Diamond-Blackfan anemia (DBA)

Definition & Overview

Rare, congenital bone marrow failure syndrome characterized by pure red cell aplasia.
Presents symptomatically in early infancy; >90% cases recognized within first year of life.

Ribosomopathy: Underlying defect in ribosome biosynthesis.
Cellular Mechanism: Erythroid progenitors highly sensitive to death by apoptosis.
Inheritance: Primarily Autosomal Dominant (40-45% inherited, 55-60% de novo). X-linked inheritance seen rarely (GATA1, TSR2).
Genetic Mutations: RPS19 is most common pathogenic variant (25-30% of cases). Other genes include RPL5, RPL11, RPS10, RPS26.

Hematologic: Profound anemia evident by 2-6 months of age.
Congenital Anomalies: Present in 40-50% of patients; >25% have multiple anomalies.
- Craniofacial (50%): Hypertelorism, broad flat nasal bridge, cleft palate, high-arched palate, microcephaly, micrognathia, microtia.
- Skeletal/Upper Limb (30-40%): Triphalangeal thumb, duplex/bifid thumb, hypoplastic or flat thenar eminence, absent radial artery.
- Urogenital (39%): Absent/horseshoe kidney, hypospadias.
- Cardiac (30%): Ventricular/atrial septal defects, coarctation of aorta.
- Ophthalmologic: Congenital glaucoma, strabismus, congenital cataract.
Growth: Short stature, low birth weight (10% of cases).

Peripheral Blood:
- Macrocytic anemia (or normocytic in early childhood) without hypersegmented neutrophils.
- Reticulocytopenia.
- Normal white blood cell and platelet counts typically, though neutropenia/thrombocytopenia may occur.
Erythrocyte Markers:
- Elevated erythrocyte adenosine deaminase (eADA) activity (in 80-85% cases).
- Elevated fetal hemoglobin (HbF).
- Increased expression of "i" antigen.
Bone Marrow: Normocellular marrow with selective, virtual absence of erythroid precursors (normoblasts).

Criteria Type	Clinical & Laboratory Features
Diagnostic (Classical)	- Age < 1 year- Macrocytic anemia without other significant cytopenias- Reticulocytopenia- Normal marrow cellularity with paucity of erythroid precursors
Major Supporting	- Positive family history- Pathogenic variant described in classical DBA
Minor Supporting	- Congenital anomalies associated with DBA- Elevated HbF- Elevated eADA- No evidence of other inherited bone marrow failure syndromes

DBA must be differentiated from Transient Erythroblastopenia of Childhood (TEC).

Feature	Diamond-Blackfan Anemia (DBA)	Transient Erythroblastopenia of Childhood (TEC)
Etiology	Genetic ribosomopathy	Acquired (post-viral, idiopathic)
Age at Diagnosis	50% by 3 months; 90% by 1 year	Usually >12 months (median 18-26 months)
Congenital Anomalies	Present in ~50%	Absent
MCV	Increased at diagnosis (80%) & in remission (100%)	Normal at diagnosis (95%); normal in remission
HbF & "i" Antigen	Elevated at diagnosis and remission	Normal at diagnosis and remission
eADA Activity	Elevated (~85% cases)	Normal or decreased
Clinical Course	Prolonged, transfusion/steroid dependent	Spontaneous recovery in weeks to months

Corticosteroids:
- Mainstay therapy; ~80% initially respond.
- Usually delayed until after age 1 year to prevent growth/neurocognitive impairment.
- Initial dose: Prednisone 2 mg/kg/day.
- Taper slowly to minimum effective dose on alternate days (target $\leq$ 0.5 mg/kg/day) to maintain Hb $\geq$ 9 g/dL.
- Monitored for toxicity (cushingoid features, pathologic fractures, cataracts).
Chronic Transfusion Therapy:
- Required for steroid-refractory, non-responsive, or highly toxic cases (~35% of patients).
- Target pretransfusion Hb >8-9 g/dL.
- Requires leukocyte-depleted, irradiated (if immunocompromised), CMV-safe RBCs.
- Iron Chelation: Mandatory to prevent iron overload morbidities (diabetes, cardiac/hepatic dysfunction) using agents like deferoxamine or deferasirox.
Hematopoietic Stem Cell Transplantation (HSCT):
- Only curative therapy.
- Indicated for transfusion dependence, steroid resistance, or significant transfusion complications.
- HLA-matched sibling donor recommended (donor must be screened to exclude silent DBA phenotype). Best outcomes if performed before 9 years of age.

Cancer Predisposition: Elevated risk for myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), colon carcinoma, osteogenic sarcoma, and female genital cancers.
Survival: Overall survival ~75% at age 40. Deaths primarily treatment-related (67%), particularly complications from iron overload, or disease-related (22%) due to severe aplastic anemia or malignancy.