Clinical and laboratory evidence for a trilineage haematopoietic defect in patients with refractory Diamond–Blackfan anaemia

Abstract

Summary. Diamond±Blackfan anaemia (DBA) is a constitutional pure red cell aplasia presenting in early childhood. In some patients, neutropenia and/or thrombocytopenia have also been observed during the course of the disease. We have followed 28 patients with steroid-refractory DBA for up to 13 years with serial peripheral blood counts and bone marrow (BM) aspirates and biopsies. In 21/28 (75%) patients, moderate to severe generalized BM hypoplasia developed, with overall cellularities ranging from 0% to 30%. Marrow hypoplasia correlated with the development of neutropenia (9/21; 43%) and/or thrombocytopenia (6/21; 29%) in many patients. No patient had either cytogenetic abnormalities or progressed to acute leukaemia, although one 13-year-old developed marked marrow ®brosis and trilineage dysplasia. We used the in vitro long-term culture-initiating cell (LTC-IC) assay to quantify multilineage, primitive haematopoietic progenitors in a representative subset of these patients. LTC-IC assays showed equivalent frequencies of cobblestone areaforming cells (CAFCs) with a mean of 5?42/10 5 cells 6 1?9 SD and 6?13/10 5 cells 6 2?6 SD in nine patients and six normal controls respectively. The average clonogenic cell output per LTC-IC, however, was signi®cantly lower in DBA patients (mean 2?16 6 1?2 SD vs. 7?36 6 2?7 SD in normal controls, P 0?0008). Our results suggest that the underlying defect in patients with severe refractory DBA may not be limited to the erythroid lineage, as was evidenced by the development of pancytopenia, bone marrow hypoplasia and reduced clonogenic cell output in LTC-IC assays.

The evolving spectrum of ‘non‐classical’ Diamond‐Blackfan anaemia – a case of eADA positive pancytopenia in a young adult

“…Measurement of eADA is considered a reasonably reliable indicator of DBA and a minor diagnostic criterion in DBA (Orfali et al, 2004;Vlachos et al, 2008), whereas the incidence of eADA elevation in severe aplastic anaemia (SAA) has not been studied to date. In addition to the unusual presentation of non-classical DBA in a young adult, this case is distinguished by progressive pancytopenia (not currently considered a diagnostic criteria for DBA; Diamond et al, 1976) that, unlike reported cases of trilineage haematopoietic defects in DBA, preceded treatment, (Giri et al, 2000). We suggest that DBA should therefore be considered in any patient with hypoplastic pancytopenia and macrocytosis, especially in the absence of the severe bone marrow hypocellularity that is characteristic of severe AA, regardless of age.…”

Mice with ribosomal protein S19 deficiency develop bone marrow failure and symptoms like patients with Diamond-Blackfan anemia

“…20 Although present at normal frequencies, the proliferation and differentiation of immature hematopoietic progenitors in DBA have shown to be impaired in vitro. 2,18,20,21 Generation of animal models for RPS19-deficient DBA is pivotal to understand the disease mechanisms and to evaluate novel therapies. Matsson et al attempted to create a mouse model with a targeted disruption of Rps19.…”

Anémie de Diamond-Blackfan

“…Néanmoins, cette question reste discutée : d'autres travaux ont fait le constat d'une réduction du nombre de progéniteurs précoces BFU-e, ce qui suggère un défaut plus en amont dans la hiérarchie de l'hématopoïèse [9,10]. En accord avec cette idée, il a été montré que la différenciation d'autres lignages hématopoïétiques pouvait être affectée chez certains patients [11,12].…”

“…La cartographie pangénomique des SNP (single nucleotide polymorphisms) réalisée dans 215 familles a révélé d'autres locus en lien avec l'ADB : une région de 18 Mb sur le chromosome 8 (8p23. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22] et des régions plus petites sur les chromosomes 6 et 10. Concernant le chromosome 10, le séquençage du gène codant la protéine ribosomique RPS24 a mis en évidence chez trois patients deux mutations non-sens et une délétion de la région codante, absentes lors de l'analyse de 200 génomes contrôles [15].…”