Duplication 9p and their implication to phenotype

Background: Trisomy 9p is one of the most common partial trisomies found in newborns. We report the clinical features and cytogenomic findings in five patients with different chromosome rearrangements resulting in complete 9p duplication, three of them involving 9p centromere alterations.Methods: the rearrangements in the patients were characterized by G-banding, SNP-array and fluorescent in situ hybridization (FISH) with different probes.Results: Two patients presented de novo dicentric chromosomes: der(9; 15)t(9; 15)(p11.2;p13) and der(9; 21)t(9; 21) (p13.1;p13.1). One patient presented two concomitant rearranged chromosomes: a der(12)t(9; 12)(q21.13;p13.33) and an psu i(9)(p10) which showed FISH centromeric signal smaller than in the normal chromosome 9. Besides the duplication 9p24.3p13.1, array revealed a 7.3 Mb deletion in 9q13q21.13 in this patient. the break in the psu i(9) (p10) probably occurred in the centromere resulting in a smaller centromere and with part of the 9q translocated to the distal 12p with the deletion 9q occurring during this rearrangement. Two patients, brother and sister, present 9p duplication concomitant to 18p deletion due to an inherited der(18)t(9; 18)(p11.2; p11.31) mat.Conclusions: the patients with trisomy 9p present a well-recognizable phenotype due to facial appearance, although the genotype-phenotype correlation can be difficult due to concomitant partial monosomy of other chromosomes. the chromosome 9 is rich in segmental duplication, especially in pericentromeric region, with high degree of sequence identity to sequences in 15p, 18p and 21p, chromosomes involved in our rearrangements. Thus, we suggest that chromosome 9 is prone to illegitimate recombination, either intrachromosomal or interchromosomal, which predisposes it to rearrangements, frequently involving pericentromeric regions.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Morphol & Genet, BR-04023900 São Paulo, BrazilUniv São Paulo, Dept Pathol, Lab Citogen, BR-05403000 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, BR-04023900 São Paulo, BrazilFAPESP: 2012/51150-0FAPESP: 2012/15572-7Web of Scienc

Neurodesenvolvimento e fenótipo cognitivo comportamental na síndrome kabuki

Objective: To describe neurocognitive and behavioral aspects in pediatric patients diagnosed with Kabuki Syndrome, a rare genetic condition whose neurobehavioral phenotype is not well known and involves associations with clinical and socioenvironmental variables. Method: This is a case-series observational study, whose sample involved 8 male patients aged 2 to 18 years-old. All of them underwent clinical genetic evaluation, as well as intellectual, behavioral and socio-environmental performance evaluations through specific tests and scales, prioritizing the normative data validated to the Brazilian population. Behavioral phenotype evaluation investigated qualitative standards for verbal and non-verbal performance, global cognitive performance in intelligence neuropsychological tests and behavioral scales of adaptive and neuropsychomotor development. The emphasis was on the identification of areas with greater fragility and better potentiality, in and inter- and intra-subject perspective, considering the influence of environmental variables such as family income, parents? level of education and parental style. Results: Among clinical aspects, there was a prevalence of neurodevelopmental delay, oral and muscular hypotonia, and mouth breathing in all samples. There was nocturnal lagophtalmos in seven patients and sleep alterations in six of the eight cases. Intellectual quotient ranged between compatibility with borderline classification in three patients, slight disability in one case and non-quantifiable in three cases with massive losses in adaptive skills. There was a significant verbal index improvement when compared to the execution index. That indicates an immature development of skills with greater dependence on visual-spatial processing. In an assessment with the Vineland Scale, the fields of adaptive skills related to communication and daily chores were the most impaired, in comparison to socialization and motor skills. Schooling difficulties were reported in all patients in school age, even those with no intellectual disability. Two cases met the criteria for Austistic Spectrum Disorder. Neuropsychological evaluation revealed indicators for visual-spatial and visual constructive disorders, as well as in the executive function, regardless of the presence of intellectual disability. Internalizing behavior problems were more frequente than externalizing ones. Conclusion: Findings suggest that neurodevelopmental delays, oral and global hypotonia, mouth breathing, lagophtalmia, and learning difficulties may be considered supporting criteria in the diagnosis of Kabuki Syndrome, additionally to the five cardinal criteria established by literature. Research on sleep disorders is suggested. Despite the heterogeneity in cognitive and behavioral expressions, intellectual performance in this syndrome may reach average levels in some cases, with immaturity in communication skills, daily chores and executive function, visual-spatial and visual-constructive disorders, as well as behavioral problems of the internalizing type. Thus, delimiting the behavioral phenotype in clinical, social-emotional and integrated adaptive patterns may contribute for the elaboration of positive strategies for early detection and intervention in patients with Kabuki Syndrome.Objetivo: Descrever os aspectos neurocognitivos e comportamentais em pacientes pediátricos com diagnóstico de Síndrome Kabuki, uma condição genética rara cujo fenótipo neurocomportamental é pouco conhecido, compreendendo associações com variáveis clínicas e socioambientais. Métodos: Trata-se de um estudo observacional do tipo série de casos. A amostra envolveu oito pacientes do sexo masculino, com idades entre dois e 18 anos. Todos os casos foram submetidos a exame genético clínico, bem como a avaliações do desempenho intelectual,comportamental e socioambiental por meio de testes e escalas específicas, priorizando-se os dados normativos validados para a população brasileira. A avaliação do fenótipo comportamental investigou padrões qualitativos de desempenho verbal e não verbal, desempenho cognitivo global em testes neuropsicológicos de inteligência e escalas comportamentais de desenvolvimento neuropsicomotor e adaptativo, procurando-se identificar os domínios de maior fragilidade e os de melhor potencialidade, em uma perspectiva interssujeitos e intrassujeitos considerando-se a influência de variáveis ambientais como renda familiar, escolarização dos pais, estilo parental. Resultados: Dentre os aspectos clínicos observou-se, em toda a amostra, atraso do neurodesenvolvimento, hipotonia muscular global e oral e respiração bucal. Identificou-se a presença de lagoftalmo noturno em sete pacientes e alterações do sono, em seis dos oito casos. O quociente intelectual variou de rendimento compatível com a classificação limítrofe em três pacientes, deficiência leve em um caso e não quantificável em três casos com intenso prejuízo nas habilidades adaptativas. Houve significativo melhor desempenho no índice verbal em comparação ao de execução, indicando imaturidade no desenvolvimento de habilidades relacionadas ao processamento viso espacial. Na avaliação pela escala Vineland, constatou-se maior prejuízo nos domínios das habilidades adaptativas relativos à comunicação e atividades de vida diária, em comparação aos de socialização e motricidade. Dificuldades escolares foram referidas em todos os pacientes em idade escolar, mesmo naqueles sem deficiência intelectual. Dois casos preencheram critérios para Transtorno do Espectro Autista. A avaliação neuropsicológica revelou indicadores de disfunção viso espacial e visoconstrutiva, bem como no funcionamento executivo, independentemente da presença de deficiência intelectual. Problemas comportamentais internalizantes foram mais frequentes que os externalizantes. Conclusões: Os achados sugerem que atraso do neurodesenvolvimento, hipotonia muscular global e oral, respiração bucal, lagoftalmo e dificuldade escolar podem ser considerados critérios de apoio no diagnóstico desta síndrome, além dos critérios cardinais estabelecidos na literatura. Sugere-se ainda pesquisar problemas do sono. Apesar da heterogeneidade das manifestações cognitivas e comportamentais, o desempenho intelectual nesta síndrome pode corresponder a níveis médios em alguns casos, com imaturidade nas habilidades de comunicação, nas atividades de vida diária e no funcionamento executivo, disfunções viso espaciais e visoconstrutivas, bem como presença de problemas comportamentais do tipo internalizantes. Assim, a delimitação do fenótipo comportamental em moldes clínicos, sócio-emocionais e adaptativos integrados pode contribuir para a elaboração de estratégias positivas de detecção e intervenção precoces em pacientes com Síndrome Kabuki.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016

A model for pediatric and neuropsychological screening assessment of children with learning disabilities

ABSTRACT Objectives: The high frequency of learning difficulties, attention disorders or developmental delay in children in the early years of schooling has resulted in a greater demand for pediatric services. Such services generally include assessments covering various specialties, are lengthy and often inaccessible to families due to prohibitively high cost. This paper presents an economically efficient model of interdisciplinary diagnosis. Methods: A group of 109 Brazilian students from public schools aged between 5 and 14 years old, referred by teachers for a history of learning disabilities, behavioral changes or language problems, was evaluated at the NANI (Nucleo de Atendimento Neuropsicologico Infantil). Assessments were performed simultaneously during a single day's attendance and comprised clinical-genetic examination, behavioral assessment and neuropsychological screening, specially developed for the process. The multiaxial system of DSM-IV was adopted for diagnostic description. Results: The results revealed heterogeneity in diagnoses which included specific learning disorders (25.7%), mild intellectual disabilities (17.43%), as well as suspected dysmorphic features (11.93%). Logistic regression showed good sensitivity of neuropsychological screening in the detection of predictive factors for specific developmental disorders, while working memory (p=0.05) and language (p=0.02) problems were found to be higher risk. Conclusions: The model adopted proved to be useful for defining the diagnosis of several conditions in infancy, and can be incorporated into specialized clinics such as psychiatric or developmental pediatric services