A 5-year-old boy of Bengali descent is brought to the pediatric clinic with a 2-year history of recurrent jaundice, dark urine, and pallor. His maternal uncle had similar symptoms and underwent splenectomy. On examination, he is icteric with moderate splenomegaly and mild hepatomegaly. Laboratory findings: Hemoglobin 8.5 g/dL, reticulocyte count 12%, indirect bilirubin 4.1 mg/dL, haptoglobin 15 mg/dL, LDH 920 U/L. Osmotic fragility test shows increased fragility of RBCs. Peripheral blood smear reveals spherocytes. The child's symptoms worsen during infections but not with fava bean ingestion. What is the most likely diagnosis?

Explanation

## Clinical Diagnosis: Hereditary Spherocytosis ### Key Clinical Features **Key Point:** The combination of chronic hemolysis with spherocytes on smear, increased osmotic fragility, family history of hemolytic anemia, and absence of trigger-dependent hemolysis (no worsening with fava beans) is diagnostic of hereditary spherocytosis (HS). ### Diagnostic Reasoning 1. **Chronic Hemolysis Pattern** - Persistent jaundice and anemia over 2 years = chronic process - Hemolysis independent of environmental triggers (unlike G6PD) - Family history of similar disease in maternal uncle = inherited membrane defect 2. **Osmotic Fragility Test (Pathognomonic)** - **Increased osmotic fragility** = RBCs lyse at higher saline concentrations than normal - Spherocytes have reduced surface area-to-volume ratio, making them osmotically fragile - This test is gold standard for HS diagnosis - G6PD deficiency shows **normal** osmotic fragility 3. **Peripheral Blood Smear** - **Spherocytes** (dense, small, dark-staining RBCs lacking central pallor) = hallmark of HS - Polychromasia reflects reticulocytosis (12% — appropriate response) - NOT bite cells or Heinz bodies (which would suggest G6PD) 4. **Absence of Trigger-Dependent Hemolysis** - No worsening with fava bean ingestion = rules out G6PD - Infection can precipitate hemolysis in HS due to splenic sequestration, but it's not the primary trigger like in G6PD ### Pathophysiology **High-Yield:** HS is caused by mutations in genes encoding RBC membrane proteins (spectrin, ankyrin, band 3, protein 4.2). Loss of membrane integrity → progressive loss of RBC surface area → spherocyte formation → osmotic fragility → splenic trapping and hemolysis. ### Differential Diagnosis Table | Feature | HS | G6PD | AIHA | Alpha-Thal | | --- | --- | --- | --- | --- | | **Osmotic fragility** | **Increased** | Normal | Normal | Normal | | **Spherocytes** | **Yes** | No | Yes (polychromasia) | No | | **Bite cells/Heinz** | No | **Yes** | No | No | | **Trigger-dependent** | No | **Yes** | No | No | | **Family history** | Autosomal dominant | X-linked | No | Autosomal recessive | | **Direct Coombs test** | Negative | Negative | **Positive** | Negative | | **RBC indices** | Normocytic | Normocytic | Normocytic | Microcytic | **Clinical Pearl:** HS is the most common inherited hemolytic anemia in Northern European and Indian populations. Splenectomy is definitive treatment (removes the site of RBC destruction), which explains why the maternal uncle underwent the procedure. ### Confirmatory Tests 1. **Osmotic fragility test** — gold standard (already done; positive) 2. **Eosin-5-maleimide (EMA) flow cytometry** — newer, more sensitive 3. **Membrane protein electrophoresis** — shows spectrin/ankyrin deficiency 4. **Direct Coombs test** — negative (rules out AIHA) **Mnemonic: SPHERO-OSMOTIC** = Spherocytes + Osmotic fragility = Hereditary Spherocytosis