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Summary: The great pathologist Paul Ehrlich in Berlin is commonly credited with describing the first clear case of aplastic anaemia in 1888: a 21‐year‐old woman who presented with haemorrhage and signs and symptoms of severe anaemia, quickly succumbing to her illness. Ehrlich's description of this patient's background and clinical course allowed individual identification. Re‐analysis of this case suggests an inherited bone marrow failure syndrome as a possible additional diagnosis. [ABSTRACT FROM AUTHOR]

Diamond-Blackfan anemia (DBA) was the first ribosomopathy described in humans. DBA is a congenital hypoplastic anemia, characterized by macrocytic aregenerative anemia, manifesting by differentiation blockage between the BFU-e/CFU-e developmental erythroid progenitor stages. In 50 % of the DBA cases, various malformations are noted. Strikingly, for a hematological disease with a relative erythroid tropism, DBA is due to ribosomal haploinsufficiency in 24 different ribosomal protein (RP) genes. A few other genes have been described in DBA-like disorders, but they do not fit into the classical DBA phenotype (Sankaran et al., 2012; van Dooijeweert et al., 2022; Toki et al., 2018; Kim et al., 2017 [ 1–4 ]). Haploinsufficiency in a RP gene leads to defective ribosomal RNA (rRNA) maturation, which is a hallmark of DBA. However, the mechanistic understandings of the erythroid tropism defect in DBA are still to be fully defined. Erythroid defect in DBA has been recently been linked in a non-exclusive manner to a number of mechanisms that include: 1) a defect in translation, in particular for the GATA1 erythroid gene; 2) a deficit of HSP70, the GATA1 chaperone, and 3) free heme toxicity. In addition, p53 activation in response to ribosomal stress is involved in DBA pathophysiology. The DBA phenotype may thus result from the combined contributions of various actors, which may explain the heterogenous phenotypes observed in DBA patients, even within the same family. [ABSTRACT FROM AUTHOR]

Diamond‐Blackfan anemia (DBA) features hypoplastic anemia and congenital malformations, largely caused by mutations in various ribosomal proteins. The aim of this study was to characterize the spectrum of genetic lesions causing DBA and identify genotypes that correlate with phenotypes of clinical significance. Seventy‐four patients with DBA from across Canada were included. Nucleotide‐level mutations or large deletions were identified in 10 ribosomal genes in 45 cases. The RPS19 mutation group was associated with higher requirement for chronic treatment for anemia than other DBA groups. Patients with RPS19 mutations, however, were more likely to maintain long‐term corticosteroid response without requirement for further chronic transfusions. Conversely, patients with RPL11 mutations were less likely to need chronic treatment. Birth defects, including cardiac, skeletal, hand, cleft lip or palate and genitourinary malformations, also varied among the various genetic groups. Patients with RPS19 mutations had the fewest number of defects, while patients with RPL5 had the greatest number of birth defects. This is the first study to show differences between DBA genetic groups with regards to treatment. Previously unreported differences in the rate and types of birth defects were also identified. These data allow better patient counseling, a more personalized monitoring plan, and may also suggest differential functions of DBA genes on ribosome and extra‐ribosomal functions. [ABSTRACT FROM AUTHOR]

The inherited bone marrow failure (IBMF) syndromes are a heterogeneous group of disorders with characteristic quantitative or qualitative abnormalities affecting one or more hematopoietic lineages. IBMF syndromes are due to germline mutations affecting structural proteins or key cellular pathways such as DNA repair, telomerase biology, and ribosomal biosynthesis. These mutations lead to single or multiple peripheral blood cytopenias that either result from an absence of one or more lineages of hematopoietic progenitors in the marrow or to an increase cell death of one or more marrow progenitor lineages. Most IBMF syndromes manifest in childhood, but some are recognized later in life depending on the severity of symptoms. This review we will summarize the clinical presentation, diagnostic findings, and genetic findings of the most frequent and best studied IBMF syndromes with a special focus on the diagnostic dilemmas which can occur during the work up of a child with suspected a IBMF syndrome. [ABSTRACT FROM AUTHOR]

Patients with inherited bone marrow failure syndromes ( IBMFS) have 'stress erythropoiesis', with anaemia, macrocytosis, increased fetal haemoglobin (Hb F) and high erythropoietin levels. In haemoglobinopathies, Hb F levels are regulated by 3 quantitative trait loci, HBS1L- MYB, BCL11A and Xmn1 - HBG2. In our study of 97 patients with an IBMFS, increased Hb F was associated with young age, male gender, anaemia, high erythropoietin levels, and alternative alleles in Xmn1 - HBG2 [adjusted P = 0·04 for the total group, driven by Fanconi anaemia ( P = 0·02) and dyskeratosis congenita ( P = 0·09)]. Thus Hb F is regulated in IBMFS by Xmn1 - HBG2, as it is in the haemoglobinopathies. [ABSTRACT FROM AUTHOR]

Leguit R J & van den Tweel J G (2010) Histopathology , 655-670 An important indication for bone marrow investigation is the presence of bone marrow failure, which manifests itself as (pan)cytopenia. The causes of cytopenia are varied and differ considerably between childhood and adulthood. In the paediatric age group inherited bone marrow failure syndromes are important causes of bone marrow failure, but they play only a minor role in later life. This review gives a comprehensive overview of bone marrow failure disorders in children and adults. We classified the causes of bone marrow failure according to the main presenting haematological abnormality, i.e. anaemia, neutropenia, thrombocytopenia or pancytopenia. The following red cell disorders are discussed: red cell aplasia, sideroblastic anaemia, congenital dyserythropoietic anaemia, haemolytic anaemia, paroxysmal nocturnal haemoglobinuria, iron deficiency anaemia, anaemia of chronic disease and megaloblastic anaemia. The neutropenias occur in the context of Shwachman-Diamond syndrome (SDS), severe congenital neutropenia, cyclic neutropenia, immune-related neutropenia and non-immune neutropenia. In addition, the following causes of thrombocytopenia are discussed: congenital amegakaryocytic thrombocytopenia, thrombocytopenia with absent radii, immune-related thrombocytopenia and non-immune thrombocytopenia. Finally, we pay attention to the following pancytopenic disorders: Fanconi anaemia, dyskeratosis congenita, aplastic anaemia, myelodysplastic syndromes and human immunodeficiency virus (HIV) infection. [ABSTRACT FROM AUTHOR]