Inherited Bone Marrow Failure Syndromes PDF

Inhireted bone Marrow Failure Syndromes PRESENTED BY : DR. HANEEN ABDULHUSAIN SUPERVISED BY :CONSULTANT DR. GHASSAN AHMED KHALEEL Introduction IBMFSs comprise a group of rare monogenic disorders characterized by blood cytopenia(s) and non-hematological effects. These include Fanco...

Inhireted bone Marrow Failure Syndromes PRESENTED BY : DR. HANEEN ABDULHUSAIN SUPERVISED BY :CONSULTANT DR. GHASSAN AHMED KHALEEL Introduction IBMFSs comprise a group of rare monogenic disorders characterized by blood cytopenia(s) and non-hematological effects. These include Fanconi anemia (FA), dyskeratosis congenita (DC), Diamond– Blackfan anemia (DBA), Shwachman–Diamond syndrome (SDS), severe congenital neutropenia (SCN), congenital dyserythropoietic anemia (CDA), congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia–absent radii (TAR), and other rare entities. Two conditions have recently been described, GATA2 deficiency and SAMD9/9L mutations, which may be more common The inherited BMF syndromes.  Some may manifest in the neonatal period (e.g., DBA and SCN), some may develop in childhood (e.g., FA or DC), and others may present at any time in life (e.g., DC or SDS). Patients with IBMFSs do not respond to immunosuppressive therapy. The IBMFSs also behave as cancer and leukemia predisposition syndromes with a high risk of developing MDS or acute myeloid leukemia (AML) and, in some types, solid tumors.  Recent advances in the genetic diagnoses of IBMFSs have identified germline mutations affecting DNA repair, telomere maintenance, and ribosome biogenesis. All these functions are necessary for the self-renewal of HSCs/ HSPCs and the generation of mature blood cells. Although aplastic anemia and IBMFSs may share similar biological features of decreased hematopoietic stem, progenitor, or precursor cells, IBMFS is caused by an intrinsic defect in HSCs, whereas aplastic anemia is caused by an exogenous attack against HSCs/ HSPCs. The Role of Inflammatory Cytokines in IBMFSs Pathogenesis There is substantial heterogeneity in the development of IBMFSs and their phenotypes even if patients share the same gene mutation. This led us to hypothesize that other factors may contribute to both hematologic and non- hematologic manifestations of IBMFSs via the production of inflammatory cytokines. A complex cytokine network produced by and acting on hematopoietic and stromal cells controls hematopoiesis. Dysregulation between lymphocyte and cytokine activities has been reported in aplastic anemia and hypoplastic MDS, but they have been understudied in IBMFSs. Furthermore, almost all the different forms of IBMFS are associated with an increased risk of myeloid and/or solid malignancies in which aberrant cytokine profiles may have a role. studies in patients and disease models have revealed common cytokine profiles and biological pathways underlying IBMFSs. Pro-inflammatory cytokines, IL-6 and IL-8, and an anti-inflammatory cytokine, TGF-β, were found to be commonly elevated in FA and SDS. The shortening of telomere length, which is the hallmark of DC, is a common feature of IBMFs. Oxidative stress and reactive oxygen species (ROS) are also commonly observed in the disease models of IBMFS. Mitochondrial dysfunction commonly found in IBMFSs may further exacerbate ROS. These stress responses collectively activate the TP53/p21 axis, p16, and p38 MAPK/NF-κB axis. Exogenous stimuli such as infection, and UV and X-ray radiation add to these pro-inflammatory signals, resulting in the secretion of inflammatory cytokines.Altogether, these events lead to cell cycle arrest and apoptosis, which may explain the pathogenesis of bone marrow failure, systemic anomaly, and cancer predisposition. Summary of inflammatory profiles in IBMFSs Inherited marrow failure syndromes with predominantly pancytopenia Fanconi Anemia FA is perhaps the most frequent form of IBMFS and may be characterized by pancytopenia or myeloid neoplasia (MDS/AML) that often arises between 5 and 15 years of age. Systemic traits include “Fanconi” facies with microphthalmia, radial deformities, and genitourinary and other malformations. During their adolescence and young adulthood, patients are at a high risk of developing MDS/AML. Later, they are predisposed to a wide range of solid tumors, particularly esophageal/pharyngeal carcinomas, and genitourinary malignancies.  In some cases the pancytopenia develops in adolescence or even in adult life. The haemoglobin and platelet count are usually first to fall; the granulocytes are usually well preserved in the early stages. As the pancytopenia develops, the bone marrow(BM) becomes progressively hypocellular. There is often a marked increase in macrophage activity with evidence of haemophagocytosis. BMF, leading to fatal haemorrhage or infection, is the main cause of death. Genetics To date, biallelic mutations in 22 causative genes have been reported. They are involved in DNA repair and genome stability, namely the FA pathways. These are autosomal recessive (FANCA, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG/XRCC9, FANCI, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/ ERCC4, FANCS/BRCA1, FANCT/UBE2T, FANCU/XRCC2, FANCV/REV7, and FANCW/RFWD3), except for FANCB, which exhibits X-linked recessive inheritance, and FANCR/RAD51, which presents a de novo autosomal dominant inheritance pattern.  FANCA, FANCG, and FANCC are the most mutated genes. A genotype–phenotype correlation may be observed in the time to develop leukemia and solid tumors in association with milder or more severe forms of mutations. FANCD2 patients often manifest a more severe phenotype and FANCD1/BRCA2 patients develop an early and rapidly lethal cancer-prone syndrome  FA cells characteristically display a high frequency of spontaneous chromosomal breakage and hypersensitivity to DNA cross-linking agents such as diepoxybutane (DEB) and mitomycin C (MMC). This genomic instability led to the development of a diagnostic test (i.e. increased chromosomal breakage in FA cells compared with normal controls after exposure to DEB/MMC) Studies have demonstrated that the proteins encoded by the FA genes participate in a complicated network important in DNA repair. Specifically, eight of the FA proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL and FANCM) interact with each other and form the FA core complex  The FA core complex is required for the activation of the FANCI-FANCD2 protein complex to a monoubiquitinated form (FANCI-FANCD2-Ub). FANCIFANCD2-Ub then interacts with DNA repair proteins (including BRCA2, BRCA1 and RAD51) leading to repair of the DNA damage. patients have biallelic mutations in BRCA2.. The BRCA2 protein is important in the repair of DNA damage by homologous recombination Inflammatory Profile of FA.Patients with FA show decreased number of B cell lymphocytes and NK cells compared to normal controls, and impaired function in cytotoxic T lymphocytes. Immunoglobulin levels are variable among FA patients; however, patients with FA who developed severe bone marrow failure showed decreased levels of IgG and IgM. increased levels of serum TGF-β, IL-6, and low soluble CD40L compared to healthy controls were reported. In another report, higher plasma levels of IL-10 in FA patients but no difference in TGF-β were noted  TNF-α and IFN-γ have been proposed as causative stress in bone marrow failure in aplastic anemia. These inflammatory cytokines may play a role in enhancing oxidative stress and DNA damage in FA pathogenesis. T cell lymphocytes from FA patients showed increased expression of TNF-α and IFN-γ in one report; however, this was not observed in the other, which showed an increased tendency of peripheral monocytes to produce TNF-α, IL-6, and IL-1β in response to low dose lipopolysaccharide.  FANCA patients showed elevated levels of IL-1β due to the constitutive activation of the PI3K-AKT pathway. Lymphoblastoid cell lines established from FANCA and FANCC patients exhibited the overexpression of secretory factors including IL-6, IL-8, MMP-2, and MMP-9 compared to control cells. Still, the contributions of inflammatory cytokines to FA pathogenesis remain to be fully determined. Inhibition of TGF- β by luspatercept, a trap for the TGF family of ligands , may be of clinical value for the anemia of FA. Lab. Evaluation and Diagnosis Fanconi anemia should be evaluated in patients presenting with signs and symptoms of pancytopenia with or without characteristic malformations and in patients with a family history of bone marrow failure A complete blood count reveals the level of RBCs, white blood cells (WBCs), and platelets and macrocytosis, and there can be high HbF levels due to increased stress. Serum erythropoietin is increased due to the low level of blood cells and the low response of hematopoietic stem cells. Bone marrow aspiration and biopsy reveal hypocellularity, aplasia with fatty marrow, and absence of myeloid, erythroid, and megakaryocyte stem cell line  The chromosomal breakage/stress cytogenetics test is a diagnostic test indicated in those with severe pancytopenia defined as an absolute neutrophil count of