A 2-week-old male neonate born at 33 weeks gestation presents with polyuria, severe dehydration, and failure to thrive. Maternal history is significant for polyhydramnios. Laboratory investigations reveal serum potassium 2.4 mEq/L, HCO3− 34 mEq/L, hypercalciuria, and elevated plasma renin activity with normal blood pressure. Renal ultrasound shows medullary nephrocalcinosis. Genetic testing confirms a homozygous mutation in the gene located on **chromosome 15** (marked **A** in the diagram), encoding the sodium-potassium-chloride cotransporter (NKCC2) of the thick ascending limb. Which of the following best explains the pathophysiology of this condition?

Question

Accepted Answer

A. Loss of NKCC2 function abolishes the lumen-positive transepithelial potential, impairing paracellular calcium and magnesium reabsorption and mimicking chronic furosemide infusion. ## Why option 1 is correct

The homozygous mutation in SLC12A1 on chromosome 15 encodes NKCC2 (sodium-potassium-chloride cotransporter), the primary active transporter of the thick ascending limb. Loss of NKCC2 function directly abolishes the lumen-positive transepithelial potential that normally drives paracellular reabsorption of calcium and magnesium. This mimics the effect of chronic furosemide infusion, causing salt wasting, activation of the renin-angiotensin-aldosterone axis (secondary hyperaldosteronism), hypokalemic metabolic alkalosis, and hypercalciuria with nephrocalcinosis. The normal blood pressure distinguishes this from primary hyperaldosteronism, as volume contraction prevents hypertension. This is Bartter syndrome Type I (antenatal form), the most severe presentation. [Harrison 21e Ch 311; Simon NKCC2 Nat Genet 1996]

## Why each distractor is wrong

- **Option 2**: ROMK channel mutations occur in Bartter Type II (chromosome 11, not 15). While ROMK defects also cause salt wasting and secondary hyperaldosteronism, the question explicitly states the mutation is on chromosome 15 (SLC12A1/NKCC2), not chromosome 11.
- **Option 3**: CLCNKB mutations cause Bartter Type III and are associated with hypocalciuria (not hypercalciuria) and sensorineural hearing loss. The clinical presentation here—hypercalciuria with medullary nephrocalcinosis—is characteristic of Type I (NKCC2), not Type III.
- **Option 4**: Gain-of-function CASR mutations cause Bartter Type V, which presents with hypocalciuria and normal or low-normal blood pressure. This patient has hypercalciuria and nephrocalcinosis, which are incompatible with Type V pathophysiology.

**High-Yield:** Bartter Type I (SLC12A1/NKCC2 on chromosome 15) = antenatal presentation + hypercalciuria + nephrocalcinosis + normal BP; mimics chronic loop diuretic effect by abolishing the lumen-positive potential needed for paracellular Ca²⁺/Mg²⁺ reabsorption.

[cite: Harrison 21e Ch 311; Simon NKCC2 Nat Genet 1996]

Answer

B. Mutation in the chloride channel gene CLCNKB impairs chloride reabsorption in the distal convoluted tubule, causing hypocalciuria and metabolic alkalosis

Answer

C. Gain-of-function mutation in the calcium-sensing receptor increases urinary calcium excretion while preserving the transepithelial potential gradient

Answer

D. Defective ROMK channel on chromosome 11 prevents potassium recycling in the thick ascending limb, leading to salt wasting and secondary hyperaldosteronism

Explanation

Why option 1 is correct

Why each distractor is wrong

Practice similar questions

Join our NEET PG community