Inherited Bone Marrow Failure Syndromes
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PROVIDER: PRJNA417131 | ENA |
REPOSITORIES: ENA
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Project description:Inherited Bone Marrow Failure Syndromes
| PRJNA417130 | ENA
Project description:<p><b>Background:</b> <ul> <li>A prospective cohort of Inherited Bone Marrow Failure Syndrome (IBMFS) will provide new information regarding cancer rates and types in these disorders.</li> <li>Mutations in IBMFS genes are relevant to carcinogenesis in sporadic cancers.</li> <li>Patients with IBMFS who develop cancer differ in their genetic and/or environmental features from patients with IBMFS who do not develop cancer.</li> <li>These cancer-prone families are well suited for cancer screening and prevention trials targeting those at increased genetic risk of cancer.</li> <li>Carriers of IBMFS gene mutations are at increased risk of cancer.</li> <li>The prototype disorder is Fanconi Anemia (FA); other IBMFS will also be studied.</li> </ul> </p> <p><b>Objectives:</b> <ul> <li>To determine the types and incidence of specific cancers in patients with an IBMFS.</li> <li>To investigate the relevance of IBMFS gene mutations in the carcinogenesis pathway of the sporadic counterparts of IBMFS-associated cancers.</li> <li>To identify risk factors for IBMFS-related cancers in addition to the primary germline mutations.</li> <li>To determine the risk of cancer in IBMFS carriers.</li> </ul> </p> <p><b>Design:</b> <ul> <li>Natural history study, with questionnaires, clinical evaluations, clinical and research laboratory tests, review of medical records, cancer surveillance.</li> <li>Primary endpoints are all cancers, solid tumors, and cancers specific to each type of IBMFS.</li> <li>Secondary endpoints are markers of pre-malignant conditions, such as leukoplakia, serum or tissue evidence of carcinogenic viruses, and bone marrow morphologic myelodyplastic syndrome or cytogenetic clones.</li> </ul> </p>
| phs001481 | dbGaP
Project description:<p>The purpose of this study is to characterize patients with Bone Marrow Failure Syndromes (BMFS) and to track the clinical course of patients with these diseases over time. An exact and comprehensive diagnosis at presentation is essential. Due to the sporadic nature of BMFS (aplastic anemia, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, pure red cell aplasia, amegakaryocytic thrombocytopenic purpura and large granular lymphocyte leukemia) most diseases have not undergone systematic long-term outcome studies.</p> <p>Individual diseases, combined under the collective entity of bone marrow failure syndromes, frequently overlap and evolve from each other. The frequency of complications, associations with other diseases, and genetic factors such as allelic polymorphisms are not well studied. Some of these syndromes are likely mediated by the cellular immune system. However, while target antigens are likely to be expressed on early hematopoietic cells, their identification has been unsuccessful.</p> <p><u>Hypothesis:</u> Clinical and epidemiologic studies may, through etiologic clues and intricate laboratory testing, facilitate the understanding of the pathophysiology of BMFS and ultimately lead to implementation of better diagnostic tools and more targeted and rational therapies.</p>
| phs000592 | dbGaP
Project description:The inherited bone marrow failure syndromes (IBMFS) are a rare yet clinically important cause of neonatal hematological and non-hematological manifestations. Many of these syndromes, such as Fanconi anemia, dyskeratosis congenita and Diamond-Blackfan anemia, confer risks of multiple medical complications later in life, including an increased risk of cancer. Some IBMFS may present with cytopenias in the neonatal period whereas others may present only with congenital physical abnormalities and progress to pancytopenia later in life. A thorough family history and detailed physical examination are integral to the work-up of any neonate in whom there is a high index of suspicion for an IBMFS. Correct detection and diagnosis of these disorders is important for appropriate long-term medical surveillance and counseling not only for the patient but also for appropriate genetic counselling of their families regarding recurrence risks in future children and generations.
| S-EPMC4747853 | biostudies-other
Project description:PURPOSE OF REVIEW:Inherited bone marrow failure syndromes (IBMFS) are a diverse set of genetic disorders characterized by the inability of the bone marrow to produce sufficient circulating blood cells. The purpose of this review is to highlight novel findings in recent years and their impact on the understanding of IBMFS. RECENT FINDINGS:Mutations in over 80 different genes have been associated with the development of bone marrow failure (BMF). The products of the genes mutated in IBMFS frequently participate in housekeeping pathways, which are important for cell growth and division rather than being specific for hematopoiesis. The common theme of these pathways, when disturbed, is the activation of p53, leading to cell cycle arrest, senescence, and cell death. With continued improvement in therapy for IBMFS, late complications, such as development of malignancies, are seen more frequently. This highlights the importance of understanding the affected pathways and their roles in cancer development. SUMMARY:The recent advancement of our understanding of IBMFS has come largely through the identification of the genetic lesions responsible for disease and the investigations of their pathways. Applied in clinical practice, these findings make it possible to unambiguously identify mutation carriers even before the development of BMF and exclude or confirm a suspected clinical diagnosis for many of the more common IBMFS. The further characterization of the pathways leading to IBMFS is likely to reveal novel targets for screening tests, prognostic biomarkers, and improved and specific therapeutics.
| S-EPMC3926810 | biostudies-literature
Project description:Telomeres are long DNA repeats and a protein complex at chromosome ends that are essential for genome integrity. Telomeres are very short in patients with dyskeratosis congenita due to germline mutations in telomere biology genes. We compared telomere length in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome with telomere length in dyskeratosis congenita. Telomere length was measured in six leukocyte subsets by automated multicolor flow fluorescence in situ hybridization, and age-adjusted using Z-scores (-2.326 = 1(st) percentile) were created. We examined individual data, and used canonical variate analysis for group comparisons and outlier detection. Most dyskeratosis congenita telomere lengths were below the 1(st) percentile, while only 2 Fanconi anemia and one each Diamond-Blackfan anemia and Shwachman-Diamond syndrome were that low. However, Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome clustered in the bottom half of the normal range. Canonical variate analysis separated dyskeratosis congenita widely from the other three syndromes by the first canonical variable (89.7% of the variance); the second variable (10.0%) separated Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and Fanconi anemia from each other. Overall, unlike in dyskeratosis congenita, telomere lengths in patients with non-dyskeratosis congenita inherited bone marrow failure syndromes were usually in the normal range, albeit shorter than in unaffected individuals. Clinicaltrials.gov identifier: 00027274.
| S-EPMC4281312 | biostudies-literature
Project description:Inherited bone marrow failure syndrome (IBMFS) encompasses a heterogeneous and complex group of genetic disorders characterized by physical malformations, insufficient blood cell production, and increased risk of malignancies. They often have substantial phenotype overlap, and therefore, genotyping is often a critical means of establishing a diagnosis. Current advances in the field of IBMFSs have identified multiple genes associated with IBMFSs and their pathways: genes involved in ribosome biogenesis, such as those associated with Diamond-Blackfan anemia and Shwachman-Diamond syndrome; genes involved in telomere maintenance, such as dyskeratosis congenita genes; genes encoding neutrophil elastase or neutrophil adhesion and mobility associated with severe congenital neutropenia; and genes involved in DNA recombination repair, such as those associated with Fanconi anemia. Early and adequate genetic diagnosis is required for proper management and follow-up in clinical practice. Recent advances using new molecular technologies, including next generation sequencing (NGS), have helped identify new candidate genes associated with the development of bone marrow failure. Targeted NGS using panels of large numbers of genes is rapidly gaining potential for use as a cost-effective diagnostic tool for the identification of mutations in newly diagnosed patients. In this review, we have described recent insights into IBMFS and how they are advancing our understanding of the disease's pathophysiology; we have also discussed the possible implications they will have in clinical practice for Korean patients.
| S-EPMC4155177 | biostudies-literature
Project description:To better understand the natural history of bone marrow failure syndromes, we analyzed 124 single nucleotide polymorphism arrays (SNP-A) from a comprehensively characterized cohort of 91 patients who had SNP-A for clinical evaluation of BMFS. 67 samples from 51 patients were genotyped with the Quad610, and 57 samples from 54 patients were genotyped with the Omni1-Quad. This submission includes 55 samples from 54 patients that were genotyped with Omni1-Quad. Illumina Infinium SNP-A genotyping was performed on DNA extracted from bone marrow aspirates using standard manufacturer's protocol
2014-01-01 | E-GEOD-48482 | biostudies-arrayexpress
Project description:To better understand the natural history of bone marrow failure syndromes, we analyzed 124 single nucleotide polymorphism arrays (SNP-A) from a comprehensively characterized cohort of 91 patients who had SNP-A for clinical evaluation of BMFS. 67 samples from 51 patients were genotyped with the Quad610, and 57 samples from 54 patients were genotyped with the Omni1-Quad. This submission includes 67 samples from 51 patients that were genotyped with Illumina Quad610 Beadchip. Illumina Infinium SNP-A genotyping was performed on DNA extracted from bone marrow aspirates using standard manufacturer's protocol
2014-01-01 | E-GEOD-48483 | biostudies-arrayexpress
Project description:Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.
| S-EPMC6142589 | biostudies-literature