Introduction
Diamond-Blackfan Anemia (DBA) is characterized by anemia (low red blood cell
counts) with decreased erythroid progenitors in the bone marrow.
This usually develops during the neonatal period. About 47% of affected individuals also have a
variety of congenital
abnormalities, including craniofacial malformations, thumb or upper limb abnormalities,
cardiac defects, urogenital malformations, and cleft palate.1
Low birth weight and generalized growth delay are sometimes observed. DBA
patients have a modest risk of developing leukemia
and other malignancies.2,3,4
Diamond
and Blackfan
described congenital hypoplastic anemia in 1938.2
In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an
association with skeletal abnormalities.5 In 1997
a region on chromosome 19 was determined to carry a gene mutated in DBA.1,6
In 1999, mutations in the ribosomal protein S19
gene (RPS19) were found to be associated with disease in 42 of 172 DBA
patients.7 In 2001, it was determined that a
second DBA gene lies in a region of chromosome 8 although evidence for further
genetic heterogeneity was
uncovered.3
The majority of cases are sporadic,
although dominant or recessive patterns of inheritance are indicated by
familial occurrence in about 15% of patients.3 The primary defects
are in the erythroid progenitor cells, where there is an intrinsic defect that
results in increased apoptosis (programmed cell death). High levels of
erythropoietin (EPO) are present in serum and urine, although a search for
mutations in the EPO receptor gene has been negative. In about 25% of sporadic
and inherited cases there are mutations in a gene (DBA1) for a ribosomal protein S19, mapped to chromosome 19q13.3,7
A second gene for DBA has been linked to chromosome 8p, and most likely other
genetic abnormalities will be identified. A unifying etiology for this disorder
and the significance of these genetic alterations is being defined.8
Although hematopoiesis is generally adequate
in fetal life, some affected infants appear pale in the first days after birth;
rarely, hydrops fetalis occurs. Profound anemia usually becomes evident by 2–6
mo of age, occasionally somewhat later. Over 50% of affected children have
congenital anomalies, including short stature, craniofacial deformities, or
defects of the upper extremities, including triphalangeal thumbs.1,2
The abnormalities are diverse, with no specific pattern emerging in the
majority of those affected.2
The RBCs are almost always macrocytic for age, but there is
no hypersegmentation of neutrophils or other peripheral blood characteristics
of megaloblastic anemia. Folic acid and vitamin B12 levels are normal.2,4 Chemical evaluation of
RBCs reveals an enzyme pattern similar to a “fetal” RBC population, and there
is also elevated fetal hemoglobin (Hb F) and increased expression of “i” antigen.
Erythrocyte adenosine deaminase (ADA) activity is increased in most patients
with this disorder, a finding that helps distinguish congenital RBC aplasia
from acquired transient erythroblastopenia of childhood.3,7 Also,
because elevated ADA activity is not a fetal RBC feature, measurement of this
enzyme is helpful in diagnosing DBA in very young infants. Thrombocytosis or
thrombocytopenia and occasionally neutropenia may also be present initially.
Reticulocytes are characteristically very low despite severe anemia. RBC
precursors in the marrow are markedly reduced in most patients, but other
marrow elements are usually normal. Serum iron levels are elevated. Bone marrow
chromosome studies are normal and, unlike in Fanconi anemia, there is no
increase in chromosomal breaks when lymphocytes are stressed with alkylating
agents.1,4
Congenital hypoplastic anemia must be differentiated from
other anemias with low reticulocyte counts. The anemia of hemolytic disease of
the newborn can have a protracted course and, on occasion, be associated with
markedly reduced erythropoiesis. This usually terminates spontaneously at 5–8
wk of age. Aplastic anemic crises characterized by reticulocytopenia and by
decreased numbers of RBC precursors, frequently caused by parvovirus B19
infections, may complicate various types of chronic hemolytic disease, but
usually after the first several months of life.5 Infection with
parvovirus B19 in utero may also cause pure RBC aplasia in infancy, even with
hydrops fetalis at birth. The absence of parvovirus B19 detected by polymerase
chain reaction (PCR) is now considered an essential feature in establishing the
diagnosis of Diamond-Blackfan anemia in young infants. The syndrome of
transient erythroblastopenia of childhood may be differentiated from
Diamond-Blackfan syndrome by its relatively late onset (although it may
occasionally develop in infants younger than 6 mo).6 In very young
infants whose RBCs have many fetal features, a determination of elevated
erythrocyte ADA activity is particularly useful because this increased enzyme
activity is not a characteristic of fetal RBCs.1
Corticosteroid therapy is beneficial in three fourths of
patients who respond initially.2,4 The mechanism of its effect is
unknown. Prednisone in three divided doses totaling 2 mg/kg/24 hr is
used as an initial trial. An increase in RBC precursors appears in bone marrow
1–3 wk after therapy is begun, and this is followed by peripheral
reticulocytosis. The hemoglobin may reach normal levels in 4–6 wk, although there
is much variability in the rate of response. Once the hemoglobin concentration
is clearly increasing, the dose of corticosteroid may be reduced gradually by
tapering divided doses and then by eliminating all except a single, lowest
effective daily dose. This dose should then be doubled, used on alternate days,
and tapered still further while maintaining the hemoglobin level at 9 g/dL
or above. In some patients, very small amounts of prednisone, as low as
2.5 mg twice a week, may be sufficient to sustain adequate erythropoiesis.
Overall, 60% of children with Diamond-Blackfan anemia initially started on
steroids stop taking the drug. This occurs because of unacceptable steroid side
effects or evolution of steroid refractoriness at acceptable steroid doses, or,
occasionally, there is spontaneous remission of anemia.2,6
In patients
who do not respond to corticosteroid therapy, transfusions at intervals of 4–8
wk are necessary to sustain normal growth and activities. Chelation therapy for
iron overload with deferoxamine administered subcutaneously through a portable
pump should be started when excess iron accumulation is reflected by serum
ferritin levels exceeding 1,500 mg/dL, but preferably after 5 yr of age,
because the medication may interfere with normal growth. An oral iron chelator,
deferiprone (L1), is in clinical trials and may be almost as effective as
deferoxamine; however, there is some controversy related to possible hepatic
toxicity. The drug is licensed for use in Canada,
the United Kingdom, and India but not in the United States. Other therapies,
including androgens, cyclosporine, cyclophosphamide, antithymocyte globulin
(ATG), high-dose intravenous immunoglobulin, high-dose methylprednisolone, EPO,
and interleukin-3 have not had a consistent beneficial effect and may have a
high incidence of side effects. Splenectomy may decrease the need for
transfusion if hypersplenism or isoimmunization develops. Stem cell
transplantation from a related histocompatible donor has a role in children who
do not respond to corticosteroids and who have demonstrated a several-year need
for RBC transfusions. The survival results for matched-related donors have been
very encouraging, but the responses have been much inferior with the use of
partially mismatched siblings or matched unrelated donors.2
Median survival is probably more than 40 yr of age,
although definitive data are lacking. The outlook is best in those who respond
to corticosteroid therapy.2 About half of patients are long-term
responders. In the others, survival depends on transfusions. Some children in
each group may eventually have spontaneous remissions (about 20%), and most of
these remissions occur in the first decade. In children who are regularly
transfused, total body iron increases and hemosiderosis ensues.5 The
liver and spleen may enlarge, and secondary hypersplenism with leukopenia and
thrombocytopenia can occur.2,5 The complications of chronic
transfusions in DBA are similar to those in β-thalassemia major, and prevention
and treatment of iron overload should be equally aggressive in both groups of
transfused patients . DBA may be a premalignant syndrome, with acute leukemia
(usually myeloid) and myelodysplasia occurring in a small fraction (less than
5%) of patients.2,4 Solid tumor malignancies also have been
reported, in particular osteosarcoma. Other significant causes of death include
complications associated with stem cell transplantation, steroid therapy (opportunistic
infections), and iron overload.2,5
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