Cases reported "Chromosomal Instability"

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1/8. Chromosome instability induced in vitro with mitomycin C in five Seckel syndrome patients.

    Seckel syndrome (SS) is an autosomal recessive entity characterized by proportionate pre- and post-natal growth retardation, microcephaly, typical facial appearance with beak-like protrusion, and severe mental retardation. A heterogeneous basis for SS was proposed since around 25% of SS patients have hematological anomalies, suggesting a subgroup of SS with chromosome instability and hematological disorders. Chromosome instability induced by mitomycin C (MMC) has been observed in previous reports. The purpose of this study is to report cytogenetic features in five patients with SS. The patients had low birth weight (mean 1,870 g), short stature (SD = 6.36), microcephaly (OFC, SD = 8.1), typical facial appearance, and multiple articular dislocations. None of them had anemia at the time of examination. In all cases their parents were healthy and non-consanguineous. lymphocytes of SS patients and a control group (n = 9) matched by age and sex were cultured with and without MMC, and harvested at 72 and 96 hr. Chromosomal aberrations (chromatid and chromosomal gaps and breaks, deletions, fragments, and exchanges) were scored in 100 metaphases per culture. A statistical increase of chromosomal aberrations was observed in 96 hr MMC cultures in all patients (40.2% vs. 2.8%). Sister chromatid exchanges were also performed with no differences between groups. Clinical and cytogenetic findings support the idea that SS may correspond to a chromosome instability syndrome.
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ranking = 1
keywords = instability
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2/8. Defective B-cell-negative selection and terminal differentiation in the ICF syndrome.

    Immunodeficiency, centromeric region instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disease. Mutations in the DNA methyltransferase 3B (DNMT3B) gene are responsible for most ICF cases reported. We investigated the B-cell defects associated with agammaglobulinemia in this syndrome by analyzing primary B cells from 4 ICF patients. ICF peripheral blood (PB) contains only naive B cells; memory and gut plasma cells are absent. Naive ICF B cells bear potentially autoreactive long heavy chain variable regions complementarity determining region 3's (V(H)CDR3's) enriched with positively charged residues, in contrast to normal PB transitional and mature B cells, indicating that negative selection is impaired in patients. Like anergic B cells in transgenic models, newly generated and immature B cells accumulate in PB. Moreover, these cells secrete immunoglobulins and exhibit increased apoptosis following in vitro activation. However, they are able to up-regulate CD86, indicating that mechanisms other than anergy participate in silencing of ICF B cells. One patient without DNMT3B mutations shows differences in immunoglobulin e (IgE) switch induction, suggesting that immunodeficiency could vary with the genetic origin of the syndrome. In this study, we determined that negative selection breakdown and peripheral B-cell maturation blockage contribute to agammaglobulinemia in the ICF syndrome.
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ranking = 0.14285714285714
keywords = instability
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3/8. Establishment and characterization of a cytogenetically complex Chinese multiple myeloma-derived cell line with homozygous p53 deletion and cyclin e overexpression.

    We describe the establishment and characterization of a new myeloma-derived cell line (MM17), originating from the sacral plasmacytoma of a 54-year-old Chinese woman diagnosed with multiple myeloma (MM). MM17 was confirmed morphologically and immunophenotypically to be clonal plasma cells positive for CD38 and CD138 and negative for EBV marker. Authenticity was confirmed using comparative genomic hybridization and dna fingerprinting studies on bone marrow aspirate, sacral tumor tissue and MM17. Combined G-banding and multicolor fluorescence in situ hybridization analyses demonstrated a primarily hypodiploid karyotype with two sidelines sharing common stemline aberrations: 6, -7, -10, -13, -14, -17, -X, der(1;17)(q10;q10), t(2;7)(q23;q11.2), t(8;14)(q24;q32) and ins(16;1)(q13;?q22q41); and a number of hypertriploid cells. The involvement of p53 alteration and cyclin e overexpression, both with relevance to the induction of chromosomal instability, was investigated in MM17 and together with two other MM derived cell lines (U266 and IM-9) for cyclin e expression. Homozygous deletion of p53 gene hitherto not reported in MM, was detected. Both MM17 and U266 with complex cytogenetic aberrations demonstrated overexpression of cyclin E1 and E2, whereas IM-9 with a normal karyotype showed cyclin E2 but not E1 overexpression. These data suggested that E1 but not E2 overexpression was associated with chromosomal abnormalities observed in MM17 and U266, which provides the first supporting evidence for the link of cyclin e and chromosomal instability in MM. This is the first characterized Chinese MM-derived cell line with homozygous p53 deletion which may serve as a valuable in vitro system for studying MM pathogenesis particularly for Chinese.
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ranking = 0.28588797847983
keywords = instability, genomic
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4/8. chromosomal instability and double minute chromosomes in a breast cancer patient.

    cytogenetic analysis was performed in peripheral blood lymphocytes (PBL) of a woman with ductal breast carcinoma, who as a hospital employee was exposed professionally for 15 years to low doses of ionizing radiation. The most important finding after the chemotherapy in combination with radiotherapy was the presence of double minutes (DM) chromosomes, in combination with other chromosomal abnormalities (on 200 scored metaphases were found 2 chromatid breaks, 10 dicentrics, 11 acentric fragments, 2 gaps, and 3 double min chromosomes). In a repeated analysis (after 6 months), DM chromosomes were still present. To rule out the possibility that the patient was overexposed to ionizing radiation at work, her blood test was compared with a group of coworkers as well as with a group of professionally unexposed people. The data rejected this possibility, but the retroactive analysis showed that the patient even at the time of employment had a moderately increased number of chromosomal aberrations (3.5%) consisting of 3 isochromatids and 4 gaps, suggesting that her initial genomic instability enhanced the later development. The finding of a continuous presence of rare DM chromosomes in her PBL (4 and 10 months after radiochemotherapy) was considered as an indicator of additional risk, which might have some prognostic significance.
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ranking = 0.71445940705126
keywords = instability, genomic
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5/8. Mitotic and meiotic instability of a telomere association involving the y chromosome.

    Constitutional telomere associations and jumping translocations (JTs) are rare events and usually occur post-zygotically. We report a telomere association involving the y chromosome which "jumped" during meiosis. A 21-year-old woman was referred for amniocentesis due to non-immune hydrops seen in a previous pregnancy. cytogenetic analysis of the amniocytes showed a 45,X,tas(Y;15)[4]/45,X[16] karyotype with the long arm of the y chromosome attached to the end of the short arm of chromosome 15. Parental chromosome analyzes revealed a tas(Y;19)[63]/45,X[7] karyotype in the father with Yq attached to the end of the short arm of chromosome 19. A phenotypically normal male was born and blood chromosome analysis confirmed a 45,X,tas(Y;15)[39]/45,X[10]/46,XY[1] karyotype. Two other male children have 46,XY karyotypes, which further demonstrates the instability of the tas(Y;19) in meiosis. fluorescence in situ hybridization (FISH) analysis with probes for theY-centromere, the Yqh region, the shared Xq/Yq telomere and SRY showed hybridization on the tas(Y;19) and tas(Y;15). A chromosome 19p specific subtelomeric probe showed hybridization to the tas(Y;19) in the father. In addition, a probe for the simple telomeric sequences TTAGGG showed positive hybridization to the junction of the associations. The presence of TTAGGG telomere repeats and unique telomere sequences indicate that the Y;15 and Y;19 associations occur with no detectable loss of any sequences. The interstitial telomere sequences at the junction of the telomere association may explain the mitotic and meiotic instability of the association.
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ranking = 0.85714285714286
keywords = instability
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6/8. chromosomal instability in two siblings with gonad deficiency: case report.

    Non-random de novo autosomal chromosomal rearrangements have not been shown to cause exocrine or gonadal dysfunction. We report on two siblings, a brother and a sister, both with de novo chromosomal rearrangements and gonadal deficiency including premature ovarian failure. They had normal phenotypes without additional manifestations of known chromosomal breakage syndromes (except for the gonadal dysfunction) and normal alpha-fetoprotein dosage level. The association of sperm abnormalities in the brother and ovarian dysfunction in the sister suggested an increased spontaneous chromosomal instability. Since the co-occurrence of chromosomal anomalies and reproductive failures may not be coincidental, we performed repeated chromosomal analysis of peripheral blood lymphocytes prior to proposing ICSI for IVF (for the brother). In both sibs, infertility was associated with random and non-random de novo autosomal chromosomal abnormalities. We discuss the possible relationship between these unusual clinical and cytogenetic features and their potential links to ataxia-telangiectasia.
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ranking = 0.71428571428571
keywords = instability
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7/8. A case with ICF syndrome lost to rubella pneumonitis.

    The immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by variable immunodeficiency, instability of the pericentromeric heterochromatin, and facial dysmorphism. Here we report a new case of ICF syndrome who died of rubella pneumonitis. A six year-old-girl who was the first child of consanguineous parents was admitted to the hospital because of bronchopneumonia. Laboratory investigations revealed pan-hypogammaglobulinemia, lymphoperria, normal proportions of peripheral blood lymphocytes with an inverted CD4/CD8 ratio, and interstitial pneumonia with a positive serology of acute rubella infection. The ICF syndrome was diagnosed by centromeric instability in the standard cytogenetic analysis. An inclusion body was demonstrated in the lung biopsy after the death of the patient. Chromosomal investigation could be helpful along with other tests for diagnosis of variable immunodeficiency accompanied by facial dysmorphism.
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ranking = 0.42857142857143
keywords = instability
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8/8. A new and a reclassified ICF patient without mutations in DNMT3B and its interacting proteins SUMO-1 and UBC9.

    The ICF syndrome (immunodeficiency, centromeric instability, facial anomalies) (OMIM#242860) is a rare autosomal, recessively inherited disorder. Another rare condition, ischiadic hypoplasia, renal dysgenesis, immunodeficiency, and polydactyly (IHRDIP, OMIM#243340), displays features that resemble those of the ICF syndrome. Due to the overlapping symptoms in both syndromes, we asked whether a shared underlying molecular defect exists. Two patients, each with the clinical characteristics of one of these syndromes, were subjected to conventional cytogenetic analysis and the determination of the methylation state of satellite II DNA. We found that both displayed the two hallmark features of the ICF syndrome, namely hypomethylation and centromeric instability of chromosomes 1 and 16. Therefore, we reclassified the patient previously diagnosed with the IHRDIP syndrome as an ICF patient. Since the majority of ICF patients are carriers of mutations in the methytransferase gene DNMT3B, we determined the sequence of its coding, splice site, and putative promoter region and analyzed its transcripts in both patients, without detecting any alterations. Similarly, the coding region of two DNMT3B-interacting proteins, SUMO-1 and UBC9, did not reveal mutations. With this study, the published number of patients that lack mutations in DNMT3B coding region increases to almost 40% of all ICF patients reported. It is, therefore, implied that a significant subset of ICF patients will have a yet unknown, alternative alteration, which may include the involvement of DNMT3B-interacting factors or aberrations of an independent pathway.
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ranking = 0.28571428571429
keywords = instability
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