A 9-year-old girl born to consanguineous parents presents with failure to thrive, severe hypertension (BP 165/110 mm Hg), polyuria, and polydipsia. Laboratory investigations reveal hypokalemia (2.5 mEq/L), metabolic alkalosis, suppressed plasma renin activity, and suppressed aldosterone levels. Urinary free cortisol-to-cortisone ratio is markedly elevated. Genetic testing reveals a homozygous loss-of-function mutation in the gene located at the region marked **A** in the diagram. Which of the following best explains the pathophysiology of this patient's condition?

Question

Accepted Answer

A. Loss of 11β-HSD2 activity allows cortisol to persistently activate the mineralocorticoid receptor in the kidney's principal cell, mimicking primary aldosteronism with suppressed aldosterone. ## Why option 1 is correct

The gene at chromosome 16q22 (marked **A**) is HSD11B2, which encodes 11β-hydroxysteroid dehydrogenase type 2. This kidney-specific isoform normally converts active cortisol to inactive cortisone in the principal cell. When HSD11B2 is deficient due to homozygous loss-of-function mutation, cortisol persists and continuously activates the mineralocorticoid receptor (MR), which has equal affinity for both cortisol and aldosterone in vitro. The MR selectivity for aldosterone is normally maintained by local enzymatic inactivation of cortisol by 11β-HSD2. Loss of this enzyme results in constitutive MR activation, producing salt retention, hypertension, hypokalemia, and metabolic alkalosis—clinically identical to primary aldosteronism but with suppressed renin and aldosterone (the key distinguishing feature). This is the definition of apparent mineralocorticoid excess (AME, OMIM 218030), an autosomal recessive disorder. The elevated urinary cortisol-to-cortisone ratio is the diagnostic hallmark.

## Why each distractor is wrong

- **Option 2**: CYP11B1 (chromosome 8, marked **C**) catalyzes the final steps of cortisol synthesis. Mutations cause 11β-hydroxylase deficiency with virilization and hypertension from 11-deoxycortisol accumulation—not the clinical picture here. The patient has elevated cortisol bioavailability, not deficiency.
- **Option 3**: SCNN1B (chromosome 16, marked **B**) encodes the epithelial sodium channel β-subunit. Gain-of-function mutations cause Liddle syndrome (hypertension with hypokalemia but elevated aldosterone and renin). Loss-of-function causes pseudohypoaldosteronism (salt wasting, hyperkalemia, elevated aldosterone)—opposite of this patient's phenotype.
- **Option 4**: The androgen receptor (chromosome X, marked **D**) is not involved in this pathophysiology. Androgen insensitivity does not explain the mineralocorticoid excess phenotype or the suppressed aldosterone with elevated cortisol ratio.

**High-Yield:** AME = 11β-HSD2 deficiency → cortisol acts as mineralocorticoid → hypertension + hypokalemia + suppressed renin/aldosterone (distinguishes from primary hyperaldosteronism). Diagnosis: elevated urinary cortisol/cortisone ratio. Treatment: spironolactone, sodium restriction, potassium supplementation.

[cite: Harrison 21e Ch 379; Stewart Lancet 1996 11β-HSD2]

Answer

B. Mutation in CYP11B1 prevents conversion of 11-deoxycortisol to cortisol, leading to shunting of precursors toward androgen synthesis

Answer

C. Androgen receptor insensitivity on chromosome X prevents normal feedback inhibition of ACTH, resulting in cortisol excess and hypokalemia

Answer

D. Defective epithelial sodium channel (SCNN1B) prevents sodium reabsorption in the collecting duct, causing salt wasting and secondary hyperaldosteronism

Explanation

Why option 1 is correct

Why each distractor is wrong

Practice similar questions

Join our NEET PG community