A newborn with Hb Bart's hydrops fetalis (gamma4 tetramers) has which underlying genotype and the most clinically critical consequence?

• A Deletion of all four alpha-globin genes (--/--); gamma4 tetramers cannot deliver oxygen due to extremely high O2 affinity, causing severe intrauterine hypoxia and hydrops ✓
• B Deletion of three alpha-globin genes (--/-alpha); produces HbH (beta4) in excess, causing moderate chronic hemolysis
• C Beta-thalassemia major with compound heterozygous beta0/beta0 mutations; compensatory gamma chain increase forms Hb Bart's
• D Sickle cell disease with alpha-thalassemia co-inheritance; gamma4 reduces sickling severity

Explanation

Hb Bart's (gamma4) results from deletion of all four alpha-globin genes (homozygous alpha0-thalassemia, --/-- genotype). In the absence of alpha chains, excess gamma chains in the fetus form tetramers (gamma4 = Hb Bart's). Gamma4 has an extremely high oxygen affinity with no Bohr effect and no cooperative O2 delivery, making it physiologically useless for tissue oxygenation — causing severe fetal hypoxia, high-output cardiac failure, and hydrops fetalis. Three alpha-gene deletion produces HbH disease (HbH = beta4 tetramer). Beta-thalassemia major does not produce Hb Bart's in neonates in the same mechanism. Co-inheritance of alpha-thalassemia in sickle cell actually reduces HbS polymerization.

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

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Written and medically reviewed by the StethoPrep medical team.