A patient with hemolytic anemia is found to have a negative direct Coombs test but positive osmotic fragility and spherocytes on the smear. Ektacytometry shows a biphasic pattern with reduced deformability at low osmolality. Which protein deficiency is most likely responsible?
- A Protein 4.2 deficiency (Japanese hereditary spherocytosis variant)
- B Ankyrin-1 deficiency (hereditary spherocytosis, spectrin-ankyrin linkage failure) ✓
- C Band 3 protein deficiency with Southeast Asian ovalocytosis
- D Spectrin beta-chain deficiency (severe recessive hereditary spherocytosis)
Explanation
Hereditary spherocytosis (HS) is most commonly caused by ankyrin-1 deficiency (autosomal dominant, ~50% of HS cases), which disrupts the vertical linkage between the lipid bilayer (via band 3) and the spectrin-actin cytoskeletal network. The resultant membrane instability leads to lipid vesiculation and membrane loss, converting biconcave discs to spherocytes with positive osmotic fragility. Ektacytometry in HS shows decreased deformability at low osmolality. Southeast Asian ovalocytosis results from a specific band 3 deletion (del400-408), producing rigid oval cells with resistance to malaria, not spherocytosis.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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