Pregnancy, Primary Aldosteronism, and AdrenalCTNNB1Mutations

Abstract

SUMMARYRecent discoveries of somatic mutations permit the recognition of subtypes of aldosteroneproducing adenomas with distinct clinical presentations and pathological features. Here we describe three women with hyperaldosteronism, two who presented in pregnancy and one who presented after menopause. Their aldosterone-producing adenomas harbored activating mutations of CTNNB1, encoding β-catenin in the Wnt cell-differentiation pathway, and expressed LHCGR and GNRHR, encoding gonadal receptors, at levels that were more than 100 times as high as the levels in other aldosterone-producing adenomas. The mutations stimulate Wnt activation and cause adrenocortical cells to de-differentiate toward their common adrenal-gonadal precursor cell type.Systematic screening detects primary aldosteronism in 5 to 10% of all patients with hypertension and in approximately 20% of patients with treatment-resistant hypertension. 1,2 A unilateral aldosterone-producing adenoma is the most common potentially curable cause of hypertension in such cases. 2 Early detection of a unilateral aldosterone-producing adenoma is important both to maximize the likelihood of a complete cure of hypertension by means of adenoma removal and to prevent the onset of resistant hypertension and the risk of long-term cardiovascular complications. 3 The Wnt pathway, through β-catenin signaling, is critical for normal adrenocortical development and maintenance, in particular the zona glomerulosa of the cortex. 4 Both the adrenal cortex and the gonads originate from a common progenitor-cell population in the Pathogenic somatic mutations of CTNNB1 have been found in 27% of adrenocortical adenomas and in 31% of adrenocortical carcinomas. 7 Some of these mutations arise in the part of exon 3 that encodes the consensus glycogen synthase kinase 3β-casein kinase 1 (GSK-3β-CK1) phosphorylation site and therefore result in loss of phosphorylation of β-catenin. This prevents the ubiquitination of β-catenin and leads to aberrant Wnt-pathway activation. 8 Until now, β-catenin mutations in adrenocortical adenomas have been mainly associated with nonfunctioning tumors. 7 Could some of these tumors be nonfunctioning only because they have not been exposed to the stimulus for hormone secretion?Here we describe three patients with hyperaldosteronism, two presenting during pregnancy and one after menopause, who were discovered to have mutations in exon 3 of CTNNB1 in their adenomas. All three mutations were predicted to stabilize nonphosphorylated β-catenin and to activate the Wnt signaling pathway. All three aldosterone-producing adenomas expressed very high levels of the gonadal receptors luteinizing hormone-chorionic gonadotropin receptor (LH-CGR) and gonadotropin-releasing hormone receptor (GNRHR). It therefore seems likely that high circulating levels of human chorionic gonadotropin, luteinizing hormone, or gonadotropin-releasing hormone (as observed in pregnancy or at menopause) led to the identification of the aldosterone-producing adenomas in the three patients. CASE ...

ENDOCRINE TUMOURS: The genomics of adrenocortical tumors

“…Berthon et al (13) recently reported Wnt/b-catenin activation in a majority of APA, related to the downregulation of a negative regulator of this pathway, named SFRP2 -this Familial adenomatous polyposis downregulation seems to be due to a high methylation of SFRP2 promoter (13). Another recent publication identified CTNNB1 mutations -encoding the b-catenin -in Conn adenomas in pregnant women (14). The relationship between the calcium signaling activation and the Wnt/b-catenin pathway remains to be elucidated.…”

Somatic and inherited mutations in primary aldosteronism

“…Teo and coworkers reported the case of three women with PA due to an APA with somatic CTNN1B mutations (p.Ser33Cys, pSer45Phe and p.Gly34Arg), two diagnosed during pregnancy and the third after menopause (Teo et al 2015). Their APA expressed high levels of luteinizing hormone-chorionic gonadotropin receptor (LHCGR) and gonadotropin-releasing hormone receptor (GNRHR), suggesting that pregnancy may reveal underlying PA (Teo et al 2015).…”

Expression of CYP11B2 in Aldosterone-Producing Adrenocortical Adenoma: Regulatory Mechanisms and Clinical Significance

“…In addition, these mutation cases have distinct char- acteristics, including male dominance, increased plasma aldosterone concentration, and lower potassium concentration, compared with cases without these mutations (Beuschlein et al 2013). In addition, Teo et al (2015) reported three cases of APA with activating mutations in CTNNB1 encoding β-catenin, associated with aberrant β-catenin accumulation in the Wnt cell-differentiation pathway and overexpression of luteinizing hormone/choriogonadotropin receptor (LHCGR) and gonadotropin-releasing hormone receptor (GnRHR). Subsequently, CTNNB1 mutations have been reported in 5.1% of APA cases, and APA tissues with CTNNB1 mutations were demonstrated to have a significantly higher CYP11B2 mRNA expression level compared with those with KCNJ5 mutations (Åkerström et al 2016).…”