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.

Genetics & Pathophysiology

• 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.

Clinical Manifestations

• 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).

Laboratory Findings

• 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).

Diagnostic Criteria

Differential Diagnosis: DBA vs. TEC

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

Management & Treatment

• 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 $\le$ 0.5 mg/kg/day) to maintain Hb $\ge$ 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.

Prognosis & Complications

• 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.