Primary hyperaldosteronism (Conn syndrome) is the most common cause of secondary hypertension. Adrenal vein sampling (AVS) is the gold standard for lateralisation. Histopathologically, bilateral adrenocortical hyperplasia in primary hyperaldosteronism most commonly results from what molecular mechanism identified in recent molecular studies?
- A Germline deletion of NF2 (merlin) causing bilateral adrenal tumourigenesis
- B Somatic gain-of-function mutations in KCNJ5 (encoding the inwardly rectifying potassium channel Kir3.4), causing cell membrane depolarisation, calcium influx, and autonomous aldosterone production ✓
- C Somatic inactivating mutations in VHL causing pseudo-hypoxic signalling and CYP11B2 upregulation
- D Constitutional activation of PRKAR1A (PKA regulatory subunit), identical to McCune-Albright syndrome
Explanation
Recent exome sequencing studies have revealed that approximately 40% of aldosterone-producing adenomas (APAs) and some cases of bilateral adrenal hyperplasia in primary hyperaldosteronism harbour somatic gain-of-function mutations in KCNJ5 (encoding Kir3.4, an inward-rectifier K+ channel). Normally, Kir3.4 maintains resting membrane potential; KCNJ5 mutations increase Na+ conductance instead of K+ selectivity, causing chronic membrane depolarisation of zona glomerulosa cells. This activates L-type voltage-gated calcium channels, causing sustained calcium influx that constitutively activates CYP11B2 (aldosterone synthase) transcription. Other mutations found in APAs include CACNA1D (Ca2+ channel), ATP1A1/ATP2B3 (Na+/K+ and Ca2+ ATPases), and CTNNB1. KCNJ5 mutations are female-predominant and associated with larger APAs.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.