Comparison of chromosome breakage in non-mosaic and mosaic patients with Fanconi anemia, relatives, and patients with other inherited bone marrow failure syndromes.
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SUBMITTER: Fargo JH
PROVIDER: S-EPMC4225000 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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Project description:PurposeThe inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders that share the inability of the bone marrow to produce an adequate number of blood cells. The 4 most frequent syndromes are Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS). All 4 syndromes have been associated with various physical abnormalities. As part of a genotype/phenotype/cancer susceptibility study, we determined the prevalence of ophthalmic manifestations in these 4 syndromes.DesignCross-sectional study of a patient cohort.ParticipantsSeventy-five patients with an IBMFS and 121 of their first-degree relatives were seen in the National Eye Institute, National Institutes of Health, from 2001 to 2007. The patient group included 22 with FA, 28 with DC, 19 with DBA, and 6 with SDS.MethodsEvery participant underwent a complete ophthalmic evaluation and digital facial photography with an adhesive paper ruler on the patient's forehead for an internal measure of scale. Interpupillary distance (IPD), inner canthal distance (ICD), outer canthal distance (OCD), palpebral fissure length (PFL), and corneal diameter (CD) were measured. Thirteen of the 22 patients with FA underwent axial length (AL) measurements by A-scan ultrasonography.Main outcome measuresType and prevalence of ophthalmic manifestations.ResultsNinety-five percent of patients with FA had at least 1 abnormal parameter, and 25% of patients had at least 4 abnormal parameters. Eighty-two percent of patients had small palpebral fissures, 69% of patients had simple microphthalmia, 64% of patients had small OCD, 55% of patients had microcornea, 28% of patients had ptosis, and 6% of patients had epicanthal folds. In patients with DC, abnormalities of the lacrimal drainage system (29%) were the most prevalent findings, followed by retinal abnormalities (pigmentary changes, retinal neovascularization, retinal detachment, exudative retinopathy) in 21%, cicatricial entropion with trichiasis and blepharitis in 7% each, and sparse eyelashes and congenital cataract in 3.5% each. No significant ophthalmic abnormalities were seen in patients with DBA or SDS.ConclusionsSyndrome-specific ocular findings are associated with FA and DC and may antedate diagnosis of the specific syndrome. Early recognition of these abnormalities is important for optimal management.
| S-EPMC2830377 | biostudies-literature
Project description:BackgroundPatients with bone marrow failure and undiagnosed underlying Fanconi anemia may experience major toxicity if given standard-dose conditioning regimens for hematopoietic stem cell transplant. Due to clinical variability and/or potential emergence of genetic reversion with hematopoietic somatic mosaicism, a straightforward Fanconi anemia diagnosis can be difficult to make, and diagnostic strategies combining different assays in addition to classical breakage tests in blood may be needed.Design and methodsWe evaluated Fanconi anemia diagnosis on blood lymphocytes and skin fibroblasts from a cohort of 87 bone marrow failure patients (55 children and 32 adults) with no obvious full clinical picture of Fanconi anemia, by performing a combination of chromosomal breakage tests, FANCD2-monoubiquitination assays, a new flow cytometry-based mitomycin C sensitivity test in fibroblasts, and, when Fanconi anemia was diagnosed, complementation group and mutation analyses. The mitomycin C sensitivity test in fibroblasts was validated on control Fanconi anemia and non-Fanconi anemia samples, including other chromosomal instability disorders.ResultsWhen this diagnosis strategy was applied to the cohort of bone marrow failure patients, 7 Fanconi anemia patients were found (3 children and 4 adults). Classical chromosomal breakage tests in blood detected 4, but analyses on fibroblasts were necessary to diagnose 3 more patients with hematopoietic somatic mosaicism. Importantly, Fanconi anemia was excluded in all the other patients who were fully evaluated.ConclusionsIn this large cohort of patients with bone marrow failure our results confirmed that when any clinical/biological suspicion of Fanconi anemia remains after chromosome breakage tests in blood, based on physical examination, history or inconclusive results, then further evaluation including fibroblast analysis should be made. For that purpose, the flow-based mitomycin C sensitivity test here described proved to be a reliable alternative method to evaluate Fanconi anemia phenotype in fibroblasts. This global strategy allowed early and accurate confirmation or rejection of Fanconi anemia diagnosis with immediate clinical impact for those who underwent hematopoietic stem cell transplant.
| S-EPMC2663612 | biostudies-literature
Project description:Immune function abnormalities have been reported in patients with Fanconi anemia (FA), dyskeratosis congenita (DC) and, rarely, in Shwachman-Diamond syndrome (SDS), and Diamond-Blackfan anemia (DBA), but large systematic studies are lacking. We assessed immunological parameters in 118 patients with these syndromes and 202 unaffected relatives. We compared the results in patients with reference values, and with values in relatives after adjusting for age, sex, corticosteroid treatment, and severe bone marrow failure (BMF). Adult patients (≥18 years) with FA had significantly lower immunoglobulins (IgG, IgA and IgM), total lymphocytes, and CD4 T cells than reference values or adult relatives (P < 0.001); children with FA had normal values. Both children and adults with FA had lower B- and NK cells (P < 0.01) than relatives or reference values. Patients with DC had essentially normal immunoglobulins but lower total lymphocytes than reference values or relatives, and lower T-, B-, and NK-cells; these changes were more marked in children than adults (P < 0.01). Most patients with DBA and SDS had normal immunoglobulins and lymphocytes. Lymphoproliferative responses, serum cytokine levels, including tumor necrosis factor-α and interferon-γ, and cytokine levels in supernatants from phytohemagglutinin-stimulated cultures were similar across patient groups and relatives. Only patients with severe BMF, particularly those with FA and DC, had higher serum G-CSF and Flt3-ligand and lower RANTES levels compared with all other groups or relatives (P < 0.05). Overall, immune function abnormalities were seen mainly in adult patients with FA, which likely reflects their disease-related progression, and in children with DC, which may be a feature of early-onset severe disease phenotype.
| S-EPMC4509864 | biostudies-literature
Project description: Not available
| S-EPMC9043929 | biostudies-literature
Project description:BackgroundPatients with inherited bone marrow failure syndromes (IBMFS) may have several risk factors for low bone mineral density (BMD). We aimed to evaluate the prevalence of low BMD in IBMFS and determine the associated risk factors.MethodsPatients with IBMFS with at least one dual-energy X-ray absorptiometry (DXA) scan were evaluated. Diagnosis of each IBMFS, Fanconi anemia (FA), dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome was confirmed by syndrome-specific tests. Data were gathered on age, height, and clinical history. DXA scans were completed at the lumbar spine, femoral neck, and forearm. BMD was adjusted for height (HAZ) in children (age ≤20 years). Low BMD was defined as a BMD Z-score and HAZ ≤-2 in adults and children, respectively, in addition to patients currently on bisphosphonate therapy.ResultsNine of thirty-five adults (26%) and eleven of forty children (27%) had low BMD. Adults with FA had significantly lower BMD Z-scores than those with other diagnoses; however, HAZ did not vary significantly in children by diagnosis. Risk factors included hypogonadism, iron overload, and glucocorticoid use.ConclusionsAdults and children with IBMFS have high prevalence of low BMD. Prompt recognition of risk factors and management are essential to optimize bone health.
| S-EPMC5570650 | biostudies-literature
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: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: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:Fanconi anemia (FA) is a rare inherited genomic instability syndrome representing one of the best examples of hematopoietic stem cell deficiency. Although FA might be an excellent candidate for bone marrow (BM) genetic correction ex vivo, knockout animal models are not sufficient to guide preclinical steps, and gene therapy attempts have proven disappointing so far. Contributing to these poor results is a characteristic and dramatic early BM-cells die-off when placed in culture. We show here that human primary FA BM cell survival can be ameliorated by using specific culture conditions that limit oxidative stress. When coupled with retrovirus-mediated transfer of the main complementation group FANCA-cDNA, we could achieve long-term reconstitution of the stem cell compartment both in vitro and in vivo. Gene-corrected BM cultures grew for >120 days, and after cultured cell transplantation into NOD/SCID mice, clonogenic human cells carrying the FANCA transgene could be detected 6 months after transduction. By comparison, untransduced cells died in culture by 15 days. Of necessity for ethical reasons, experiments were conducted on a very limited number of primary BM cells. By using low cytokine regimen and conditions matching regulatory requirements, a contingent of gene-corrected cells slowly emerges with an unmet potential for in vivo engraftment. Future therapeutic applications of stem cells might be expanding from these data. In addition, we provide a model of gene-corrected human primary cell growth that carries the potential to better delineate the combined role of both DNA damage and oxidative stress in the pathogenesis of FA.
| S-EPMC1413721 | biostudies-literature