of cases. In addition, potentially relevant CNVs were detected in two cases (993 kb duplication in 15q21.1 and 706 kb duplication in 2p22.3). Genes inside the CNV regions found in this study, such as IRX4, BMPR1A, SORBS2, ID2, ROCK2, E2F6, GATA4, SOX7, SEMAD6D, FBN1, and LTPB1 are known to participate in cardiac development and could be candidate genes for CHD. Conclusion: These data showed that patients presenting CHD with extra cardiac anomalies and exclusion of 22q11.2 DS should be investigated by CMA. The present study emphasizes the possible role of CNVs in CHD.

INTRODUÇÃO: O exame intraoperatório por congelação tornou-se um procedimento de rotina na avaliação do linfonodo sentinela axilar no câncer de mama. OBJETIVOS: Avaliar a acurácia e a sensibilidade do FS na detecção de metástases em linfonodo sentinela axilar e investigar o valor preditivo para metástases de variáveis, como idade dos pacientes, estadiamento, tipo histológico, grau e expressão do receptor de estrogênio do tumor. MATERIAL E MÉTODOS: Foram analisados, retrospectivamente, os resultados de 177 procedimentos de congelação. A idade dos pacientes e as características dos tumores foram organizadas em um banco de dados e a relação com a presença de metástases foi analisada. RESULTADOS: Foram detectadas metástases em 22 (12%) casos. Todas as macrometastases e uma micrometastases foram detectadas pelo método de congelação. Micrometastases adicionais foram identificadas nas análises pós-operatórias, cinco por coloração com hematoxilina e eosina (H) e três por imuno-histoquímica. O método de congelação mostrou acurácia geral de 95%, sensibilidade de 64% e especificidade de 100%. Nenhuma associação significativa foi observada entre a presença de metástases e as variáveis analisadas. CONCLUSÃO: Nossos resultados mostram que o exame por congelação possui acurácia e sensibilidade elevadas para a detecção de macrometastases; no entanto, é pouco eficiente na identificação de micrometastases. O uso de imuno-histoquímica melhora a detecção de metástases na análise pós-operatória. A idade do paciente e as características do tumor, como estadiamento, tipo histológico, grau e a expressão do receptor de estrogênio têm de valor preditivo baixo para metástases nodais em câncer de mama.

INTRODUCTION: Intraoperative frozen section analysis has become a routine procedure to evaluate the status of axillary sentinel lymph nodes in breast cancer. OBJECTIVES: To evaluate the accuracy and sensitivity of FS in the detection of metastases in axillary sentinel lymph nodes and to investigate the predictive value of variables such as patients' age, tumor staging, histology, grade, and estrogen receptor expression. MATERIAL AND METHODS: We analyzed retrospectively the results of 177 FS procedures. The patients' age and tumor characteristics were organized in a database and the association with the presence of metastases was analyzed. RESULTS: Metastases were detected in 22 cases (12%). All macrometastases and one micrometastasis were detected by FS. Additional micrometastases were detected in post-operative analysis, from which five were determined by hematoxylin and eosin staining (H) and three by immunohistochemistry (IHC). FS diagnosis data proved to have an overall accuracy of 95%, sensitivity of 64%, and specificity of 100%. None of the analyzed variables showed significant association with lymph node metastases. CONCLUSION: Our results show that intraoperative FS is a highly accurate and sensitive method to detect macrometastases. However, it is inaccurate in the detection of micrometastases. The use of IHC improves the detection of micrometastases in postoperative analyses. The patient's age and tumor characteristics such as staging, histology, grade and estrogen receptor expression have low predictive value for lymph node metastasis in breast cancer.

A estimulação precoce traz benefícios significativos aos indivíduos com síndrome de Down (SD), a seus familiares e à sociedade. Este estudo avaliou o efeito do aconselhamento genético (AG) sobre o comportamento de adesão de pais ao tratamento de estimulação, os fatores que influenciaram o acesso ao AG e ao tratamento e a satisfação com o AG. Participaram do estudo 12 casais de pais, entrevistados mediante roteiros semiestruturados, em três etapas: pré-AG, pós-AG e follow-up. Apesar da dificuldade de acesso ao AG e aos tratamentos, a maioria ficou satisfeita com o AG recebido. Este processo influenciou significantemente o comportamento de adesão ao tratamento, pois, provavelmente, as orientações recebidas foram responsáveis pela mudança do comportamento. Regras bem-definidas promovem modificações comportamentais e são úteis na SD. Operam como estímulo discriminativo para o comportamento de adesão dos pais ao tratamento de seus filhos.

Early stimulation provides significant benefits for Down syndrome individuals, their families and society. This study evaluated the effect of genetic counseling on the adherence behavior of parents to stimulation therapy, the factors that influence access to genetic counseling and to treatment and the satisfaction supplied by counseling. The parents of 12 individuals participated in this study using routine semi-structured interviews at three stages: before counseling, after counseling and follow-up. In spite of the difficulties to access genetic counseling and treatment, most parents were satisfied with the service. This process significantly influenced the adherence to treatment as, probably, the guidance was responsible for changes in behavior. Well-defined rules, useful in Down syndrome, promoted behavioral changes. Rules function as a discriminative stimulus for parents to adherence to the treatment of their children.

La estimulación precoz trae beneficios significativos para los individuos con síndrome de Down (SD), familiares y sociedad. Este estudio evaluó el efecto del asesoramiento genético (AG) sobre el comportamiento de adhesión de los padres al tratamiento de estimulación, los factores que influenciaron el acceso al AG, al tratamiento y la satisfacción con el AG. Participaron del estudio 12 parejas de padres, entrevistados con el uso de cuestionario semi-estructurados, en tres etapas: pre-AG, pos-AG y follow-up A pesar de la dificultad de acceso al AG y a los tratamientos, la mayoría se quedó satisfecho con el AG recibido. Este proceso influyó significativamente en el comportamiento de adhesión al tratamiento pues, probablemente, las orientaciones recibidas fueron responsables por el cambio de comportamiento. Reglas bien definidas promueven modificaciones de comportamiento y son útiles en el SD. Operan como estímulo discriminatorio para el comportamiento de adhesión de los padres al tratamiento de sus hijos.

The velocardiofacial syndrome (VCFS), a condition associated with 22q11.2 deletions, is characterized by a typical facies, palatal anomalies, learning disabilities, behavioral disturbances and cardiac defects. We investigated the frequency of these chromosomal deletions in 16 individuals with VCFS features who presented no cardiac anomalies, one of the main characteristics of VCFS. Fluorescent in situ hybridization (FISH) with the N25 (D22S75; 22q11.2) probe revealed deletions in ten individuals (62%). Therefore, even in the absence of cardiac anomalies testing for the 22q11.2 microdeletions in individuals showing other clinical features of this syndrome is recommended.

INTRODUÇÃO: Os linfomas gástricos primários representam cerca de 50% dos linfomas não-Hodgkin extranodais e de 2% a 8% das neoplasias malignas do estômago. A maioria é formada pela proliferação de linfócitos B, que ocorre a partir do tecido linfóide associado à mucosa. Esse tecido, inexistente no estômago em condições normais, surge como conseqüência de gastrite crônica, na maioria das vezes associada à bactéria Helicobacter pylori. A inflamação crônica provocada pela infecção bacteriana parece sensibilizar linfócitos T, levando a estímulo constante de linfócitos B, que passam a proliferar inicialmente em padrão reacional. Posteriormente surgem alterações genômicas nessas células, que provocam ganho proliferativo, seleção clonal e transformação neoplásica, dando origem a linfoma de baixo grau. Alterações genéticas adicionais, como mutações em p53, podem induzir transformação para alto grau. MATERIAL E MÉTODOS: Foram estudados 32 casos de linfomas gástricos: 15 de baixo e 17 de alto grau. Foram investigados sexo e idade dos pacientes, características morfológicas das lesões,índice de proliferação celular e colonização pelo Helicobacter pylori. Verificou-se a expressão de CD20, Ki-67, p53, BCL-2 e BCL-6 por imuno-histoquímica. RESULTADOS: Os linfomas gástricos ocorreram mais freqüentemente em homens, e a faixa etária mais elevada foi observada no grupo de baixo grau. Lesões linfoepiteliais foram observadas em 93% dos linfomas desse grupo. O índice de proliferação celular e a expressão do p53 foram mais elevados no grupo de alto grau. A expressão do BCL-2 foi mais elevada nos linfomas de baixo grau. Não houve diferença significante quanto à expressão do BCL-6 nos dois grupos. CONCLUSÃO: Os resultados sugerem a participação dos genes p53 e BCL-2 na patogênese e na evolução dos linfomas gástricos.

INTRODUCTION: Primary gastric lymphomas account for 50% of the extranodal non-Hodgkin lymphoma and for 2% to 8% of the malignant gastric neoplasms. Most of them arise from B lymphocytes proliferation of the mucosaassociated lymphoid tissue. This tissue is not present in stomach in normal conditions; it arises secondarily to chronic gastritis, frequently associated to the bacterium Helicobacter pylori. Chronic inflammation of the bacterium infection seems to induce T lymphocytes, leading to persistent stimulation of B lymphocytes that initially proliferate in a reactive fashion. After that, there are some genomic changes in the lymphoid cells, including BCL-2 and BCL-6 mutation inducing some proliferating gain, clonal selection and neoplastic transformation, originating the lowgrade gastric lymphoma. Additional genetic changes, like p53 mutation, can induce high-grade transformation. MATERIAL AND METHODS: We revised 32 cases of gastric lymphomas: 15 low and 17 high-grade. The age and the gender of those patients were investigated. The morphological characteristics of the lesions and Helicobacter pylori colonization were assessed. Immunohistochemistry to CD20, Ki-67, p53, BCL-2 and BCL-6 was performed. RESULTS: Gastric lymphomas occur more frequently in males and patients' age is more advanced in the low grade group. Lymphoepithelial lesions were observed in 93% of this lymphoma group. The proliferative rate and p53 expression were greater in the high grade group. The BCL-2 expression was higher in the low grade lymphoma group. There were no significant differences in BCL-6 expression in both groups. CONCLUSION: The results suggest that genes P53 and BCL-2 play a role in the pathogenesis and evolution of gastric lymphomas.

Relatamos uma criança do sexo feminino com tetrassomia da região cromossômica 15q11-q13 e distúrbio autístico associado com retardo mental, problemas de desenvolvimento e distúrbios comportamentais. A combinação de metodologias da citogenética clássica e molecular pela técnica de hibridação in situ fluorescente, demonstrou o cariótipo como 47,XX,+mar.ish der(15) (D15Z1++,D15S11++,GABRB3++,PML). Duplicação do segmento 15q proximal representa a mais consistente anomalia cromossômica relatada em associação com autismo. A contribuição dos genes das subunidades do recepetor GABA, assim como outros genes mapeados nessa região, para os sintomas clínicos da doença é discutida.

We report a female child with tetrasomy of the 15q11-q13 chromosomal region, and autistic disorder associated with mental retardation, developmental problems and behavioral disorders. Combining classical and molecular cytogenetic approaches by fluorescence in situ hybridization technique, the karyotype was demonstrated as 47,XX,+mar.ish der(15)(D15Z1++,D15S11++,GABRB3++,PML-). Duplication of the 15q proximal segment represents the most consistent chromosomal abnormality reported in association with autism. The contribution of the GABA receptor subunit genes, and other genes mapped to this region, to the clinical symptoms of the disease is discussed.