# Molecular pathology of primary aldosteronism and hypercortisolism: Impact on adrenal surgery

**Authors:** Tobias Carling, Constantine A. Stratakis, Fabio R. Faucz, C. Christofer Juhlin

PMC · DOI: 10.1016/j.isci.2026.114910 · iScience · 2026-02-05

## TL;DR

New genetic discoveries in adrenal disorders are improving surgical treatments and patient outcomes for conditions like primary aldosteronism and hypercortisolism.

## Contribution

Identification of specific genes linked to adrenal hormone disorders and their impact on precision surgical approaches.

## Key findings

- Genes like PRKACA, PRKAR1A, and ARMC5 are associated with hypercortisolism.
- Molecular insights enable function-preserving adrenal surgery with reduced complications.
- Postoperative genetic analysis helps guide further treatment decisions.

## Abstract

Recent advances in molecular pathology have elucidated the genetic underpinnings of benign aldosterone- and cortisol-producing adrenal lesions, identifying genes encoding mainly potassium and voltage-gated calcium channels in primary aldosteronism (PA), and PRKACA, PRKAR1A, ARMC5 in hypercortisolism. These insights are increasingly guiding precise, function-preserving surgery, such as mini back scope adrenalectomy (MBSA) at high-volume centers with reduced morbidity and risk of adrenal insufficiency, even in complex bilateral cases. Postoperative pathological analysis assessing hormone secretion and genetics provides prognostic information and directs further therapy, whether medical or surgical. A modern approach to PA and hypercortisolism, influenced by an enhanced understanding of the molecular pathophysiology, is likely to improve outcomes and expand adrenalectomy usage and indications as the morbidity and mortality associated with these endocrinopathies are increasingly recognized.

Health sciences; Medicine; Medical specialty; Surgery

## Linked entities

- **Genes:** PRKACA (protein kinase cAMP-activated catalytic subunit alpha) [NCBI Gene 5566], PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha) [NCBI Gene 5573], ARMC5 (armadillo repeat containing 5) [NCBI Gene 79798]
- **Diseases:** primary aldosteronism (MONDO:0001422), hypercortisolism (MONDO:0018912)

## Full-text entities

- **Genes:** KDM1A (lysine demethylase 1A) [NCBI Gene 23028] {aka AIMAH3, AOF2, BHC110, CPRF, KDM1, LSD1}, GNAS (GNAS complex locus) [NCBI Gene 2778] {aka AHO, AIMAH1, C20orf45, GNAS1, GPSA, GSA}, APC (APC regulator of Wnt signaling pathway) [NCBI Gene 324] {aka BTPS2, DESMD, DP2, DP2.5, DP3, GS}, PRKAR1B (protein kinase cAMP-dependent type I regulatory subunit beta) [NCBI Gene 5575] {aka MASNS, PRKAR1}, PRKACA (protein kinase cAMP-activated catalytic subunit alpha) [NCBI Gene 5566] {aka CAFD1, PKACA, PPNAD4}, KCNJ5 (potassium inwardly rectifying channel subfamily J member 5) [NCBI Gene 3762] {aka CIR, GIRK4, KATP1, KIR3.4, LQT13}, CACNA1H (calcium voltage-gated channel subunit alpha1 H) [NCBI Gene 8912] {aka CACNA1HB, Cav3.2, ECA6, EIG6, HALD4}, CYP11B1 (cytochrome P450 family 11 subfamily B member 1) [NCBI Gene 1584] {aka CPN1, CYP11B, FHI, P450C11}, PDE11A (phosphodiesterase 11A) [NCBI Gene 50940] {aka PPNAD2}, PDE8B (phosphodiesterase 8B) [NCBI Gene 8622] {aka ADSD, PPNAD3}, CACNA1D (calcium voltage-gated channel subunit alpha1 D) [NCBI Gene 776] {aka CACH3, CACN4, CACNL1A2, CCHL1A2, Cav1.3, PASNA}, ARMC5 (armadillo repeat containing 5) [NCBI Gene 79798] {aka AIMAH2}, CYP11B2 (cytochrome P450 family 11 subfamily B member 2) [NCBI Gene 1585] {aka ALDOS, CPN2, CYP11B, CYP11BL, CYPXIB2, P-450C18}, SLC30A1 (solute carrier family 30 member 1) [NCBI Gene 7779] {aka ZNT1, ZRC1}, CLCN2 (chloride voltage-gated channel 2) [NCBI Gene 1181] {aka CIC-2, CLC2, ECA2, ECA3, EGI11, EGI3}, CADM1 (cell adhesion molecule 1) [NCBI Gene 23705] {aka BL2, IGSF4, IGSF4A, NECL2, Necl-2, RA175}, DNAH8 (dynein axonemal heavy chain 8) [NCBI Gene 1769] {aka ATPase, SPGF46, hdhc9}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha) [NCBI Gene 5573] {aka ACRDYS1, ADOHR, CAR, CNC, CNC1, PKR1}, ATP2B3 (ATPase plasma membrane Ca2+ transporting 3) [NCBI Gene 492] {aka CFAP39, CLA2, OPCA, PMCA3, PMCA3a, SCAX1}, GIPR (gastric inhibitory polypeptide receptor) [NCBI Gene 2696] {aka PGQTL2}, PRKACB (protein kinase cAMP-activated catalytic subunit beta) [NCBI Gene 5567] {aka CAFD2, PKA C-beta, PKACB}, ATP1A1 (ATPase Na+/K+ transporting subunit alpha 1) [NCBI Gene 476] {aka CMT2DD, HOMGSMR2}, GPR101 (G protein-coupled receptor 101) [NCBI Gene 83550] {aka GPCR6, PAGH2, PITA2}, POMC (proopiomelanocortin) [NCBI Gene 5443] {aka ACTH, CLIP, LPH, MSH, NPP, OBAIRH}, MEN1 (menin 1) [NCBI Gene 4221] {aka MEAI, SCG2}
- **Diseases:** hyperkalemia (MESH:D006947), metabolic syndrome (MESH:D024821), BMiNAD (MESH:C566472), AVS (MESH:D000310), neuropsychiatric disturbances (MESH:D001523), diabetes (MESH:D003920), adrenal insufficiency (MESH:D000309), malignancy (MESH:D009369), Endocrine Tumors (MESH:D004701), adenomas (MESH:D000236), obesity (MESH:D009765), PPNAD (MESH:C566469), gynecomastia (MESH:D006177), adrenal cortical disorders (MESH:D018268), PA (OMIM:617027), fragility fractures (MESH:D005600), AHC (MESH:D003480), adrenal disease (MESH:D000307), hypertension (MESH:D006973), hereditary leiomyomatosis-kidney cancer syndrome (MESH:C535516), multiple endocrine neoplasia type 1 (MESH:D018761), APDH (MESH:D001477), adrenocortical lesions (MESH:D000306), familial adenomatous polyposis (MESH:D011125), MACS (MESH:C535280), producing (MESH:C564985), osteoporosis (MESH:D010024), cardiovascular complications (MESH:D002318), adrenal endocrinopathies (MESH:C567425), hypokalemia (MESH:D007008), nodular adrenal enlargement (MESH:D006332), CPA (MESH:D049913), CNC (MESH:D056733), APAs (MESH:D006929), BMAD (MESH:C565662), FH- (OMIM:143890), diffuse hyperplasia (MESH:D006965)
- **Chemicals:** 11C-metomidate (MESH:C084586), 68Ga-pentixafor (MESH:C000597686), aldosterone (MESH:D000450), Cortisol (MESH:D006854), eplerenone (MESH:D000077545), cAMP (MESH:D000242), chloride (MESH:D002712), potassium (MESH:D011188), sodium (MESH:D012964), Baxdrostat (-), spironolactone (MESH:D013148), steroid (MESH:D013256), calcium (MESH:D002118)
- **Species:** Homo sapiens (human, species) [taxon 9606]
- **Mutations:** L205R, p.Leu206Arg

## Full text

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## Figures

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## References

114 references — full list in the complete paper: https://tomesphere.com/paper/PMC12927063/full.md

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Source: https://tomesphere.com/paper/PMC12927063