Diamond-Blackfan anemia: a “cultural” diagnosis

Comment on Ohene-Abuakwa et al, page 838

In vitro erythroid cultures may be necessary to detect nonpenetrant Diamond-Blackfan anemia.

The diagnosis of Diamond-Blackfan anemia (DBA) was easy when it was first described in the 1930s: severe congenital anemia in a transfusion-dependent child.¹  DBA is now defined as “[1] normochromic (usually macrocytic but occasionally normocytic) anemia developing early in childhood; [2] reticulocytopenia; [3] normocellular bone marrow with selective deficiency of red cell precursors; [4] normal or slightly decreased leukocyte counts; and [5] normal or often increased platelet counts.”^2(p318) Clinical and molecular genetic studies have revealed that the inheritance of DBA is consistent with an autosomal dominant mechanism; some familial and apparently sporadic cases have germ-line mutations in the RPS19 gene, which encodes ribosomal protein S19. More complete evaluationsof family members identified individuals who were obligate carriers of DBA by pedigree position and/or documented mutations in RPS19, but who clinically did not have the DBA phenotype. Laboratory parameters that support a DBA diagnosis include mild anemia, macrocytosis, elevated fetal hemoglobin (markers of fetallike stress erythropoiesis),³  and elevated red cell adenosine deaminase(ADA).⁴  However,these findings were not always observed, even in individuals with a definitive “DBA” diagnosis.

Ohene-Abuakwa and colleagues in this issue of Blood provide new insights into the pathophysiology of DBA, which also shed light on the silent carrier or nonpenetrant individual. They have adapted the 2-phase liquid erythroid culture system⁵  to demonstrate that the pre-erythropoietin stage of erythroid commitment is intact in DBA, while the erythropoietin-dependent phase of erythroid expansion and terminal maturation is defective. They observed this abnormality in late erythropoiesis among DBA patients representing the entire range of phenotypic severity, both with and without detectable mutations in RPS19, including nonanemic relatives with increased adenosine deaminase as their only sign of possible DBA.FIG1 

Confirmation of this “cultural” test as a means of identifying DBA carriers in families without mutations in RPS19 would lead to a series of important questions that are equally applicable to other dominantly inherited bone marrow failure syndromes in which silent carriers are observed: (1) Will clinical bone marrow failure develop as patients age, despite their normal phenotype? (2) Are such individuals suitable stem cell transplant donors for affected family members? (3) What is the risk of leukemia or solid tumors of the types known to develop in persons with an unequivocal diagnosis of the disorder? (4) What is the risk of clinical bone marrow failure in the offspring of silent carriers? The authors of the current paper mention that anemia developed subsequently in one of the relatives in whom they found reduced in vitro erythropoiesis. There is also a case report of a bone marrow transplant from an HLA-identical sibling in which there was stem cell but not erythroid engraftment,⁶  suggesting that there was a specific defect in erythropoiesis.

It is not currently feasible to perform in vitro erythroid culture assays on all relatives in DBA families. Nevertheless, the studies by Ohene-Abuakwa et al suggest that such cultures should be considered in the evaluation of potential stem cell donor relatives, even for those in whom there is no evidence of DBA by hemoglobin, mean cell volume, hemoglobin F, ADA, or a germ-line mutation in RPS19. Identification of new DBA genes in RPS19-negative families will eventually provide the most direct information regarding affection status, but tissue culture assays of the type described by Ohene-Abuakwa et al may be an important interim approach. Hematopoietic cell biology has not yet been completely replaced by molecular studies. ▪