A 4-year-old boy presents with acute onset pallor, jaundice, dark urine, and hemoglobinuria after eating fava beans. CBC shows Hb 6.2 g/dL, reticulocyte count 12%, peripheral smear shows 'bite cells' and Heinz bodies on crystal violet staining. What is the MOST LIKELY explanation for why females are rarely as severely affected as hemizygous males in this condition?

• A The X-linked gene has incomplete penetrance in females carrying one affected allele
• B Estrogen protects red cell membranes from oxidative damage in females
• C Lyonization (random X-inactivation) results in a mosaic of normal and deficient red cells in heterozygous females, so enough normal cells survive to prevent severe hemolysis ✓
• D Females have higher baseline glutathione levels that compensate for G6PD deficiency

Explanation

G6PD deficiency is X-linked recessive. In heterozygous females, random X-inactivation (lyonization) results in approximately half of the red cells having normal G6PD activity and half being deficient. The normal cells survive oxidative stress, preventing the severity of hemolytic crisis seen in hemizygous males who lack any normal G6PD. Rarely, heterozygous females with extremely skewed X-inactivation (majority of cells expressing the deficient X) can be as severely affected as males. This is the classic genetic explanation for the sex difference—not estrogen protection, incomplete penetrance, or glutathione levels.

Reference: Ghai Essential Pediatrics, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.