Inherited Bone Marrow Failure Syndrome, TAM
Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and increased risk of malignant disease. IBMFS may affect all blood cell lineages, causing clinical
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Inherited Bone Marrow Failure Syndrome, TAM Etsuro Ito, Kiminori Terui, and Tsutomu Toki
Abstract Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of genetic disorders characterized by bone marrow failure, congenital anomalies, and increased risk of malignant disease. IBMFS may affect all blood cell lineages, causing clinical symptoms similar to aplastic anemia, or they may be restricted to one or two blood cell lineages with symptoms specific to the affected cell lineage. Early and accurate diagnosis of the disease is important, as there are implications for management and long-term follow-up. However, diagnosis is often difficult due to the wide varieties of clinical presentation. Recent advances in our understanding of IBMFS have largely come from the identification of the causative genes and investigations of their pathways. In this chapter, advances in the pathobiology and clinical management of two representative diseases, Diamond-Blackfan anemia and Fanconi’s anemia, will be described. Trisomy 21, the genetic hallmark of Down syndrome (DS), is the most frequent human chromosomal abnormality. In neonates with DS, about 5–10% develop transient abnormal myelopoiesis (TAM). Almost all cases of TAM have mutations in GATA1. In most cases, it resolves spontaneously within 3 months. However, early death occurs in about 20% of the cases. Furthermore, approximately 20% of TAM patients develop myeloid leukemia of DS (ML-DS) within 4 years of life. Human tumors have been shown to progress by the accumulation of genetic abnormalities. The malignant progression from TAM to ML-DS offers a unique model to study the stepwise development of cancer pathogenesis. Recent studies have provided fascinating insights into the pathogenesis of TAM, details that may provide insight not only into DS leukemia but also contribute to our understanding of the pathogenesis of other leukemias.
E. Ito, M.D., Ph.D. (*) • K. Terui, M.D., Ph.D. • T. Toki, Ph.D. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2017 E. Ishii (ed.), Hematological Disorders in Children, DOI 10.1007/978-981-10-3886-0_7
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7.1 Inherited Bone Marrow Failure Syndrome 7.1.1 Diamond-Blackfan Anemia 7.1.1.1 Introduction Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia characterized by normochromic macrocytic anemia and reticulocytopenia in the peripheral blood and the loss of erythroblasts in the bone marrow. It generally presents in the first year of life. Approximately 40% of DBA patients have variable malformations [1–3]. In addition, the patients have a predisposition for malignancies [4]. DBA was first reported by Dr. Josephs in 1936 and refined as a distinct clinical entity by Drs. Diamond and Blackfan in 1938 [5, 6]. DBA has been associated with heterozygous mutations or large deletions in ribosomal protein (RP) genes in more than 50% of patients [7–17], suggesting that DBA is cause
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