Somatic Beta-Catenin (CTNNB1) mutations Are Rare Whereas KCNJ5 Mutations May be Found in GnRH/LH- Responsive Primary Aldosteronism
Presentation Number: MON 362
Date of Presentation: April 3rd, 2017
Nadia Gagnon*1, Katia Caceres2, Nada El Ghorayeb1, Natasha Ludwig2, Andre Lacroix1 and Isabelle Bourdeau1
1Centre hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada, 2Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
Background: Recently, somatic activating mutations of CTNNB1, encoding b-catenin in the Wnt cell-differentiation pathway were identified in aldosterone-producing adenomas (APA) from two pregnant women and one postmenopausal woman. It was suggested that in these cases the CTNNB1 mutations may lead to the aberrant overexpression of LHCGR and GNRHR in the aldosterone-secreting adenomas. 1
Objective: To determine the prevalence of somatic mutations of CTNNB1, KCNJ5 and GNAS in a cohort of patients with PA characterized in vivo for GnRH/LH responsive aldosterone secretion.
Method: We studied a cohort of 15 patients with confirmed diagnosis of primary aldosteronism, who underwent unilateral adrenalectomy. Before surgery, these patients were evaluated with an in vivo clinical protocol to evaluate the possible regulation of aldosterone secretion modulated by the adrenocortical aberrant expression of various G-protein coupled hormone receptors (GPCR). Tumoral DNA was extracted from fresh frozen adrenal tissues and specific exons of the coding regions were directly sequenced for the presence of CTNNB1 (exon 3), KCNJ5 (exon 2) and GNAS (exons 8 and 9) genetic alterations.
Results: We studied 15 patients with confirmed PA including 11 APAs, 3 aldosterone-secreting bilateral macronodular adrenal hyperplasia (BMAH) and 1 bilateral hyperplasia (IHA) with a concomitant unilateral cortisol-secreting adenoma. The in vivo stimulation with 100 mcg GnRH iv was performed in all patients and showed a positive response ( >50% renin-independent increase of aldosterone) in 10 patients (8 APA and 2 BMAH), a partial response (>25% increase of aldosterone) in 2 patients (1 adenoma and 1 bilateral hyperplasia) and no response in 3 patients (2 APAs and 1 BMAH). No CTNNB1 mutations were found but 2 KCNJ5 genetic alterations were identified in the adrenocortical adenoma of a 35 yo man with a partial response in aldosterone of 25% to GnRH: the somatic c.451G>C, p.Gly151Arg KCNJ5 mutation which is known to be pathogenic and the c.121C>T, p.Arg41Cys KCNJ5 mutation. A GNAS c.601C>T, p.Arg201Cys mutation was found in the cortisol-secreting adenoma of the patient with concomitant aldosterone-secreting bilateral hyperplasia but no GNAS mutations were found in any aldosterone-secreting tissues.
Conclusion: Aberrant regulation of aldosterone by GnRH/LH is frequent in primary aldosteronism but is not often associated with somatic CTNNB1 or GNAS mutations while it may be found with somatic KCNJ5 mutations.
Nothing to Disclose: NG, KC, NE, NL, AL, IB