Endocrine Abstracts (2018) 55 OC2 | DOI: 10.1530/endoabs.55.OC2

Episodic primary aldosteronism associated with a novel gain-of-function mutation in a cell adhesion molecule

Xilin Wu1,2, Sumedha Garg3 & Morris Brown1

1Queen Mary University of London, London, UK; 2Barts Health, London, UK; 3University of Cambridge, Cambridge, UK.

Case history: A 46-year-old headmaster with a 10-year history of hypertension presented with a BP of 164/116 mmHg on four antihypertensive drugs. He had occasional headaches, chest ‘aches’, and described one syncopal episode after an ‘exhausting rowing session’. A low plasma renin (routinely measured in our resistant hypertensives) and 26/20 mmHg fall in BP on changing hydrochlorothiazide to amiloride, led to investigations for primary aldosteronism (PA).

Investigations: Plasma electrolytes were normal. Initial plasma renin (10 mU/l) and aldosterone (537 pmol/l) were also below Endocrine Society thresholds for investigating PA. However values fluctuated between diagnostic (aldosterone 647 pmol/l, renin 5.0 mU/l) and completely normal (aldosterone 147 pmol/l, renin 11.0 mU/l) despite withdrawal of interfering medications. A 13 mm right adrenal nodule (HU4) was observed on CT. Initial adrenal vein sampling showed no increase in aldosterone or cortisol secretion compared to IVC from the contra-lateral (left) adrenal, but repeat during ACTH infusion showed a lateralisation index >7:1 (right:left).

Results and treatment: He successfully underwent a right adrenalectomy. H&E plus immunohistochemistry showed a zona glomerulosa-type macroadenoma, and adjacent microadenoma (cluster) with compact cells staining densely for CYP11B2, but only patchy weak staining for CYP11B1. At 3 years post surgery he remains normotensive off treatment, but complained of weight loss, muscle fasciculation, cramps and fatigue. Plasma aldosterone (150 pmol/l) and renin (0.4 nmol/l per hr) were normal. A random cortisol was 115 nmol/l, but a repeat pre-and post-synacthen showed values of 225 nmol/l (baseline), 463 nmol/l (30 min) and 640 nmol/l (60 min). On DNA sequencing the adenoma was negative for all known somatic mutations. Whole exome sequencing revealed a novel Valine-to-Aspartate mutation in the transmembrane domain of a cell adhesion molecule, whose transfection into H295R adrenocortical cells caused 10–20 fold increase in aldosterone synthesis and secretion.

Points for discussion: The significance of the new mutation was supported by the discovery of a similar patient in Munich, and studies point to the importance of cell-cell contact for regulation of normal zona glomerulosa function. The combination of variable aldosterone secretion by our patient, and experimental evidence of diurnal fluctuations, suggest that this mutation may cause episodic PA, and therefore be commonly missed. Borderline adrenal insufficiency many years post-adrenalectomy, not due to CYP11B1-expression (cortisol-cosecretion) by the adenoma, may be under-recognised. It is consistent with previously described genetic variants in the promoter of CYP11B1, which are compensated (and masked) by over-production of ACTH, but only while both adrenals are intact.

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