Gene expression profiling of bone marrow mesenchymal stem cells from Osteogenesis Imperfecta patients during osteoblast differentiation.

Mesenchymal stem cells (MSCs) are precursors present in adult bone marrow that are able to differentiate into osteoblasts, adipocytes and chondroblasts that have gained great importance as a source for cell therapy. Recently, a number of studies involving the analysis of gene expression of undifferentiated MSCs and of MSCs in the differentiation into multiple lineage processes were observed but there is no information concerning the gene expression of MSCs from Osteogenesis Imperfecta (OI) patients. Osteogenesis Imperfecta is characterized as a genetic disorder in which a generalized osteopenia leads to excessive bone fragility and severe bone deformities. The aim of this study was to analyze gene expression profile during osteogenic differentiation from BMMSCs (Bone Marrow Mesenchymal Stem Cells) obtained from patients with Osteogenesis Imperfecta and from control subjects. Bone marrow samples were collected from three normal subjects and five patients with OI. Mononuclear cells were isolated for obtaining mesenchymal cells that had been expanded until osteogenic differentiation was induced. RNA was harvested at seven time points during the osteogenic differentiation period (D0, D+1, D+2, D+7, D+12, D+17 and D+21). Gene expression analysis was performed by the microarray technique and identified several differentially expressed genes. Some important genes for osteoblast differentiation had lower expression in OI patients, suggesting a smaller commitment of these patient's MSCs with the osteogenic lineage. Other genes also had their differential expression confirmed by RT-qPCR. An increase in the expression of genes related to adipocytes was observed, suggesting an increase of adipogenic differentiation at the expense osteogenic differentiation.

Nutritional intervention with hypocaloric diet for weight control in children and adolescents with Prader-Willi Syndrome.

Prader-Willi Syndrome (PWS) is a genetic disorder caused by the lack of expression of paternal alleles in the proximal region of the long arm of chromosome 15. Low inhibitory control and hyperphagia are two of the most severe neurobehavioral symptoms of the syndrome. The aim of the present study was to assess the efficiency of nutritional training program with the use hypocaloric diet for weight control in a group of five children and adolescents with PWS. The intervention program consisted of 10 sessions for parents' orientation during 8months. Patients had their anthropometric measures assessed (weight, height and body mass index - BMI). The main results indicate weight maintenance, height increase, and BMI decrease after intervention. These results were considered indicators of the program's efficiency.

Restrição alimentar e problemas de comportamento de crianças com Síndrome de Prader-Willi / Dietary restriction and behavioral problems of children with Prader Willi syndrome

A síndrome de Prader Willi (SPW) é uma doença genética causada pela deleção de genes na região 15q11-13. Associa-se com deficiência intelectual e alterações neurocomportamentais de difícil manejo. O objetivo do estudo foi comparar os problemas de comportamento de dois grupos de crianças e adolescentes com SPW em função da possibilidade de acesso livre e de acesso restrito a alimentos no ambiente familiar. A amostra foi composta por 12 crianças e adolescentes com diagnóstico citogenético-molecular para SPW (seis em cada grupo) e suas respectivas mães. Das crianças e adolescentes foi registrado o peso corporal em Kg e junto às mães foi aplicado o Inventário de Comportamentos para Crianças e Adolescentes entre 6 e 18 anos (CBCL/6-18). Houve diferenças estatisticamente significativas entre os grupos em relação a problemas de ansiedade e depressão, violação de regras e desafio e oposição. O grupo de acesso restrito ao alimento apresentou maior número de problemas comportamentais...

Prader-Willi syndrome (PWS) is a genetic disorder caused by a deletion of genes in region 15q11-13. It is associated with intellectual disability and unwieldy neurobehavioral alterations. The aim of the study was to compare behavior problems of two groups of children and adolescents with PWS considering the possibility of free or restricted access to food at home. The sample was composed of 12 children and adolescents with cytogenetic-molecular diagnosis of SPW (6 in each group) and their mothers. Children and adolescents had their body weight recorded and the Child Behavior Checklist for ages 6-18 years old (CBCL/6-18) was answered by the mothers. The groups presented statistically significant differences related to problems of anxiety and depression, violation of rules and defiance and opposition. The group with restricted access to food presented more behavioral problems...

Restrição alimentar e problemas de comportamento de crianças com Síndrome de Prader-Willi / Dietary restriction and behavioral problems of children with Prader Willi syndrome

A síndrome de Prader Willi (SPW) é uma doença genética causada pela deleção de genes na região 15q11-13. Associa-se com deficiência intelectual e alterações neurocomportamentais de difícil manejo. O objetivo do estudo foi comparar os problemas de comportamento de dois grupos de crianças e adolescentes com SPW em função da possibilidade de acesso livre e de acesso restrito a alimentos no ambiente familiar. A amostra foi composta por 12 crianças e adolescentes com diagnóstico citogenético-molecular para SPW (seis em cada grupo) e suas respectivas mães. Das crianças e adolescentes foi registrado o peso corporal em Kg e junto às mães foi aplicado o Inventário de Comportamentos para Crianças e Adolescentes entre 6 e 18 anos (CBCL/6-18). Houve diferenças estatisticamente significativas entre os grupos em relação a problemas de ansiedade e depressão, violação de regras e desafio e oposição. O grupo de acesso restrito ao alimento apresentou maior número de problemas comportamentais.(AU)

Prader-Willi syndrome (PWS) is a genetic disorder caused by a deletion of genes in region 15q11-13. It is associated with intellectual disability and unwieldy neurobehavioral alterations. The aim of the study was to compare behavior problems of two groups of children and adolescents with PWS considering the possibility of free or restricted access to food at home. The sample was composed of 12 children and adolescents with cytogenetic-molecular diagnosis of SPW (6 in each group) and their mothers. Children and adolescents had their body weight recorded and the Child Behavior Checklist for ages 6-18 years old (CBCL/6-18) was answered by the mothers. The groups presented statistically significant differences related to problems of anxiety and depression, violation of rules and defiance and opposition. The group with restricted access to food presented more behavioral problems.(AU)

Fenótipo comportamental de crianças e adolescentes com síndrome de Prader-Willi / Behavioral phenotype of children and adolescents with Prader-Willi syndrome

OBJETIVO: Identificar, em um grupo de crianças e adolescentes com síndrome de Prader-Willi, as principais características do fenótipo comportamental. MÉTODOS: A amostra foi composta por 11 crianças e adolescentes com diagnóstico clínico e citogenético-molecular da síndrome de Prader-Willi. A técnica de coleta de dados foi o Inventário dos Comportamentos de Crianças e Adolescentes entre 6 e 18 anos (CBCL/6-18). A análise de correlação bivariada, com nível de significância p<0,05, foi usada para testar a associação entre as variáveis analisadas. RESULTADOS: Os principais resultados mostraram um perfil comportamental considerado como clínico em várias das escalas do CBCL/6-18. Observou-se um padrão comportamental com alta frequência de respostas de agressão, quebra de regras e oposição. Identificaram-se correlações estatisticamente significativas entre problemas de atenção e sociais e problemas de pensamento e comportamento de quebrar as regras. CONCLUSÕES: Os pacientes investigados representam um grupo com risco psiquiátrico e alterações de comportamento que, em longo prazo, poderão evoluir para transtornos de 2009humor, do déficit de atenção e hiperatividade e transtorno desafiador e de oposição, dentre outros.

OBJECTIVE: To identify the main characteristics of the behavioral phenotype of children and adolescents with Prader-Willi syndrome. METHODS: Eleven children and adolescents with clinical and cytogenetic-molecular diagnosis of Prader-Willi syndrome were studied. Data collection was obtained by the Child Behavior Checklist for Ages 6-18 (CBCL/6-18). Bivariate correlations were used to test the association between the analyzed variables, being significant p<0.05. RESULTS: The behavioral profile obtained was considered as clinical in different scales of the CBCL/6-18 tool. A behavioral pattern with high frequency of aggression, rule breaking and opposition was observed. Statistically significant correlations between attention and social problems and between thought problems and breaking rules were identified. CONCLUSIONS: The studied patients represent a group of psychiatric risk, with behavioral changes that, in the long-term, can lead to mood disorders, attention deficit hyperactivity disorder and oppositional defiant behavior, among other disorders.

Microarquitetura óssea de uma família portadora de osteogênese imperfeita, tipo I: análise comparativa entre as ferramentas oferecidas pela osteossonografia e osteossonometria -terceira geração falangeal e a densitometria óssea convencional / Bone microarchitecture of a family with osteogenesis imperfecta type I:comparative analysis of the parameters offered by osteosonography - third generation phalangeal and standard bone densitometry

Em cinco membros de uma família portadora de osteogênese imperfeita (OI), tipo I, com idades entre 8 e 58 anos foi realizada a análise da topologia óssea (microarquitetura e composição óssea) por meio da osteossonografia e osteossonometria – terceira geração falangeal, sendo comparada com os resultados da “densitometria óssea” convencional (Dexa-Lombar). Por meio da captação do registro elétrico do perfi l biofísico ósseo (PB) dos ossos endostal, trabecular e cortical na metáfise das falanges foram analisadas seis ferramentas, a saber: elasticidade, homogeneidade, estrutura óssea global, curvas de regressão específicas para a qualidade óssea e quantidade óssea e os cortes sonotomográficos. Os parâmetros que avaliam as propriedades mecânicas ósseas adicionaram importantes informações que facilitaram o entendimento da clínica dos portadores de OI. O estudo comparativo permitiu detectar graus variados de deterioração da matriz mesenquimal proteica óssea, colágeno ósseo, refinando, desde tenra idade e o diagnóstico da antiga doença denominada “doença dos ossos frágeis”. As ferramentas aplicadas adicionaram novas informações que facilitam a compreensão sobre os eventos de fratura. A fratura variou de 1 a 25 vezes, por paciente, ocorreu em todos os membros desde a infância e não guardou relação com a idade. O parâmetro UBPI que analisa a qualidade óssea registrou ampla dispersão em seus valores, oscilando de 0,34 a 0,83. O padrão do PB dos ossos endostal, trabecular e cortical é compatível com o padrão dos portadores de graves deteriorações na matriz mesenquimal proteica como deve ser observado na OI, condição impossível de ser definida quando avaliamos apenas a “densidade óssea” convencional. (...)

Five members of a family with osteogenesis imperfecta (OI) type I aged 8 to 58 years were submitted to complete analysis of bone topology(microarchitecture and bone composition) by third-generation phalangeal osteosonography and the results were compared to those obtained by standard bone densitometry. The following features were analyzed by the electrical recording of bone profile (BP) of endosteal, trabecular and cortical bone of the phalangeal metaphysis: elasticity, homogeneity, global bone structure, specific regression curves for ultrasound bone bone profi le index quality, bone quantity and sonotomographic sections. The parameters that evaluate the mechanical properties of bone added important information and facilitated the clinical understanding of subjects affected by OI. The comparative study permitted the detection of varying degrees of deterioration of the bone protein mesenchymal matrix and of bone collagen, with a refinement of the diagnosis of the disease long termed “brittle bone disease” from a tender age. The methods applied added new information that facilitated the understanding of fracture events. The fracture event ranged from 1 to 25 times per patient, occurred in all family members since childhood, and was not related to age. The UBPI parameter, which analyzes bone quality, showed a wide dispersal of values, ranging from 0.34 to 0.83. The BP pattern of endosteal, trabecular and cortical bone was compatible with the pattern of subjects with severe deterioration of the mesenchymal protein matrix, as observed in OI, a condition that is impossible to define when only bone “density” is evaluated. The six parameters offered by third-generation phalangeal osteosonography provided more encompassing information and satisfi ed the concepts of the New Bone Biology, as well as the more recent guidelines of the National Osteoporosis Foundation; 1999.

Genetic counseling.

OBJECTIVE: The objective of this review of genetic counseling (GC) is to describe the current concepts and philosophical and ethical principles accepted by the great majority of countries and recommended by the World Health Organization, the stages of the process, its results and the psychological impact that a genetic disease has on a family. SOURCES: The concepts presented are based on an historical synthesis of the literature on GC since the 1930s until today, and the articles cited represent the most important research published which today provides the foundation for the theory and practice of GC. SUMMARY OF THE FINDINGS: The modern definition of GC is a process of communication that deals with the human problems related with the occurrence of a genetic disease in a family. It is of fundamental importance that health professionals are aware of the psychological aspects triggered by genetic diseases and the ways in which these can be managed. In the field of human and medical genetics we are still living in a phase in which technical and scientific aspects predominate, with little emphasis on the study of emotional reactions and people's processes of adaptation to these diseases, which leads to clients having a low level of understanding of the events that have taken place, with negative consequences for family life and for society. CONCLUSIONS: The review concludes by discussing the need to refer families with genetic diseases for GC and the need for professionals working in this area to invest more in humanizing care and developing non-directive psychological GC techniques.

Aconselhamento genético: [revisão] / Genetic counseling: [review]

OBJETIVO: Esta revisão sobre aconselhamento genético (AG) teve o objetivo de mostrar os conceitos atuais e os princípios filosóficos e éticos aceitos na grande maioria dos países e recomendados pela Organização Mundial da Saúde, as fases do processo, seus resultados e o impacto psicológico de uma doença genética em uma família. FONTES DOS DADOS: Os conceitos apresentados são baseados em uma síntese histórica da literatura sobre AG desde a década de 1930 até o momento atual, sendo que os artigos citados representam os principais trabalhos publicados e que hoje fundamentam a teoria e a prática do AG. SÍNTESE DOS DADOS: O AG modernamente é definido como um processo de comunicação que trata dos problemas humanos relacionados à ocorrência de uma doença genética em uma família. É fundamental que os profissionais da saúde conheçam os aspectos psicológicos desencadeados pela doença genética e como estes aspectos podem ser manejados. Vivemos ainda na genética humana e médica uma fase de predomínio dos aspectos técnicos e científicos e de pouca ênfase no estudo das reações emocionais e dos processos de adaptação das pessoas a estas doenças, o que leva ao baixo entendimento dos clientes sobre os fatos ocorridos, com conseqüências negativas sobre a vida familiar e para a sociedade. CONCLUSÕES: Conclui-se pela necessidade de que as famílias com doenças genéticas sejam encaminhadas para AG e que os profissionais desta área invistam mais na humanização do atendimento, desenvolvendo mais as técnicas do AG psicológico não-diretivo.

OBJECTIVE: The objective of this review of genetic counseling (GC) is to describe the current concepts and philosophical and ethical principles accepted by the great majority of countries and recommended by the World Health Organization, the stages of the process, its results and the psychological impact that a genetic disease has on a family. SOURCES: The concepts presented are based on an historical synthesis of the literature on GC since the 1930s until today, and the articles cited represent the most important research published which today provides the foundation for the theory and practice of GC. SUMMARY OF THE FINDINGS: The modern definition of GC is a process of communication that deals with the human problems related with the occurrence of a genetic disease in a family. It is of fundamental importance that health professionals are aware of the psychological aspects triggered by genetic diseases and the ways in which these can be managed. In the field of human and medical genetics we are still living in a phase in which technical and scientific aspects predominate, with little emphasis on the study of emotional reactions and people's processes of adaptation to these diseases, which leads to clients having a low level of understanding of the events that have taken place, with negative consequences for family life and for society. CONCLUSIONS: The review concludes by discussing the need to refer families with genetic diseases for GC and the need for professionals working in this area to invest more in humanizing care and developing non-directive psychological GC techniques.

Orofacial findings and dental treatment in an 8-year-old patient with trisomy 18: a case report.

Trisomy 18 is characterized by: psychomotor disabilities, dysmorphic features, organ malformations, including mental retardation, growth deficiency, poor motor ability, micrognathia, microcephaly, congenital heart defects, and kidney abnormalities. The oral findings typically observed in these patients are: cleft lip and a high, narrow, and sometimes cleft palate. The degree of severity of the malformations is directly related to life expectancy. Only 5% to 10% of affected infants survive beyond the first year of life. Although trisomy 18 has been widely investigated from a medical standpoint, there is a lack of reports addressing the oral manifestations and dental treatment approach in affected children, presumably due to their shortened life expectancy. The purpose of this article was to present the case of an 8-year-old child diagnosed with trisomy 18 and address the clinical features observed--emphasizing the disease-specific oral, craniofacial, and dental findings. Dental care management of the patient is described.

[Investigation of neurodevelopment delay etiology: resources and challenges]. / Investigação das causas de atraso no neurodesenvolvimento: recursos e desafios.

To verify the reach of development delay investigation, we brought the experience in the pediatrics, infantile neurology and clinical genetics diagnoses, with resources of a tertiary health care, in 73 children, from 1 to 47 months age, between 1999 and 2001, attending a Stimulation Program of the Association of Parents and Friends of Exceptional Children of Batatais-SP. With a transversal and prospective method, six groups were identified: motor disturbances, dysmorphisms, malnutrition, macrocephaly, microcephaly and motor delay. In the analysis of the contribution of the antecedents, physical or laboratory exams to the diagnosis, it stands out the brain image in the groups "motor disturbances" and "macrocephaly"; and for the remaining groups, the physical examination and maternal data. The causes were detected in 48 (66%), being 38.4% of environmental and 24.6% genetics origin. It is emphasized the specialist evaluation, and the need of appropriate flow of information in the net of health.

Investigação das causas de atraso no neurodesenvolvimento: recursos e desafios / Investigation of neurodevelopment delay etiology: resources and challenges

Com o objetivo de verificar o alcance da investigação de causas do retardo no desenvolvimento neuromotor (RDNM), apresenta-se a experiência no atendimento em Pediatria, Neurologia Infantil e Genética Clínica, em nível terciário, de 73 crianças de 1 a 47 meses, do Programa de Estimulação da APAE de Batatais-SP, entre 1999 e 2001. Utilizando-se método transversal, prospectivo, inicialmente identificaram-se 6 grupos, segundo a semiologia clínica dominante - distúrbios motores, dismorfias, desnutrição, macrocefalia, microcefalia e unicamente atraso motor. Analisando-se a proporção com que os antecedentes e exames contribuíram para o diagnóstico, nos grupos "distúrbios motores" e "macrocefalia" destacaram-se os exames de imagem; nos demais grupos, o exame físico na criança e antecedentes maternos. As causas do RDNM foram detectadas em 48 crianças (66 por cento), sendo de origem ambiental 38,4 por cento e genética 24,6 por cento. Ressalta-se a relevância da avaliação especializada e necessidade de fluxo adequado de informações na rede de saúde.

Splenopancreatic field abnormality is not unique to trisomy 13.

Splenopancreatic fusion is an uncommon finding, usually only seen as part of the splenopancreatic field abnormality associated with trisomy 13. It may present itself either as ectopic splenic tissue in the cauda pancreatis, as ectopic pancreatic tissue in the spleen or accessory spleen, or as fusion of the cauda pancreatis and splenic hilum. In this study, we report four unrelated congenital anomaly cases presenting trisomy 21, osteocraniostenosis syndrome, isolated congenital heart defect, and oligohydramnios sequence due to prune belly syndrome, in which fusion was observed. This demonstrates that, although it may be more common in trisomy 13, this phenomenon should not be interpreted as pathognomonic to that syndrome.

Caudal dysplasia sequence: severe phenotype presenting in offspring of patients with gestational and pregestational diabetes.

The association of maternal diabetes mellitus and congenital anomalies is well established. Children of insulin-dependent diabetic women have an increased risk of congenital malformations, especially major multiorgan defects. The cardiovascular, central nervous, gastrointestinal, genitourinary and musculoskeletal are the most affected body systems. Studies also show that offspring of women with gestational diabetes (specially those with fasting hyperglycaemia) tend to have higher rates of congenital anomalies. We report two cases of infants born to unrelated mothers: one with diabetes mellitus first detected during pregnancy (gestational diabetes) and the other with pregestational diabetes. Both infants had amelia of the lower limbs (suggestive of caudal dysplasia sequence), together with cardiovascular, skeletal, urinary and gastrointestinal defects. While pregestational diabetes seems to leave no doubt about its teratogenicity, the association of gestational diabetes and fetal/newborn malformations is still under discussion. Complete absence of the lower limbs has not been reported in association with gestational diabetes, but it may represent a spectrum of the caudal dysplasia sequence. The presentation of two cases with the same clinical phenotype of mothers with gestational and pregestational diabetes supports the evidence that gestational diabetes can be responsible for the development of the most severe form of the caudal dysplasia sequence.

Newborn with malformations and a combined duplication of 9pter-q22 and 16q22-qter resulting from unbalanced segregation of a complex maternal translocation.

We report a patient with duplication of 9pter-q22 combined with duplication of 16q22-qter. The chromosome anomaly was the result of a 3:1 segregation of a maternal translocation (46,XX,t[9;16;21]). This newborn had intrauterine growth retardation and microcephaly, the characteristic recognizable pattern of trisomy 9p, cerebellar hypoplasia, a porencephalic cyst in the parieto-occipital region, and rocker-bottom feet. We compare the clinical features with another previously described case of duplication of an identical 9p segment combined with distal 16q duplication of a similar, but not identical segment, as well as with cases with duplication of either one of the two segments.

A further case of a Prader-Willi syndrome phenotype in a patient with Angelman syndrome molecular defect

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct human neurogenetic disorders; however, a clinical overlap between AS and PWS has been identified. We report on a further case of a patient showing the PWS phenotype with the AS molecular defect. Despite the PWS phenotype, the DNA methylation analysis of SNRPN revealed an AS pattern. Cytogenetic and FISH analysis showed normal chromosomes 15 and microsatellite analysis showed heterozygous loci inside and outside the 15q11-13 region. The presence of these atypical cases could be more frequent than previously expected and we reinforce that the DNA methylation analysis is important for the correct diagnosis of severe mental deficiency, congenital hypotonia and obesity

Distinct nonrandom patterns of chromosomal deletions in giant-cell lesions of bone

Cytogenetic analyses were performed on a bone giant cell reparative granuloma (GCRG) and on three bone giant cell tumors (GCT). The present GCRG case is the second to be described cytogenetically. A modal chromosome number of 46 was observed in all samples. Clonal chromosome abnormalities were detected in all cases. The numerical alterations most frequently observed involved the loss of chromosomes 17 and 18. Among the structural anomalies observed, there was preferential involvement of chromosomes 6 and 10. Three GCT cases presented del(10)(p13) and two cases presented del(6)(q25) (1 GCRG and 1 GCT). These breakpoints mapped on 10p and 6q may harbour genes of importance in the development of bone giant cell tumors

Sotos syndrome (cerebral gigantism): analysis of 8 cases.

Sotos syndrome or cerebral gigantism is characterized by macrocephaly, overgrowth, mental retardation and central nervous system abnormalities. Congenital heart defects may be present. We report 8 patients with this syndrome and relate their clinical features, neuroimaging and echocardiographic findings.

Sotos syndrome (cerebral gigantism): analysis of 8 cases

Sotos syndrome or cerebral gigantism is characterized by macrocephaly, overgrowth, mental retardation and central nervous system abnormalities. Congenital heart defects may be present. We report 8 patients with this syndrome and relate their clinical features, neuroimaging and echocardiographic findings

Cicatricial upper eyelid retraction in encephalocraniocutaneous lipomatosis: a report of two cases and review of literature.

PURPOSE: To describe two patients with encephalocraniocutaneous lipomatosis (ECCL) and to review the literature on this disorder. METHODS: Brain and orbit CT scans were performed on two patients with ECCL. Both patients were examined by the same ophthalmologist and neurologist during at least a 2-year follow-up period. RESULTS: Unilateral skull hamartomas, intracranial abnormalities, epibulbar choristomas, and ocular adnexal changes including a specific form of cicatricial upper eyelid retraction were present in both patients. CONCLUSIONS: ECCL is a special form of oculocerebrocutaneous disease that has significant adnexal findings that are essential for the diagnosis of this rare disorder.

A further case of a Prader-Willi syndrome phenotype in a patient with Angelman syndrome molecular defect.

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct human neurogenetic disorders; however, a clinical overlap between AS and PWS has been identified. We report on a further case of a patient showing the PWS phenotype with the AS molecular defect. Despite the PWS phenotype, the DNA methylation analysis of SNRPN revealed an AS pattern. Cytogenetic and FISH analysis showed normal chromosomes 15 and microsatellite analysis showed heterozygous loci inside and outside the 15q11-13 region. The presence of these atypical cases could be more frequent than previously expected and we reinforce that the DNA methylation analysis is important for the correct diagnosis of severe mental deficiency, congenital hypotonia and obesity.