A neonate develops severe hemolytic anemia within 24 hours of birth. Peripheral smear shows hypochromia, microcytosis, target cells and nucleated red blood cells. Hemoglobin electrophoresis shows predominantly Hb Barts (gamma4 tetramers). Which molecular defect underlies this condition?

• A Deletion of all four alpha-globin genes (--/-- genotype) ✓
• B Compound heterozygosity for beta0-thalassemia mutations
• C Homozygous delta-beta thalassemia
• D Hb H disease with three alpha-gene deletions (--/-alpha genotype)

Explanation

Hb Barts hydrops fetalis is caused by deletion of all four alpha-globin genes (alpha0/alpha0 homozygous, --/-- genotype). Without alpha chains, gamma chains form tetramers (Hb Barts, gamma4), which have extreme oxygen affinity and are functionally useless for oxygen delivery, resulting in severe hydrops and intrauterine/neonatal death. Hb H disease (--/-alpha) causes moderate hemolytic anemia; homozygous beta-thalassemia presents after 6 months when fetal hemoglobin switches; delta-beta thalassemia is milder.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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