Endocrine Pathology, Pathology, USMLE Step 1 - Full Vignette with Extended Explanations

Описание: A 37-year-old man presents with resistant hypertension, episodic headaches, muscle cramps, and polydipsia after recent travel. Notably, he shows hypokalemia and metabolic alkalosis, with markedly elevated plasma aldosterone and suppressed renin levels. Despite extensive noncontributory testing and a pending adrenal CT, genetic analysis of an adrenal nodule reveals a somatic mutation. What aspects of this clinical scenario should prompt consideration of underlying molecular mechanisms driving his aldosterone excess?

VIDEO INFO
Category: Endocrine Pathology, Pathology, USMLE Step 1
Difficulty: Hard - Advanced level - Challenges experienced practitioners
Question Type: Mechanism
Case Type: Typical Presentation

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QUESTION
A 37-year-old man with resistant hypertension is evaluated for episodic headaches, muscle cramps, and polydipsia. He recently returned from Asia; he quit smoking 10 years ago after 30 pack-years. He takes no diuretics. Past history includes chronic fatigue syndrome, hypertriglyceridemia, and coronary artery disease; no known allergies....

OPTIONS
A. Somatic KCNJ5 selectivity-filter mutation in a zona glomerulosa adenoma increases Na+ conductance, depolarizes the membrane, activates voltage-gated Ca2+ channels (e.g., Cav1.3), elevates intracellular Ca2+, upregulates CYP11B2 (aldosterone synthase), and drives autonomous aldosterone overproduct...
B. Somatic ATP1A1 loss-of-function in the Na+/K+-ATPase generates membrane depolarization and Ca2+ influx to stimulate CYP11B2, a mechanism seen in a subset of aldosterone-producing adenomas but typically distinct from KCNJ5 channelopathies.
C. Somatic CACNA1D gain-of-function in L-type Ca2+ channels directly augments Ca2+ entry at physiologic voltages, enhancing aldosterone synthase expression and secretion independent of renin, representing another genetic mechanism in aldosterone-producing adenomas. Clinically, tumors with CACNA1D va...
D. Constitutive Wnt/beta-catenin (CTNNB1) activation promoting cell proliferation with secondary aldosterone excess, a pathway reported in some adrenocortical tumors but not the canonical ion-channel-driven mechanism in classic aldosterone-producing adenomas.

CORRECT ANSWER
A. Somatic KCNJ5 selectivity-filter mutation in a zona glomerulosa adenoma increases Na+ conductance, depolarizes the membrane, activates voltage-gated Ca2+ channels (e.g., Cav1.3), elevates intracellular Ca2+, upregulates CYP11B2 (aldosterone synthase), and drives autonomous aldosterone overproduction.

EXPLANATION
Primary aldosteronism with a somatic mutation in an inwardly rectifying potassium channel strongly suggests KCNJ5-mutant aldosterone-producing adenoma. KCNJ5 selectivity-filter mutations increase Na+ permeability, depolarize zona glomerulosa cells, open voltage-gated Ca2+ channels (e.g., Cav1.3), raise intracellular Ca2+, and drive CYP11B2 expression and aldosterone synthesis independent of renin. This mechanism explains the elevated aldosterone with suppressed renin, hypokalemic alkalosis, and resistant hypertension.

Other mechanisms occur in subsets of adenomas: ATP1A1 loss-of-function (Na+/K+-ATPase) causes depolarization and Ca2+ influx; CACNA1D gain-of-function directly enhances L-type Ca2+ channel activity; CTNNB1 activation is more proliferative and less canonical for autonomous aldosterone biosynthesis....


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