LYDIE DA COSTA (PARIS)
DIAMOND-BLACKFAN ANEMIA, A RARE CONGENITAL ERYTHROBLASTOPENIA
Lydie Da Costa, MD, PhD, Hematology lab, Robert Debré Hospital, Paris University, EA4666 Hematim,
Laboratoire d’Excellence GR-Ex, Paris, France
Diamond-Blackfan anemia (DBA) is a rare congenital erythroblastopenia with an incidence of
7 cases per million life birth, which is diagnosed early in infancy (median age at diagnosis: 2
month-old; at 5-y-old, 98% of the DBA cases are diagnosed). The inheritance is heterogenous,
mostly sporadic in 55% of DBA cases and in the familial cases, the inheritance is autosomal
dominant, but some recessive and X-linked inheritance is associated with rare DBA cases
mostly in DBA-like diseases. DBA is revealed by the signs of anemia in an infant (pallor, failure
to thrive, and difficulties during feedings) and in 50% of the DBA cases, in addition to the
anemia, various congenital malformations, mostly in the cephalic area and the extremities
(thumbs) are reported. The malformative syndrome includes short stature and growth
retardation (22%), which is usually reported as well during pregnancy with hypotrophy at birth
reported in 28% of the cases (1, 2). Growth retardation is often worsen by the side effects of
the treatment, iron overload from iterative transfusions in spite an iron chelation or steroid
therapy. DBA is also a rare cause of unexplained anemia during pregnancy or responsible for
hydrops fetalis (3, 4). DBA is characterized by a blockade in early erythroid differentiation
between the BFU-e/CFU-e erythroid progenitor stages (5), leading to the characterized i)
erythroblastopenia which is on the bone marrow smear, the absence or less than 5% of
erythroid precursors in an otherwise normal bone marrow and ii) the moderate to severe
anemia usually macrocytic, aregenerative (absence or less than 20x109/L reticulocytes). The
other cell lineages are usually normal but neutropenia, thrombocytopenia even
thrombocytosis may be present at diagnosis. In 90% of the non-transfused DBA patients, an
increased activity of the erythrocyte adenosine deaminase activity is reported. HbF is still
often elevated after 6 month-1 year of age, meanwhile non specific and seen as well in other
inherited bone marrow failures (IBMF). EPO level is high, in response to the anemia with only
few progenitors able to bind EPO. Like the phenotype, the DBA genotype is highly
heterogenous. RPS19 was the first gene identified in 1999 and the most frequently mutated
gene involved in DBA (25% of DBA cases). The other most frequent mutated genes are RPL5,
RPL11, RPS26, RPL35a, RPS10, RPS24 genes. Including RPS19 gene they are responsible for
»50% of the mutated DBA affected patients (6-8). Large deletions in these previous genes
identified by MLPA or CGH account for 20% of the DBA cases (9-12). The other RP genes are
only responsible very DBA cases. In addition to the RP genes from the small and the large
ribosomal subunits, 3 genes are not RP genes: TSR2 gene but it is still related to ribosome
since it is able to bind RPS26 and involved in pre-rRNA processing, GATA1(13), the major
transcription factor of the erythropoiesis and EPO genes (14). We now indeed describe DBA
syndrome which includes the classical DBA (erythroblastopenia related to a defect in rRNA
maturation (RP genes, TSR2, ..), the DBA-like diseases ((erythroblastopenia unrelated to a
defect in ribosome biogenesis (EPO gene and apart the ADA2 deficiency), and DBA-like related
to a mutation in GATA1 gene, which is characterized by an hypoplastic anemia associated with
dyserythropoiesis and dysmekacaryopoiesis features, unusual in DBA. Only few DBA patients
are described with mutation in GATA1 gene (none in the French registry) (15-17). DBA is part
of the inherited bone marrow failure syndrome and acknowledged as the first ribosomopathy
in 2005. The RP haploinsufficiency is responsible for a defect in ribosomal RNA (rRNA)
maturation (18). The relation of a RP haploinsufficiency and the quite specific tropism
erythroid defect is still matter of debate meanwhile large progresses have been made. Indeed,
it has been found that p53 is activated in DBA either in the DBA patients or after CD34+