Cromossomo Y na síndrome de Turner: revisão da literatura

Turner syndrome (TS) is one of the most common types of aneuploidy among humans, and is present in 1:2000 newborns with female phenotype. Cytogenetically, the syndrome is characterized by sex chromosome monosomy (45,X), which is present in 50-60% of the cases. The other cases present mosaicism, with a 45,X cell line accompanied by one or more other cell lines with a complete or structurally abnormal X or Y chromosome. The presence of Y-chromosome material in patients with dysgenetic gonads increases the risk of gonadal tumors, especially gonadoblastoma. The greatest concern is the high risk of developing gonadoblastoma or other tumors and virilization during puberty if chromosome Y-specific sequences are present. The role of the Y chromosome in human oncogenesis is still controversial. Even though gonadoblastoma is a benign tumor, it can undergo transformation into invasive dysgerminoma in 60% of the cases, and also into other, malignant forms of germ cell tumors. Although some authors have questioned the high incidence of gonadoblastoma (around 30%), the risk of developing any kind of gonadal lesion, whether tumoral or not, justifies investigation of Y-chromosome sequences by means of the polymerase chain reaction (PCR), a highly sensitive, low-cost and easy-to-perform technique. In conclusion, mosaicism of both the X and the Y chromosome is a common finding in TS, and detection of Y-chromosome-specific sequences in patients, regardless of their karyotype, is necessary in order to prevent the development of gonadal lesions.A síndrome de Turner (ST) é uma das aneuploidias mais comuns em humanos e está presente em 1:2000 recém-nascidas com fenótipo feminino. Citogeneticamente, a síndrome é caracterizada por uma monossomia de cromossomo sexual (45,X) em 50-60% dos casos. Os demais casos apresentam mosaicismo com uma linhagem celular 45,X acompanhada de outra(s) com o cromossomo X ou Y íntegros ou com alterações estruturais. A presença de material do cromossomo Y em pacientes com gônadas disgenéticas aumenta o risco de tumores gonadais, especialmente gonadoblastoma. A consideração mais importante diz respeito ao elevado risco de desenvolvimento de gonadoblastoma ou outros tumores e a virilização na puberdade se sequências cromossomo Y-específicas estiverem presentes. O papel do cromossomo Y na oncogênese dos cânceres humanos ainda é controverso. Apesar de o gonadoblastoma ser um tumor benigno, ele pode transformar-se num disgerminoma invasivo em 60% dos casos e também em outras formas malignas de tumores de células germinativas. Apesar de alguns autores questionarem a alta incidência (em torno de 30%) de gonadoblastoma, o risco do desenvolvimento de qualquer tipo de lesão gonadal, tumoral ou não, justifica a pesquisa de sequências do cromossomo Y por PCR (reação de polimerase em cadeia), técnica de alta sensibilidade, baixo custo e fácil execução. Em conclusão, o mosaicismo cromossômico tanto do X como do Y é um fato comum na ST e a detecção de sequências cromossomo Y-específicas nas portadoras, independentemente do seu cariótipo, é necessária para prevenir o desenvolvimento de lesões gonadais.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Centro de Extensão UniversitáriaUniversidade Federal de São Paulo (UNIFESP) Department of Medicine Division of EndocrinologyUNIFESP, Department of Medicine Division of EndocrinologySciEL

A prevalência do polimorfismo A1298C e não do C677T do gene MTHFR está relacionada à ocorrência de aneuploidias cromossômicas em mulheres brasileiras portadoras da síndrome de Turner

BACKGROUND: Dysfunctions in the folate metabolism can result in DNA hypomethylation and abnormal chromosome segregation. Two common polymorphisms of this enzyme (C677T and A1298C) reduce its activity, but when associated with aneuploidy studies the results are conflicting. The objective of the present study is to analyze the MTHFR gene polymorphisms in women with Turner Syndrome and in a control group, correlating the findings to the chromosomal aneuploidy. METHODS: The study comprised 140 patients with Turner Syndrome, of which 36 with chromosome mosaicism and 104 non-mosaics, and a control group of 209 fertile and healthy women without a history of any offspring with aneuploidy. Polymorphisms C677T and A1298C were studied by RFLP-PCR and the results were statistically analyzed. RESULTS: The frequency of genotypes MTHFR 677CC, 677CT and 677TT in the patients with Turner Syndrome and chromosome mosaicism was, respectively, 58.3%, 38.9% and 2.8%. Among the patients with non-mosaic Turner Syndrome, 47.1% presented genotype 677CC, 45.2% genotype 677CT, and 7.7% genotype 677TT. Among the 209 individuals of the control group, genotypes 677CC, 677CT and 677TT were found at the following frequencies: 48.3%, 42.1% and 9.6%, respectively. As for polymorphism A1298C, the patients with Turner Syndrome and chromosome mosaicism presented genotypes 1298AA, 1298AC and 1298CC at the following frequencies: 58.3%, 27.8% and 13.9%, respectively. Among the non-mosaic Turner Syndrome patients, genotype 1298AA was found in 36.5%, genotype 1298AC in 39.4%, and genotype 1298CC in 22.1%. In the control group, genotypes 1298AA, 1298AC and 1298CC were present at the following frequencies: 52.6%, 40.7% and 6.7%, respectively. CONCLUSION: No correlation was observed between the MTHFR gene polymorphism 677 and chromosomal aneuploidy in the Turner Syndrome patients. However, the MTHFR gene polymorphism at position 1298, mainly genotype 1298CC that reduces the enzyme efficiency, was more frequent in the group of Turner Syndrome patients, suggesting its involvement in mechanisms related to chromosomal imbalances.INTRODUÇÃO: Disfunções no metabolismo dos folatos podem resultar em hipometilação do DNA e na segregação cromossômica anormal. Dois polimorfismos comuns no gene MTHFR (C677T e A1298C) reduzem a atividade da enzima e, quando associados a estudos de aneuploidias apresentam resultados conflitantes. O objetivo do presente estudo foi a análise dos polimorfismos do gene MTHFR em mulheres portadoras da síndrome de Turner e em indivíduos de grupo-controle, correlacionando os achados ao mecanismo de formação de aneuploidias cromossômicas. MÉTODOS: Foram estudadas 140 portadoras da síndrome de Turner sendo 36 com mosaicismo cromossômico e 104 não-mosaicos, e um grupo-controle composto por 209 mulheres férteis e saudáveis sem história de prole com aneuplodia. Os polimorfismos MTHFR C677T e A1298C foram estudados por RFLP-PCR e os resultados analisados estatisticamente. RESULTADOS: A freqüência dos genótipos MTHFR 677CC, 677CT e 677TT nas pacientes portadoras de síndrome de Turner e mosaicismo cromossômico foi, respectivamente, 58,3%, 38,9% e 2,8%. Das pacientes portadoras de síndrome de Turner não-mosaico, 47,1% apresentaram o genótipo 677CC, 45,2% o genótipo 677CT e 7,7% apresentaram o genótipo 677TT. Nos 209 indivíduos do grupo-controle, os genótipos 677CC, 677CT e 677TT foram encontrados nas seguintes freqüências: 48,3%, 42,1% e 9,6%, respectivamente. Quanto ao polimorfismo A1298C, as portadoras de síndrome de Turner e mosaicismo cromossômico apresentaram os genótipos 1298AA, 1298AC e 1298CC nas seguintes freqüências: 58,3%, 27,8% e 13,9%, respectivamente. Já nas portadoras de Síndrome de Turner não-mosaico, o genótipo 1298AA foi encontrado em 36,5%, o genótipo 1298AC em 39,4% e o genótipo 1298 CC em 22,1% . No grupo-controle, os genótipos 1298AA, 1298AC e 1298CC estavam presentes nas freqüências 52,6%, 40,7% e 6,7%. CONCLUSÃO: Não foi observada correlação entre o polimorfismo C677T do gene MTHFR e a aneuploidia cromossômica presente nas portadoras de síndrome de Turner. O polimorfismo A1298C do gene MTHFR, principalmente o genótipo 1298CC, foi mais freqüente nas portadoras de síndrome de Turner, sugerindo seu envolvimento no mecanismo de formação de aneuploidias cromossômicas.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Federal University of São Paulo Department of Medicine Endocrinology DivisionFederal University of São Paulo Department of Morphology and Genetics Genetics DivisionUniversity of Cuiabá General Hospital Medical Genetics and Molecular Biology UnitGenetics Division of Medicine College from ABCUNIFESP, Department of Medicine Endocrinology DivisionUNIFESP, Department of Morphology and Genetics Genetics DivisionSciEL

Clinical checklists in the selection of mentally retarded males for molecular screening of fragile X syndrome

Fragile X syndrome is the most frequent cause of inherited mental retardation. The phenotype in this syndrome is quite variable and less conspicuous in younger patients, making clinical diagnosis difficult and thus making molecular diagnosis necessary. The use of clinical checklists in mentally retarded individuals can help selecting patients to be given priority in the molecular investigation for the fragile-X mutation in the FMR1 gene. We evaluated two clinical checklists in a sample of 200 Brazilian male patients with mental retardation. The highest scores in the two checklists concentrated among the 19 males (9.5%) found to carry full mutations. Our results confirm the importance of fragile-X checklists as a clinical tool in the study of mentally retarded patients.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidade Federal de São Paulo (UNIFESP)Universidade de São Paulo Instituto de Biociências Departamento de Genética e Biologia EvolutivaUNIFESPSciEL

Clinical implications of the detection of Y-chromosome mosaicism in Turner's syndrome: report of 3 cases

Objective: To determine the clinical implications of the presence of a Y chromosome in Turner's syndrome patients with karyotype abnormalities.Design: To investigate the presence of Y-chromosome sequences in different tissue samples.Setting: Endocrinology outpatient clinic of a federal university in Brazil.Patient(s): Five Turner's syndrome patients with karyotype abnormalities such as marker chromosomes, additional material, or ring chromosomes.Intervention(s): Peripheral blood, oral epithelial cells, and hair root samples were collected.Main Outcome Measure(s): the SRY gene and the DYZ3 repeat region were amplified by polymerase chain reaction followed by gel electrophoresis mobility of amplified genomic DNA, and ultraviolet visualization. Prophylactic gonadectomy was offered to the Y-positive patients.Result(s): the analysis of the different tissues revealed that three of the five patients studied presented Y-chromosome mosaicism. These three patients underwent prophylactic gonadectomy, and in one of them, the histopathologic study of the gonads disclosed hilus cell hyperplasia and stromal luteoma with contralateral nodular hyperthecosis.Conclusion(s): A systematic search for Y-chromosome mosaicism in Turner's syndrome patients is justified by the risk of developing gonadal tumors or androgen-producing lesions. (Fertil Steril (R) 2008; 90: 1197.e17-e20. (C) 2008 by American Society for Reproductive Medicine.)Universidade Federal de São Paulo, Lab Esteroides, Dept Med, Div Endocrinol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Div Genet, Dept Morphol & Genet, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Lab Esteroides, Dept Med, Div Endocrinol, BR-04039032 São Paulo, BrazilUniversidade Federal de São Paulo, Div Genet, Dept Morphol & Genet, BR-04039032 São Paulo, BrazilWeb of Scienc

Detection of hidden Y mosaicism in Turner's syndrome: Importance in the prevention of gonadoblastoma

The presence of Y chromosome fragments in patients with Turner's syndrome (TS) is known to increase the risk of gonadoblastoma. The investigation of Y sequences is usually performed only in the presence of marker chromosomes and therefore does not rule out the presence of hidden mosaicism in patients with 45,X TS without any marker.Aims: 1. To investigate the presence of hidden Y mosaicism in non-mosaic 45,X patients with TS, using samples from different tissues, and its association with the development of gonadoblastoma.Study design: Twenty patients with a 45,X karyotype were studied. The SRY and DYZ3 sequences were amplified by PCR, using genomic DNA from peripheral blood, oral epithelial,cells and hair roots. Prophylactic gonadectomy was offered to the Y-positive patients.Results: The analysis of the different tissues revealed that seven (35%) out of the 20 patients studied presented hidden chromosome Y mosaicism. Four of these patients underwent prophylactic gonadectomy, and bilateral gonadoblastoma was found in one of them.Conclusions: A systematic search for hidden Y chromosome mosaicism in patients with TS and 45,X karyotype is justified by the possibility of developing gonadoblastoma.Univ Fed Sao Paulo, Dept Med, Div Endocrinol, BR-04023062 Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Morphol, Div Genet, BR-04023062 Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Med, Div Endocrinol, BR-04023062 Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Morphol, Div Genet, BR-04023062 Sao Paulo, BrazilWeb of Scienc