2,378 research outputs found

    Pregnancy in fanconi anaemia with bone marrow failure: A case report and review of the literature

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    BACKGROUND: Fanconi anaemia is a rare inherited disease characterized by congenital abnormalities, progressive bone marrow failure and predisposition to malignancy. Successful pregnancies in transplanted patients have been reported. In this paper we will describe the pregnancy of a patient with Fanconi anaemia without transplantation. CASE PRESENTATION: A 34-year-old nulliparous woman with Fanconi anaemia was referred to our institution. Pregnancy was complicated by progressive pancytopenia and two severe infections. C-section was performed at 36 weeks. Both infant and mother are well. CONCLUSION: Successful pregnancy in a Fanconi anaemia patient with bone marrow failure is possible. The mode of delivery in patients with bone marrow failure should be determined by obstetric indications. The case highlights the safe outcome of the pregnancy with strict clinical and laboratory control by a multidisciplinary team

    Fanconi anaemia with bilateral diffuse pulmonary arterio venous fistulae: a case report

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    <p>Abstract</p> <p>Background</p> <p>We report a patient with cytogenetically confirmed Fanconi anaemia with associated diffuse bilateral pulmonary arterio-venous fistulae. This is only the second reported case of diffuse pulmonary arterio-venous fistulae with Fanconi anaemia.</p> <p>Case Presentation</p> <p>A 16 year old Sri Lankan boy, with a cytogenetically confirmed Fanconi anaemia was admitted to University Medical Unit, National Hospital of Sri Lanka for further assessment and treatment. Both central and peripheral cyanosis plus clubbing were noted on examination. The peripheral saturation was persistently low on room air and did not improve with supplementary Oxygen. Contrast echocardiography failed to demonstrate an intra cardiac shunt but showed early crossover of contrast, suggesting the possibility of pulmonary arterio-venous fistulae. Computed tomography pulmonary angiogram was inconclusive. Subsequent right heart catheterisation revealed bilateral diffuse arterio-venous fistulae not amenable for device closure or surgical intervention.</p> <p>Conclusion</p> <p>To our knowledge, this is the second reported patient with diffuse pulmonary arterio-venous fistulae associated with Fanconi anaemia. We report this case to create awareness among clinicians regarding this elusive association. We recommend screening patients with Fanconi anaemia using contrast echocardiography at the time of assessment with transthoracic echocardiogram. Though universal screening may be impossible given the cost constraints, such screening should at least be performed in patients with clinical evidence of desaturation or when a therapeutic option such as haematopoietic stem cell transplantation is considered. Treatment of pulmonary arteriovenous fistulae would improve patient outcome as desaturation by shunting worsens the anaemic symptoms by reducing the oxygen carrying capacity of blood.</p

    Rescue of replication failure by Fanconi anaemia proteins

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    Chromosomal aberrations are often associated with incomplete genome duplication, for instance at common fragile sites, or as a consequence of chemical alterations in the DNA template that block replication forks. Studies of the cancer-prone disease Fanconi anaemia (FA) have provided important insights into the resolution of replication problems. The repair of interstrand DNA crosslinks induced by chemotherapy drugs is coupled with DNA replication and controlled by FA proteins. We discuss here the recent discovery of new FA-associated proteins and the development of new tractable repair systems that have dramatically improved our understanding of crosslink repair. We focus also on how FA proteins protect against replication failure in the context of fragile sites and on the identification of reactive metabolites that account for the development of Fanconi anaemia symptoms

    Mutation analysis of the Fanconi anaemia A gene in breast tumours with loss of heterozygosity at 16q24.3

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    The recently identified Fanconi anaemia A (FAA) gene is located on chromosomal band 16q24.3 within a region that has been frequently reported to show loss of heterozygosity (LOH) in breast cancer. FAA mutation analysis of 19 breast tumours with specific LOH at 16q24.3 was performed. Single-stranded conformational polymorphism (SSCP) analysis on cDNA and genomic DNA, and Southern blotting failed to identify any tumour-specific mutations. Five polymorphisms were identified, but frequencies of occurrence did not deviate from those in a normal control population. Therefore, the FAA gene is not the gene targeted by LOH at 16q24.3 in breast cancer. Another tumour suppressor gene in this chromosomal region remains to be identified. © 1999 Cancer Research Campaig

    Chromosomal radiosensitivity and instability in triple negative and/or young breast cancer and Fanconi Anaemia patients in South Africa

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    A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, and the Faculty of Medicine and Health Sciences, Ghent University, Belgium in fulfilment of the requirements for the joint degree of Doctor of Philosophy / Doctor in Health Sciences Johannesburg, 2018.Introduction: Breast cancer is the leading cancer in women in South Africa (SA). Triple negative breast cancer (TNBC) is clinically characterised by the lack of expression of estrogen, progesterone and HER2/NEU receptors. These breast cancers occur frequently in young African women and are associated with aggressive disease progression, poor prognosis and BRCA1 mutations. TN patients with operable tumours may undergo surgery under general anaesthetics. Treatment of TNBC poses a clinical challenge as these tumours are unresponsive to hormonal or HER2 targeted therapy. Defects in BRCA1 and other DNA repair genes contribute to chromosomal instability and radiosensitivity and cause irregularities in the cell cycle checkpoints in the S/G2 phase. Studies have shown the overlap of breast cancer susceptibility genes and Fanconi Anaemia (FA) genes. FA is an autosomal recessive disorder defined by cellular hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC) and defects in DNA repair genes. FA patients are known to be radiosensitive and have defects with DNA repair. These patients are at high risk to develop leukaemia and solid tumours that may require radiotherapy. Diagnosis of FA patients often includes detecting chromosomal aberrations induced by a cross-linking agent. Molecular tests are also conducted to identify mutations in FA genes. It has previously been shown that FA patients undergoing radiotherapy display increased clinical radiosensitivity. Evidence suggests that FA patients are chromosomally radiosensitive to ionising radiation (IR). Chromosomal radiosensitivity can be evaluated using the cytokinesis-block micronucleus (CBMN) assay in different phases of the cell cycle. Micronuclei (MNi) serve as biomarkers for radiation-induced DNA damage repair and defects in DNA repair mechanisms can be reflected in chromosomal radiosensitivity. A number of factors could influence the MNi yield such as storage time and temperature, and cytotoxic agents such as anaesthetics. As radiotherapy is considered a principle treatment in the management of TNBC, it is important to investigate in vitro chromosomal radiosensitivity of South African TN breast cancer patients. Chromosomal instability and radiosensitivity of FA patients has previously not been investigated in SA. The overall aim of this study was to investigate chromosomal instability and radiosensitivity of lymphocytes in South African breast cancer patients, FA patients and parents compared to healthy individuals using the G0 and S/G2 CBMN assay. The effect of age, ethnicity and mutations in breast cancer susceptibility genes was also investigated. Furthermore, storage time and effect of anaesthetics on MNi yield was investigated. Methods: For the G0 MN assay, heparinised blood in culture medium was irradiated at 0Gy (Baseline), 2 and 4 Gy followed by the immediate stimulation of lymphocytes using phytohaemagglutinin (PHA). Cytochalasin B was added 23 hours later to inhibit cell division. The S/G2 MN assay is a modified version of the G0 MN assay. In this assay, the cultures are first stimulated with PHA and irradiated 72 hours post stimulation. Eight hours post irradiation cells were fixed. The Mitomycin C (MMC) MN assay is similar to the G0 MN assay except the DNA damage is induced using MMC. Results: Chromosomal instability is significantly elevated in TNBC, young and older breast cancer patients. Radiation-induced MN values in the G0 MN assay are significantly enhanced in a total unselected group of breast cancer patients compared to healthy individuals. However, when subdividing the breast cancer patients in a TNBC group, the enhanced radiation-induced MNi are not observed. We cannot demonstrate a correlation between the age of the patients and chromosomal radiosensitivity but an effect of ethnicity is noted in our breast cancer population. In the S/G2 MN assay, TNBC patients continued to exhibit a decreased chromosomal radiosensitivity. We also demonstrated that increased storage time can influence MNi yields in patients and controls; anaesthetics influenced spontaneous MNi yields. The FA patients in our study demonstrate higher MNi when compared to parents and controls indicating chromosomal instability and chromosomal radiosensitivity in the G0 as well as in the S/G2 phase of the cell cycle. This is not seen in the FA heterozygotes. With the MMC assay, the detection of significantly higher MN is noted in as well the FA patients as well as the FA carriers. Conclusions: Chromosomal instability and radiosensitivity of breast cancer and FA patients are notably higher when compared to healthy individuals. The association of BRCA mutations in TN and young patients highlight the importance of radiosensitivity information in the understudied SA population. FA carriers can be at risk for breast cancer with mutations associated with breast cancer susceptibility genes. As a functional assay, the MMC MN assay will be useful in the identification of FA carriers who may be at risk of breast cancer. Data on radiosensitivity of patients with defects in DNA repair genes could provide important information for radiotherapy management of cancer.LG201

    Chromosomal integrity after UV irradiation requires FANCD2-mediated repair of double strand breaks

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    Fanconi Anemia (FA) is a rare autosomal recessive disorder characterized by hypersensitivity to inter-strand crosslinks (ICLs). FANCD2, a central factor of the FA pathway, is essential for the repair of double strand breaks (DSBs) generated during fork collapse at ICLs. While lesions different from ICLs can also trigger fork collapse, the contribution of FANCD2 to the resolution of replication-coupled DSBs generated independently from ICLs is unknown. Intriguingly, FANCD2 is readily activated after UV irradiation, a DNA-damaging agent that generates predominantly intra-strand crosslinks but not ICLs. Hence, UV irradiation is an ideal tool to explore the contribution of FANCD2 to the DNA damage response triggered by DNA lesions other than ICL repair. Here we show that, in contrast to ICL-causing agents, UV radiation compromises cell survival independently from FANCD2. In agreement, FANCD2 depletion does not increase the amount of DSBs generated during the replication of UV-damaged DNA and is dispensable for UV-induced checkpoint activation. Remarkably however, FANCD2 protects UV-dependent, replication-coupled DSBs from aberrant processing by non-homologous end joining, preventing the accumulation of micronuclei and chromatid aberrations including non-homologous chromatid exchanges. Hence, while dispensable for cell survival, FANCD2 selectively safeguards chromosomal stability after UV-triggered replication stress.Fil: Federico, Maria Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Vallerga, María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Radl, Daniela Betiana. Autoridad Regulatoria Nuclear; ArgentinaFil: Paviolo, Natalia Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Bocco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Di Giorgio, Marina. Autoridad Regulatoria Nuclear; ArgentinaFil: Soria, Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Gottifredi, Vanesa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin
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