Abstract Background: Three patients with a syndrome of LH/HCG-activated primary aldosteronism in pregnancy or menopause carrying somatic CTNNB1 mutations were reported four years ago (Teo et al. NEJM 2015). This proved but half the story. Diagnosis of an APA in a 12-year old boy with severe hypertension revealed an apparently essential co-driver mutation. Methods: WES of tumour and blood was performed in the pubertal boy. Candidate genes were Sanger sequenced in other APAs from GB/Ireland, and France with known or suspected CTNNB1 mutations. LHCGR, GNRHR and CYP11B2 expression were measured in all available patients’ APAs and the adjacent adrenal gland (AAG) by RT-PCR. RNA and gDNA from the zona glomerulosa (ZG) of the proband’s AAG were collected by laser capture microdissection for Sanger sequencing of GNA11 and CTNNB1. Function of mutant genes was assessed by measurement of aldosterone production and LHCGR expression by immunofluorescence (IFC) in NCI-H295R adrenocortical cells and primary human APA cells. Results: The proband’s APA contained a p.(S45F) somatic mutation in CTNNB1, and a p.(Q209P) somatic mutation of the GTPase-activating residue (Q209) in GNA11. Mutations of Q209, to P or H, were also found in six other GB/Irish patients with previously identified mutations of CTNNB1 (S33C, G34R, T41A, S45F, or S45P). All seven patients remain normotensive 2-12 years post-adrenalectomy, including some with long-standing pre-operative hypertension. Four of the 13 French patients with CTNNB1 exon 3 mutant APAs have somatic mutation of Q209 of either GNA11 (n=3) or GNAQ. In comparison with their own AAG, the GB/Irish double mutant APAs showed an increase in expression of LHCGR, CYP11B2 and GNRHR by 32-166, 158-18980, and 1174-6642 fold, respectively. All four French double-mutants had >10 fold higher LHCGR than APAs with single mutations of CTNNB1 or other genes. Hyperplasia of ZG was observed in the ZG of the boy’s AAG but no APCC was detected. Homozygous or heterozygous Q209P mutation of GNA11 was detected in multiple ZG samples in RNA and/or gDNA but WT in CTNNB1 exon 3. H295R cells (CTNNB1 S45P) were GNA11 WT. Overexpression of GNA11 Q209 mutation increased aldosterone secretion to 465% of GNA11 WT overexpressing cells (n=6, P<0.001) and CYP11B2 expression was also increased several-fold. Smaller increases were seen in primary human adrenal cells after double-transfection by GNA11 and CTNNB1 mutants (n=3, P<0.001). This also caused membrane expression of LHCGR, visualised by IFC. Conclusions: APAs with double mutation of GNA11/GNAQ Q209 and CTNNB1 have a distinct phenotype, in which hypertension is triggered by high LH or HCG, and cured in all cases by adrenalectomy. GNA11/Q mediates the aldosterone response to ANGII, and the Q209 codon is analogous to the Q227 of GNAS, mutated in McCune Albright. Mosaicism for GNA11 may cause ZG hyperplasia.