Primary aldosteronism (PA) is the most common type of secondary hypertension occurring in ∼10% of hypertensive patients. Up to 50% of PA is caused by aldosterone-producing adenomas (APA). This study is to identify the potential biological processes and canonical pathways involved with aldosterone regulation, APA formation, or APA and ZG cell functions.
Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.
Presence of a hypofunctioning pigmented adenoma are commonly asymptomatic and is usually only found during an autopsy. In contrast, hyperfunctioning pigmented adenoma is a rare clinical entity and in the majority of cases results in Cushing's syndrome. In this case study, we report a 66-year-old male who presented instead with the clinical and biochemical features of Conn's syndrome. On laparoscopic adrenalectomy, it was found that the tumour had a functioning black adenoma which does not usually present with Conn's syndrome but rather to that of a Cushing's. The intraoperative changes and histopathological findings are discussed.
Primary aldosteronism (PA) is the most common type of secondary hypertension occurring in ∼10% of hypertensive patients. Up to 50% of PA is caused by aldosterone-producing adenomas (APA). We recently performed a microarray assay using 21 pairs of zona glomerulosa (ZG) and zona fasciculata (ZF), and 14 paired APAs. This study is to identify the potential biological processes and canonical pathways involved with aldosterone regulation, APA formation, or APA and ZG cell functions.
Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.
An adrenal incidentaloma is defined as an adrenal mass measuring at least 1 cm that is discovered surreptitiously in an imaging study done for reasons other than the evaluation of adrenal disease. The increase in the prevalence of adrenal incidentalomas has paralleled the increase in diagnostic imaging done for evaluation of other abdominal pathologies. However, most of these adrenal incidentalomas are benign non-hyperfunctioning adenomas. When an adrenal incidentaloma is discovered, the simultaneous presence of hypokalemia, metabolic alkalosis, mild hypernatremia, and mild to severe drug-resistant hypertension may alert a clinician to underlying primary hyperaldosteronism. We present a case of adrenal incidentaloma noted in a patient with end-stage renal disease on hemodialysis which presented a diagnostic challenge due to the correction of metabolic parameters with hemodialysis. The patient was found to have an aldosterone-producing adenoma based on an elevated aldosterone-to-renin ratio and was started on a mineralocorticoid antagonist.
Aldosterone-producing adenoma (APA) is a common curable cause of hypertension. Somatic mutations in five genes (KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1) have been found to cause the excess aldosterone production of two thirds of APAs [1-4]. KCNJ5 mutant APAs, the most common and largest, had explicit genotype-phenotype relationship - a low protein expression of KCNJ5 relative to their peritumoural zona glomerulosa (ZG) and a zona fasciculata-like composition [5-6]. Conversely for the other genes, controversy arises on whether they have the opposite cell phenotype [4,7-8]. This prospective study aim to to characterize the histopathological-specific mutation spectrum of APAs.
Primary aldosteronism (PA) causes a persistently elevated blood pressure (BP) due to
excessive release of the hormone aldosterone from the adrenal glands. Classically, it is called
Conn’s syndrome and is described as the triad of hypertension and hypokalemia with the
presence of unilateral adrenal adenoma. It can be cured with surgical resection of the
aldosterone-secreting adenoma leading to resolution of hypertension, hypokalemia and
increased cardiovascular risk associated with hyperaldosteronism. We present a case of a man
with previous ischemic heart disease (IHD) who presented with resistant hypertension.
Investigations for secondary causes of hypertension revealed an elevated aldosterone level
and saline suppression test confirmed the diagnosis of PA. Radiological examination revealed
a left adrenal adenoma and a normal right adrenal gland. However, adrenal venous sampling
showed lateralization of aldosterone secretion towards the right. He subsequently underwent
a laparoscopic right adrenalectomy which improved his BP control promptly. This case
highlights the importance of recognizing the need to investigate for secondary causes of
hypertension. It also underscores the importance of dynamic tests, which may not be easily
accessible to most clinicians but should pursue, to allow a definitive diagnosis and effective
treatment.
Approach to patients who manifest with features of Cushing's syndrome often begin with exclusion of exposure to excessive exogenous source of glucocorticoids (GC). Most guidelines advocate no further assessment if excessive exogenous GC use is present. We present a case of a 66-year-old lady who was noted to have typical features of Cushing's syndrome. As she gave a very clear history of ingesting exogenous GC for a year, no further work up was undertaken. Despite cessation of GC for a year, she continued to have thin skin and easy bruising. Upon admission for hypertensive emergency, her clinician took note of her changes and investigated her for endogenous Cushing's syndrome. Her cortisol post overnight dexamethasone suppression test was 707 nmol/l. Post low dose dexamethasone suppression test yielded a cortisol of 1133.2 nmol/l. 24 hours urine cortisol was 432.2 nmol/l. Plasma ACTH was 1.1 pmol/l, indicating an ACTH independent Cushing's syndrome. We proceeded with Computed tomography scan (CT scan) of adrenals which revealed a right adrenal adenoma measuring 4.4 × 3.4 × 4.0 cm. Right retroperiteneoscopic adrenalectomy was done. Histopathology examination was consistent with adrenal cortical adenoma with foci of myelolipoma. Post adrenalectomy she developed hypocortisolism secondary to contralateral adrenal suppression which lasted up to the present date. Her cutaneous and musculoskeletal manifestations improved substantially. Co-occurrence of endogenous and exogenous Cushing's syndromes is uncommon but should be considered in patients whose Cushingnoid features do not resolve after cessation of exogenous GC.