Primary aldosteronism is the most prevalent form of secondary hypertension. To explore molecular mechanisms of autonomous aldosterone secretion, we performed exome sequencing of aldosterone-producing adenomas (APAs). We identified somatic hotspot mutations in the ATP1A1 (encoding an Na(+)/K(+) ATPase α subunit) and ATP2B3 (encoding a Ca(2+) ATPase) genes in three and two of the nine APAs, respectively. These ATPases are expressed in adrenal cells and control sodium, potassium and calcium ion homeostasis. Functional in vitro studies of ATP1A1 mutants showed loss of pump activity and strongly reduced affinity for potassium. Electrophysiological ex vivo studies on primary adrenal adenoma cells provided further evidence for inappropriate depolarization of cells with ATPase alterations. In a collection of 308 APAs, we found 16 (5.2%) somatic mutations in ATP1A1 and 5 (1.6%) in ATP2B3. Mutation-positive cases showed male dominance, increased plasma aldosterone concentrations and lower potassium concentrations compared with mutation-negative cases. In summary, dominant somatic alterations in two members of the ATPase gene family result in autonomous aldosterone secretion.

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Disease-specific OS is still poor in ATC. Treatment factors associated with improved OS provide a rationale to devise treatment pathways for routine care. Collaborative research structures should be aimed to advance treatment of ATC.

Objective: Pheochromocytomas are rare chromaffin cell-derived tumors causing paroxysmal episodes of headache, palpitation, sweating and hypertension. Life-threatening complications have been described in case reports and small series. Systematic analyses are not available. We took an opportunity of a large series to make a survey. Design and methods: We analyzed records of patients diagnosed with pheochromocytomas in three geographically spread German referral centers between 2003 and 2012 (nZ135). Results: Eleven percent of the patients (ten women, five men) required in-hospital treatment on intensive care units (ICUs) due to complications caused by unsuspected pheochromocytomas. The main reasons for ICU admission were acute catecholamine induced Tako-Tsubo cardiomyopathy (nZ4), myocardial infarction (nZ2), acute pulmonary edema (nZ2), cerebrovascular stroke (nZ2), ischemic ileus (nZ1), acute renal failure (nZ2), and multi organ failure (nZ1). One patient required extracorporeal membrane oxygenation due to a hypertensive crisis with lung edema occurring during delivery (nZ1). Two patients died of refractory shock and pheochromocytomas were found postmortem. Two patients were treated by emergency surgery. Compared to pheochromocytoma patients without life-threatening events (nZ120), patients with complications had a significant larger maximal tumor diameter (7.0 vs 4.5 cm, P!0.01), higher levels of catecholamines (20-vs ninefold upper limit of normal, P!0.01), and tended to be younger (42 vs 51 years, PZ0.05). Conclusion: Although pheochromocytomas are rare, they are likely to be associated with a life-threatening situation. Clinicians have to be aware of these situations and perform a timely diagnosis.