What is the most likely diagnosis for a patient presenting with pallor, irritability, mild jaundice, splenomegaly (enlarged spleen), anemia (low Hemoglobin (Hb) level), and abnormal red blood cells (RBCs) on peripheral blood smear, including microspherocytes and anisocytosis?

Hereditary Spherocytosis

The most likely diagnosis is C. Hereditary spherocytosis (HS), based on the pathognomonic finding of microspherocytes on peripheral blood smear combined with anemia, jaundice, splenomegaly, and elevated reticulocyte count indicating chronic hemolysis.

Key Diagnostic Features Present

The patient demonstrates the classic triad of hereditary spherocytosis 1:

• Anemia (Hb 82 g/L, below normal 112-165 g/L) 1
• Jaundice (mild, indicating elevated indirect bilirubin from hemolysis) 1, 2
• Splenomegaly (enlarged by 4 cm, present in approximately 80% of HS cases) 1, 2

Critical Laboratory Findings

Peripheral blood smear findings are diagnostic:

• Microspherocytes (++) - This is the hallmark morphologic finding that distinguishes HS from other hemolytic anemias 1, 3
• Anisocytosis (mild) - Consistent with HS where variable red cell sizes are commonly observed 3
• Elevated reticulocyte count (9%, normal 0.2-1.2%) - Indicates active hemolysis with compensatory bone marrow response 1, 2

Red cell indices support the diagnosis:

• Normal MCV (80 fL) with elevated MCH (39 pg/cell) - This pattern reflects the spherocytic shape where surface area is lost but hemoglobin content remains relatively preserved 3
• The microcytosis observed in HS is due to membrane loss rather than iron deficiency 3

Why Not the Other Options

A. Biliary obstruction is excluded because:

• Biliary obstruction causes conjugated (direct) hyperbilirubinemia, not the unconjugated hyperbilirubinemia seen in hemolysis 1
• The elevated reticulocyte count indicates active red cell production in response to hemolysis, not obstruction 1
• Microspherocytes are not a feature of biliary obstruction 1

B. Sickle cell anemia is excluded because:

• Sickle cell disease shows characteristic sickle cells (drepanocytes) on peripheral smear, not spherocytes 1
• The MCV in sickle cell disease is typically elevated (80-100 fL), not normal with elevated MCH 1
• The clinical presentation and geographic/ethnic context would differ significantly 1

Pathophysiology Confirmation

The mechanism in HS involves:

• Loss of red cell membrane surface area due to defects in membrane proteins (ankyrin, band 3, spectrin, or protein 4.2) 1
• Spherocytes have reduced deformability and become trapped in the spleen 1
• Splenic sequestration and destruction is the primary cause of hemolysis 1
• This explains both the splenomegaly and the chronic hemolytic pattern 1, 2

Clinical Implications

Common complications to monitor include:

• Cholelithiasis - Occurs with increased frequency due to chronic hemolysis and elevated bilirubin 1, 2, 4
• Aplastic crises - Particularly following parvovirus B19 infection 1
• Hemolytic episodes - May be triggered by infections or other stressors 1

Confirmatory testing should include:

• Osmotic fragility test (increased fragility expected) 3
• Eosin-5'-maleimide (EMA) binding by flow cytometry (reduced binding confirms HS) 4
• Genetic testing for mutations in ANK1, SPTB, SPTA1, SLC4A1, or EPB42 genes 2

Important caveat: While 10 patients in one series had no family history 2, the absence of family history does not exclude HS, as de novo mutations can occur and some cases may have incomplete penetrance 2.