Bianca Bianco

Detection of Hidden Y Mosaicism in Turner's Syndrome: Importance in the Prevention of Gonadoblastoma

UNLABELLED The presence of Y chromosome fragments in patients with Turners 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.

Y chromosome in Turner syndrome: review of the literature

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.

Analysis of FOXP3 polymorphisms in infertile women with and without endometriosis.

OBJECTIVE To evaluate FOXP3 polymorphisms (rs3761549, rs3761548, rs2232368, rs2232366, and rs2280883) in a group of infertile women with and without endometriosis and controls. DESIGN Case control study. SETTING Human Reproduction Outpatient Clinic of Faculdade de Medicina do ABC. PATIENT(S) The study groups were 177 infertile women with endometriosis, 71 women with idiopathic infertility, and 171 fertile women as controls. INTERVENTION(S) The FOXP3 polymorphisms were identified by TaqMan polymerase chain reaction (PCR). The results were analyzed statistically. MAIN OUTCOME MEASURE(S) Genotype distribution, allele frequency, and haplotype analysis of the FOXP3 polymorphisms. RESULT(S) Single-marker analysis revealed that FOXP3 rs3761549 was significantly associated with endometriosis. In the infertile group without endometriosis, single-marker analysis revealed statistical difference for rs2280883 and rs2232368 FOXP3 polymorphisms. No associations were found with rs3761548 and rs2232366 either for endometriosis-related infertility group or idiopathic infertility group. Haplotype analysis of five FOXP3 polymorphisms identified a haplotype CTTGA associated with endometriosis and ACTAG associated with idiopathic infertility. CONCLUSION(S) This is the first study to report an association between FOXP3 polymorphisms and endometriosis and/or infertility. These findings require replication in other populations but suggest that the FOXP3 polymorphisms can be associated with risk of idiopathic infertility (rs2280883 and rs2232368) and endometriosis (rs3761549) in Brazilian women.

Frequency of endometriotic lesions in peritoneum samples from asymptomatic fertile women and correlation with CA125 values

CONTEXT AND OBJECTIVE Serological testing for CA125 has been widely used to detect endometriosis and to monitor its progression. However, controversy still exists regarding the usefulness of the plasma CA125 assay for diagnosing endometriosis. Furthermore, some authors have described superficial endometriosis as a cyclical and normal phenomenon in womens lives, and have indicated that development and progression of this disease would only occur in some women as a result of immunological changes. This study aimed to determine the frequency of endometriosis and the correlation between serum CA125 levels and the presence of endometriotic lesions in the peritoneum of asymptomatic fertile patients. DESIGN AND SETTING Cross-sectional study at the Family Planning outpatient clinic of Faculdade de Medicina do ABC. METHODS Eighty asymptomatic fertile patients who underwent tubal sterilization surgery were studied. Blood and peritoneum samples were collected. CA125 levels were measured from blood samples, and peritoneum biopsies were studied using histopathological tests. RESULTS Histopathological evaluation of the peritoneum revealed that 16.25% of the patients had minimal or mild endometriosis. There was no statistically significant difference in CA125 levels between patients with and without endometriosis. CONCLUSION The presence of endometriotic lesions in the peritoneum of fertile patients supports the hypothesis that incidental findings of minimal or mild endometriosis may not be of clinical significance, and that the progression of the disease probably occurs as a result of immunological and genetic abnormalities. Serum CA125 levels did not show any diagnostic significance with regard to detecting the disease.

The possible role of genetic variants in autoimmune-related genes in the development of endometriosis

Numerous hypotheses have been put forward to explain the presence of ectopic endometrial tissue and stroma. The immune system participates in the homeostasis of the peritoneal cavity, and modifications in its functioning have been advanced to explain endometriosis and its consequences. Recently, the powerful anti-inflammatory effect of progesterone was recognized as a potential causal factor for endometriosis and could contribute to the autoimmune nature of endometriosis, as well as to more specific local and systemic changes. Autoimmune and inflammatory diseases are a diverse group of complex diseases characterized by loss of self-tolerance causing immune-mediated tissue destruction. Just as in autoimmune diseases, in endometriosis similar immunologic alterations occur, such as an increase in the number and cytotoxicity of macrophages, polyclonal increase in the activity of B lymphocytes, abnormalities in the functions and concentrations of B and T lymphocytes, and reduction in number or activity of natural killer cells. Furthermore, the presence of specific antiendometrial and antiovary antibodies was found both in endometriosis and infertility. Genetic factors play a role in the pathogenesis of endometriosis, and autoimmunity genes are therefore reasonable candidate genes for endometriosis and endometriosis-associated infertility. Single nucleotide polymorphisms are common in the human genome and affect the function of crucial components of the T-cell-antigen-receptor signaling pathways; they could have profound effects on the function of the immune system and thus on the development of autoimmune diseases. Here, we conducted a critical medical literature review about the possible role of genetic variants in autoimmune-related genes in the development of endometriosis.

OC-125 immunostaining in endometriotic lesion samples.

PurposeTo determine the presence of OC-125 staining in endometriotic lesions and to verify whether there is an association with endometriosis stage.MethodsThirteen patients from the Family Planning programs (group I) and 53 patients from the Chronic Pelvic Pain outpatient clinic (group II) were studied. Endometriotic lesions were excised from areas of endometriosis incidence and studied by histopathological assay and by immunohistochemistry for OC-125 staining.ResultsThe histopathological study disclosed that all patients from group I had minimal/mild endometriosis. In group II, 39.6% had minimal/mild endometriosis, and 60.4% had moderate/severe endometriosis. OC-125 staining was negative in all samples from group I. In group II, OC-125 staining was positive in 52.4% patients with minimal/mild endometriosis and in 81.2% with moderate/severe endometriosis.ConclusionThe data suggest that the OC-125 antibody is probably related to endometriosis activity and, consequently, to the progression and severity of the illness.

Methylenetetrahydrofolate reductase polymorphisms are related to male infertility in Brazilian men.

OBJECTIVE The objective of this study was to analyze the distribution of the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in idiopathic infertile Brazilian patients with nonobstructive azoospermia (NOA) or severe oligozoospermia and fertile Brazilian men as controls to explore the possible association of these polymorphisms and male infertility. METHODS A case-control study was carried out, including 156 idiopathic infertile Brazilian patients with NOA (n=49) or severe oligozoospermia (n=107) and 233 fertile men as controls. Polymorphisms C677T and A1298C were studied by quantitative polymerase chain reaction and the results were statistically analyzed. RESULTS The frequency of genotypes MTHFR 677CC, 677CT, and 677TT in idiopathic infertile men with NOA were 55.1%, 30.6%, and 14.3% (p=0.0305); 50.6%, 42.0%, and 7.5% (p=0.0006) regarding the severe oligozoospermic men; and 71.7%, 53.0%, and 5.6% in the control group. As for polymorphism A1298C, regarding the NOA group, the frequencies of the 1298AA, 1298AC, and 1298CC genotypes were 53.0%, 28.6%, and 18.4% (p=0.0132); 42.0%, 44.9%, and 13.1% (p=0.0188) among the severe oligozoospermic group; and 55.8%, 38.2%, and 6.0% (14/233) in the control group. CONCLUSION The data suggest that MTHFR C677T and A1298C could be important genetic factors predisposing to infertility in Brazilian infertile men.

Prevalence of the polymorphism MTHFR A1298C and not MTHFR C677T is related to chromosomal aneuploidy in Brazilian Turner Syndrome patients

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.

Analysis of vitamin D receptor gene polymorphisms in women with and without endometriosis.

An aberrant immunologic mechanism has been suggested to be involved in the pathogenesis of endometriosis. Genetic alterations in the vitamin D receptor gene (VDR) may lead to important defects in gene activation that principally affect immune function. We have hypothesized a possible relationship between endometriosis and/or infertility and the VDR polymorphisms (ApaI, TaqI, FokI, and BmsI). The study was a case-control study including 132 women with endometriosis-related infertility, 62 women with idiopathic infertility, and 133 controls. VDR polymorphisms were studied by restriction fragment length polymorphism. We found relatively similar VDR polymorphism genotype frequencies in cases and controls. When patients with minimal/mild and moderate/severe endometriosis were studied separately, no difference was found. When we compared infertile groups with and without endometriosis there was no statistically significant difference. The data suggest that VDR polymorphisms did not play an important role in the pathogenesis of endometriosis and/or infertility in the Brazilian women studied.

PTPN22 C1858T Polymorphism in Women with Endometriosis

Citation Gomes FMCS, Bianco B, Teles JS, Christofolini DM, de Souza AMB, Guedes AD, Barbosa CP. PTPN22 C1858T polymorphismin women with endometriosis. Am J Reprod Immunol 2010; 63: 227–232