Diamond-Blackfan anemia (DBA)

Introduction

Diamond-Blackfan anemia (DBA) is a rare, congenital bone marrow failure syndrome characterized by macrocytic anemia, reticulocytopenia, and a selective paucity of red blood cell (RBC) precursors in an otherwise normocellular bone marrow.
The disorder typically becomes symptomatic in early infancy, with more than 90% of cases recognized within the first year of life.
Up to 50% of affected individuals present with additional, extrahematopoietic congenital anomalies.

DBA affects approximately 5 to 10 individuals per million live births.
Substantial phenotypic diversity exists even among family members sharing the exact same pathogenic genetic variant, suggesting the presence of genetic modifiers.

DBA is classified as a ribosomopathy, resulting from defective ribosome biosynthesis which leaves erythroid progenitors and precursors highly sensitive to apoptosis.
The majority of cases are caused by pathogenic variants in small or large subunit-associated ribosomal protein (RP) genes.
Transmission is primarily autosomal dominant, accounting for at least 40–50% of cases, though incomplete penetrance and variable expressivity are common.
Two genes, GATA1 (an erythroid transcription regulator) and TSR2, exhibit X-linked inheritance.
RPS19 is the most commonly mutated gene, accounting for approximately 20–25% of cases. Other frequently implicated genes include RPL5, RPL11, RPS10, and RPS26.

Profound anemia typically becomes evident between 2 and 6 months of age.
Approximately 25% of patients are anemic at birth, and rarely, the condition may present as hydrops fetalis.
While white blood cell and platelet counts are usually normal at presentation, neutropenia or thrombocytopenia can occur, and trilineage marrow failure may develop with increasing age.

Approximately 40–50% of patients exhibit congenital anomalies, with more than one anomaly present in 25% of cases.
Craniofacial (50%): Depressed nasal bridge, high-arched or cleft palate, microcephaly, micrognathia, microtia, low-set ears, and ptosis.
Upper Limb and Hand (30–40%): Thumb deformities (triphalangeal, hypoplastic, absent, duplicated, or bifid), flattened thenar eminence, and an absent radial pulse.
Genitourinary (39%): Absent or horseshoe kidneys, hypospadias.
Cardiac (30%): Ventricular septal defect, atrial septal defect, coarctation of the aorta.
Growth: Low birth weight is seen in 10% of patients, and over 60% fall below the 25th percentile for height (short stature).

DBA is a recognized cancer predisposition syndrome with a cumulative incidence of cancer reaching almost 14% by 45 years of age.
Patients have an elevated risk for myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), osteogenic sarcoma, colorectal and other gastrointestinal carcinomas, and female genital cancers.

Complete Blood Count: Anemia is characteristically macrocytic for age, accompanied by severe reticulocytopenia.
Peripheral Smear: Reveals macrocytosis but lacks the hypersegmented neutrophils characteristic of classical megaloblastic anemia.
Fetal RBC Characteristics: Elevated fetal hemoglobin (HbF) and increased expression of the "i" antigen are prominent.
Enzyme Assays: Erythrocyte adenosine deaminase (eADA) activity is elevated in 80–85% of patients, serving as a crucial marker for distinguishing DBA from other conditions in young infants.
Bone Marrow: Aspirate shows normal overall cellularity but a virtual absence or marked reduction of normoblasts. A maturation arrest at the proerythroblast stage is common, while the myeloid and megakaryocytic series remain normal.
Iron Studies: Serum iron levels are characteristically elevated.

Major: Presence of a known DBA gene mutation, or a positive family history.
Minor: Congenital anomalies characteristic of DBA, elevated HbF, elevated eADA, macrocytosis, and no evidence of another inherited bone marrow failure syndrome.

Transient Erythroblastopenia of Childhood (TEC): An acquired, temporary RBC aplasia often preceded by a viral illness. Unlike DBA, TEC typically presents after 1 year of age, features normocytic RBCs, normal HbF, normal eADA, and lacks congenital anomalies. TEC resolves spontaneously.
Parvovirus B19 Infection: Can cause pure red cell aplasia in infancy or hydrops fetalis in utero. It is distinguished by PCR testing of the bone marrow.
Pearson Syndrome: A multisystem mitochondrial disorder presenting with macrocytic anemia and early marrow failure. Differentiated by the presence of ringed sideroblasts, vacuolated marrow precursors, exocrine pancreatic dysfunction, and mitochondrial DNA deletions.
Fanconi Anemia: Differentiated by the presence of increased chromosomal breakage upon exposure to alkylating agents like diepoxybutane (DEB) or mitomycin C.

Corticosteroids are the initial mainstay of treatment, with approximately 80% of patients showing a response.
Initiation is frequently delayed until after 1 year of age to prevent severe impairment of linear growth and neurocognitive development.
The initial trial is prednisone or prednisolone at 2 mg/kg/day; an RBC precursor response is typically seen in 1 to 3 weeks, followed by peripheral reticulocytosis.
Once the hemoglobin level reaches 9 to 10 g/dL, the dose is slowly tapered to a target maintenance dose not exceeding 0.5 mg/kg/day or 1 mg/kg every other day.
Unacceptable side effects (cushingoid features, pathologic fractures, cataracts, growth failure) or steroid refractoriness necessitate the discontinuation of steroids and transition to chronic transfusions.

Chronic packed red blood cell transfusions are required in approximately 35% of patients (those who are steroid-refractory, non-responders, or cannot tolerate low-dose maintenance).
Transfusions are administered every 3 to 5 weeks to maintain a hemoglobin level greater than 8 to 9 g/dL.
Blood products should be leukocyte-depleted, and if a stem cell transplant is contemplated, CMV-safe products should be utilized.
Transfusion-related iron overload must be actively monitored and managed with iron chelation therapy (e.g., deferoxamine, deferasirox) to prevent endocrine and organ dysfunction.

Allogeneic HSCT is the only curative therapy for the hematologic defect in DBA.
Indications include steroid resistance, unacceptable steroid toxicity, and transfusion dependence coupled with complications like iron overload or alloimmunization.
HLA-matched sibling HSCT is recommended, optimally performed between the ages of 3 and 9 years to precede severe iron overload.
Potential family donors must be rigorously screened (including genetic testing, HbF, and eADA) to rule out a silent DBA phenotype.

L-leucine has shown promise in clinical trials, demonstrating erythroid responses and increased linear growth velocity in a subset of patients.

Spontaneous remission of anemia (achieving independence from steroids and transfusions) occurs in approximately 20 to 25% of patients, most often within the first decade of life.
The overall actuarial survival is approximately 75% at 40 years of age.
Survival outcomes are higher (~87%) for steroid-responsive patients compared to transfusion-dependent patients (~57%).
Treatment-related complications, primarily iron overload and post-transplant morbidities, account for 67% of deaths, while DBA-related issues (such as malignancy and severe aplastic anemia) account for 22%.