Which of the following is the primary defect in hereditary spherocytosis?

Explanation

## Hereditary Spherocytosis: Membrane Protein Defect **Key Point:** Hereditary spherocytosis (HS) is caused by deficiencies in red cell membrane skeleton proteins, most commonly spectrin or ankyrin, leading to loss of membrane integrity and osmotic fragility. ### Pathophysiology The red cell membrane is supported by a cytoskeletal network of proteins linked to the lipid bilayer. In HS: 1. Spectrin or ankyrin deficiency weakens the membrane skeleton 2. RBCs lose biconcave shape and become spherical 3. Spherocytes are osmotically fragile and lyse in hypotonic solutions 4. Splenic macrophages recognize and destroy spherocytes → hemolysis ### Key Laboratory Findings - **Osmotic fragility test:** Increased fragility (hallmark finding) - **Eosin-5-maleimide (EMA) binding test:** Reduced fluorescence (most sensitive modern test) - **Peripheral smear:** Spherocytes (dense, small RBCs lacking central pallor) - **Reticulocytosis:** Elevated (compensatory response) **High-Yield:** Spectrin and ankyrin are the two most commonly deficient proteins in HS. Defects in other membrane proteins (band 3, protein 4.2) are less common but also cause HS. **Clinical Pearl:** Patients often present with neonatal jaundice, splenomegaly, and chronic hemolysis. Splenectomy is curative because the spleen is the primary site of spherocyte destruction. **Mnemonic:** **SHAPE** — Spectrin/ankyrin deficiency → Hemolysis → Anemia → Pigment gallstones → Elevated reticulocytes