Subscribe to RSS
DOI: 10.1055/s-0035-1565198
Bilateral Idiopathic Adrenal Hyperplasia: Genetics and Beyond
![](https://www.thieme-connect.de/media/hmr/201513/lookinside/thumbnails/10.1055-s-0035-1565198-1.jpg)
Abstract
Bilateral adrenal hyperplasia currently accounts for up to 2 thirds of cases of primary aldosteronism. As such, it represents a major opportunity for targeted medical management as opposed to unilateral surgically correctable forms of the disease. Although the majority of cases of primary aldosteronism are sporadic, bilateral adrenal hyperplasia may occur in the context of familial hyperaldosteronism where it is associated with specific germline mutations. Over the past 5 years, impressive progress has been made in our understanding of the genetic basis underlying primary aldosteronism, allowing us to identify and characterize new familial forms of the disease and to understand the mechanisms involved in the formation of aldosterone producing adenoma. In contrast, our knowledge of the genetic contribution to the development of bilateral adrenal hyperplasia, and in a larger context, to renin and aldosterone levels in the general population, is still poor. This review summarizes our current knowledge on the genetics of bilateral adrenal hyperplasia and addresses some open questions to be addressed by future research. In particular, genome-wide association studies in large populations may provide clues to understanding the genetic susceptibility underlying the development of primary aldosteronism.
Key words
adrenal adenoma - adrenal cortex - aldosterone - mineralocorticoid - renin-angiotensin-aldosterone systemPublication History
Received: 31 August 2015
Accepted: 29 October 2015
Article published online:
26 November 2015
Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart,
Germany
-
References
- 1 Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, Young Jr WF, Montori VM. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 3266-3281
- 2 Hannemann A, Wallaschofski H. Prevalence of primary aldosteronism in patient’s cohorts and in population-based studies – a review of the current literature. Horm Metab Res 2012; 44: 157-162
- 3 Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension 2013; 62: 331-336
- 4 Mulatero P, Tizzani D, Viola A, Bertello C, Monticone S, Mengozzi G, Schiavone D, Williams TA, Einaudi S, La Grotta A, Rabbia F, Veglio F. Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (Primary Aldosteronism in TOrino-GENetic forms). Hypertension 2011; 58: 797-803
- 5 Zennaro MC, Boulkroun S, Fernandes-Rosa F. An update on novel mechanisms of primary aldosteronism. J Endocrinol 2015; 224: R63-R77
- 6 Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Akerstrom G, Wang W, Carling T, Lifton RP. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 2011; 331: 768-772
- 7 Azizan EA, Poulsen H, Tuluc P, Zhou J, Clausen MV, Lieb A, Maniero C, Garg S, Bochukova EG, Zhao W, Shaikh LH, Brighton CA, Teo AE, Davenport AP, Dekkers T, Tops B, Kusters B, Ceral J, Yeo GS, Neogi SG, McFarlane I, Rosenfeld N, Marass F, Hadfield J, Margas W, Chaggar K, Solar M, Deinum J, Dolphin AC, Farooqi IS, Striessnig J, Nissen P, Brown MJ. Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension. Nat Genet 2013; 45: 1055-1060
- 8 Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, Fonseca AL, Korah R, Starker LF, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Akerstrom G, Bjorklund P, Carling T, Fahlke C, Hidalgo P, Lifton RP. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 2013; 45: 1050-1054
- 9 Beuschlein F, Boulkroun S, Osswald A, Wieland T, Nielsen HN, Lichtenauer UD, Penton D, Schack VR, Amar L, Fischer E, Walther A, Tauber P, Schwarzmayr T, Diener S, Graf E, Allolio B, Samson-Couterie B, Benecke A, Quinkler M, Fallo F, Plouin PF, Mantero F, Meitinger T, Mulatero P, Jeunemaitre X, Warth R, Vilsen B, Zennaro MC, Strom TM, Reincke M. Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension. Nat Genet 2013; 45: 440-444
- 10 Plouin PF, Amar L, Chatellier G. Trends in the prevalence of primary aldosteronism, aldosterone-producing adenomas, and surgically correctable aldosterone-dependent hypertension. Nephrol Dial Transplant 2004; 19: 774-777
- 11 Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A, Palumbo G, Parenti G, Porteri E, Semplicini A, Rizzoni D, Rossi E, Boscaro M, Pessina AC, Mantero F. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol 2006; 48: 2293-2300
- 12 Scholl UI, Stolting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, Prasad ML, Goh G, Carling T, Juhlin CC, Quack I, Rump LC, Thiel A, Lande M, Frazier BG, Rasoulpour M, Bowlin DL, Sethna CB, Trachtman H, Fahlke C, Lifton RP. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. eLife 2015; 4: e06315
- 13 Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel JM. A chimaeric 11beta-hydroxylase aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 1992; 355: 262-265
- 14 Stowasser M, Gordon RD. Primary aldosteronism: learning from the study of familial varieties. J Hypertens 2000; 18: 1165-1176
- 15 Stowasser M, Bachmann AW, Huggard PR, Rossetti TR, Gordon RD. Treatment of familial hyperaldosteronism type I: only partial suppression of adrenocorticotropin required to correct hypertension. J Clin Endocrinol Metab 2000; 85: 3313-3318
- 16 Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Finn WL, Krek AL. Clinical and pathological diversity of primary aldosteronism, including a new familial variety. Clin Exp Pharmacol Physiol 1991; 18: 283-286
- 17 Lafferty AR, Torpy DJ, Stowasser M, Taymans SE, Lin JP, Huggard P, Gordon RD, Stratakis CA. A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22). J Med Genet 2000; 37: 831-835
- 18 Mulatero P, Tauber P, Zennaro MC, Monticone S, Lang K, Beuschlein F, Fischer E, Tizzani D, Pallauf A, Viola A, Amar L, Williams TA, Strom TM, Graf E, Bandulik S, Penton D, Plouin PF, Warth R, Allolio B, Jeunemaitre X, Veglio F, Reincke M. KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. Hypertension 2012; 59: 235-240
- 19 Scholl UI, Nelson-Williams C, Yue P, Grekin R, Wyatt RJ, Dillon MJ, Couch R, Hammer LK, Harley FL, Farhi A, Wang WH, Lifton RP. Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci USA 2012; 109: 2533-2538
- 20 Oki K, Plonczynski M, Lam M, Gomez-Sanchez E, Gomez-Sanchez C. The potassium channel, Kir3.4 participates in angiotensin II-stimulated aldosterone production by a human adrenocortical cell line. Endocrinology 2012; 153: 4328-4335
- 21 Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, Strom TM, Monticone S, Amar L, Meatchi T, Mantero F, Cicala MV, Quinkler M, Fallo F, Allolio B, Bernini G, Maccario M, Giacchetti G, Jeunemaitre X, Mulatero P, Reincke M, Zennaro MC. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension 2014; 64: 354-361
- 22 Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, Horne MJ, Dietrich D, Riemer J, Kucukkoylu S, Reimer EN, Reis AC, Goh G, Kristiansen G, Mahajan A, Korah R, Lifton RP, Prasad ML, Carling T. Novel Somatic Mutations in Primary Hyperaldosteronism are related to the Clinical, Radiological and Pathological Phenotype. Clin Endocrinol (Oxf) 2015; Aug 7 DOI: 10.1111/cen.12873[Epub ahead of print].
- 23 Akerstrom T, Willenberg HS, Cupisti K, Ip J, Backman S, Moser A, Maharjan R, Robinson B, Iwen KA, Dralle H, Cxxx DV, Backdahl M, Botling J, Stalberg P, Westin G, Walz MK, Lehnert H, Sidhu S, Zedenius J, Bjorklund P, Hellman P. Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas. Endocr Relat Cancer 2015; 22: 735-744
- 24 Boulkroun S, Beuschlein F, Rossi GP, Golib-Dzib JF, Fischer E, Amar L, Mulatero P, Samson-Couterie B, Hahner S, Quinkler M, Fallo F, Letizia C, Allolio B, Ceolotto G, Cicala MV, Lang K, Lefebvre H, Lenzini L, Maniero C, Monticone S, Perrocheau M, Pilon C, Plouin PF, Rayes N, Seccia TM, Veglio F, Williams TA, Zinnamosca L, Mantero F, Benecke A, Jeunemaitre X, Reincke M, Zennaro MC. Prevalence, Clinical, and Molecular Correlates of KCNJ5 Mutations in Primary Aldosteronism. Hypertension 2012; 59: 592-598
- 25 Murthy M, Xu S, Massimo G, Wolley M, Gordon RD, Stowasser M, O’Shaughnessy KM. Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism. Hypertension 2014; 63: 783-789
- 26 Oki K, Plonczynski MW, Luis Lam M, Gomez-Sanchez EP, Gomez-Sanchez CE. Potassium Channel Mutant KCNJ5 T158A Expression in HAC-15 Cells Increases Aldosterone Synthesis. Endocrinology 2012; 153: 1774-1782
- 27 Li NF, Li HJ, Zhang DL, Zhang JH, Yao XG, Wang HM, Abulikemu S, Zhou KM, Zhang XY. Genetic variations in the KCNJ5 gene in primary aldosteronism patients from Xinjiang, China. PLoS One 2013; 8: e54051
- 28 Wu VC, Wu CK, Chang YC, Young GH, Chen SC, Yang WS, Chen CY, Wang WJ, Lin CY, Lin YH, Lin SL, Chueh SC, Wu KD. group Ts . Association of the variations in the HSD3beta gene with primary aldosteronism. J Hypertens 2013; 31: 1396-1405 discussion 1405
- 29 Assie G, Libe R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, Barreau O, Lefevre L, Sibony M, Guignat L, Rodriguez S, Perlemoine K, Rene-Corail F, Letourneur F, Trabulsi B, Poussier A, Chabbert-Buffet N, Borson-Chazot F, Groussin L, Bertagna X, Stratakis CA, Ragazzon B, Bertherat J. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N Engl J Med 2013; 369: 2105-2114
- 30 Zilbermint M, Xekouki P, Faucz FR, Berthon A, Gkourogianni A, Schernthaner-Reiter MH, Batsis M, Sinaii N, Quezado MM, Merino M, Hodes A, Abraham SB, Libe R, Assie G, Espiard S, Drougat L, Ragazzon B, Davis A, Gebreab SY, Neff R, Kebebew E, Bertherat J, Lodish MB, Stratakis CA. Primary Aldosteronism and ARMC5 Variants. J Clin Endocrinol Metab 2015; 100: E900-E909
- 31 Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, Fonseca AL, Korah R, Starker LF, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Akerstrom G, Bjorklund P, Carling T, Fahlke C, Hidalgo P, Lifton RP. Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 2013; 45: 1050-1054
- 32 Mulatero P, Verhovez A, Morello F, Veglio F. Diagnosis and treatment of low-renin hypertension. Clin Endocrinol (Oxf) 2007; 67: 324-334
- 33 Zennaro MC, Boulkroun S, Fernandes-Rosa F. Inherited forms of mineralocorticoid hypertension. Best Pract Res Clin Endocrinol Metab 2015; 29: 633-645
- 34 Wambach G, Helber A, Bonner G, Konrads A, Hummerich W, Meurer KA, Kaufmann W. Characterization of a group of essential hypertensives with impaired regulation of aldosterone. Clin Exp Hypertension 1982; 4: 1835-1849
- 35 Newton-Cheh C, Guo CY, Gona P, Larson MG, Benjamin EJ, Wang TJ, Kathiresan S, O’Donnell CJ, Musone SL, Camargo AL, Drake JA, Levy D, Hirschhorn JN, Vasan RS. Clinical and genetic correlates of aldosterone-to-renin ratio and relations to blood pressure in a community sample. Hypertension 2007; 49: 846-856
- 36 Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N, Benjamin EJ, Levy D. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med 2004; 351: 33-41
- 37 Meneton P, Galan P, Bertrais S, Heudes D, Hercberg S, Menard J. High plasma aldosterone and low renin predict blood pressure increase and hypertension in middle-aged Caucasian populations. J Hum Hypertens 2008; 22: 550-558
- 38 Kupari M, Hautanen A, Lankinen L, Koskinen P, Virolainen J, Nikkila H, White PC. Associations between human aldosterone synthase (CYP11B2) gene polymorphisms and left ventricular size, mass, and function. Circulation 1998; 97: 569-575
- 39 Sookoian S, Gianotti TF, Gonzalez CD, Pirola CJ. Association of the C-344T aldosterone synthase gene variant with essential hypertension: a meta-analysis. J Hypertens 2007; 25: 5-13
- 40 McManus F, Sands W, Diver L, MacKenzie SM, Fraser R, Davies E, Connell JM. APEX1 regulation of aldosterone synthase gene transcription is disrupted by a common polymorphism in humans. Circ Res 2012; 111: 212-219
- 41 Lieb W, Chen MH, Teumer A, de Boer RA, Lin H, Fox ER, Musani SK, Wilson JG, Wang TJ, Volzke H, Petersen AK, Meisinger C, Nauck M, Schlesinger S, Li Y, Menard J, Hercberg S, Wichmann HE, Volker U, Rawal R, Bidlingmaier M, Hannemann A, Dorr M, Rettig R, van Gilst WH, van Veldhuisen DJ, Bakker SJ, Navis G, Wallaschofski H, Meneton P, van der Harst P, Reincke M, Vasan RS, Consortium CK, Icbp . EchoGen C. Genome-wide meta-analyses of plasma renin activity and concentration reveal association with the kininogen 1 and prekallikrein genes. Circulation. Cardiovasc Genet 2015; 8: 131-140
- 42 Spyroglou A, Bozoglu T, Rawal R, De Leonardis F, Sterner C, Boulkroun S, Benecke AG, Monti L, Zennaro MC, Petersen AK, Doring A, Rossi A, Bidlingmaier M, Warth R, Gieger C, Reincke M, Beuschlein F. Diastrophic dysplasia sulfate transporter (SLC26A2) is expressed in the adrenal cortex and regulates aldosterone secretion. Hypertension 2014; 63: 1102-1109
- 43 Imrie H, Freel M, Mayosi BM, Davies E, Fraser R, Ingram M, Cordell HJ, Farrall M, Avery PJ, Watkins H, Keavney B, Connell JM. Association between aldosterone production and variation in the 11beta-hydroxylase (CYP11B1) gene. J Clin Endocrinol Metab 2006; 91: 5051-5056
- 44 Heitzmann D, Derand R, Jungbauer S, Bandulik S, Sterner C, Schweda F, El Wakil A, Lalli E, Guy N, Mengual R, Reichold M, Tegtmeier I, Bendahhou S, Gomez-Sanchez CE, Aller MI, Wisden W, Weber A, Lesage F, Warth R, Barhanin J. Invalidation of TASK1 potassium channels disrupts adrenal gland zonation and mineralocorticoid homeostasis. Embo J 2008; 27: 179-187
- 45 Penton D, Bandulik S, Schweda F, Haubs S, Tauber P, Reichold M, Cong LD, El Wakil A, Budde T, Lesage F, Lalli E, Zennaro MC, Warth R, Barhanin J. Task3 potassium channel gene invalidation causes low renin and salt-sensitive arterial hypertension. Endocrinology 2012; 153: 4740-4748
- 46 Davies LA, Hu C, Guagliardo NA, Sen N, Chen X, Talley EM, Carey RM, Bayliss DA, Barrett PQ. TASK channel deletion in mice causes primary hyperaldosteronism. Proc Natl Acad Sci USA 2008; 105: 2203-2208
- 47 Guagliardo NA, Yao J, Hu C, Schertz EM, Tyson DA, Carey RM, Bayliss DA, Barrett PQ. TASK-3 channel deletion in mice recapitulates low-renin essential hypertension. Hypertension 2012; 59: 999-1005
- 48 Bandulik S, Tauber P, Penton D, Schweda F, Tegtmeier I, Sterner C, Lalli E, Lesage F, Hartmann M, Barhanin J, Warth R. Severe hyperaldosteronism in neonatal Task3 potassium channel knockout mice is associated with activation of the intraadrenal renin-angiotensin system. Endocrinology 2013; 154: 2712-2722
- 49 Jung J, Barrett PQ, Eckert GJ, Edenberg HJ, Xuei X, Tu W, Pratt JH. Variations in the potassium channel genes KCNK3 and KCNK9 in relation to blood pressure and aldosterone production: an exploratory study. J Clin Endocrinol Metab 2012; 97: E2160-E2167
- 50 van Leeuwen N, Caprio M, Blaya C, Fumeron F, Sartorato P, Ronconi V, Giacchetti G, Mantero F, Fernandes-Rosa FL, Simian C, Peyrard S, Zitman FG, Penninx BW, de Kloet ER, Azizi M, Jeunemaitre X, Derijk RH, Zennaro MC. The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels. Hypertension 2010; 56: 995-1002
- 51 Boulkroun S, Samson-Couterie B, Dzib JF, Lefebvre H, Louiset E, Amar L, Plouin PF, Lalli E, Jeunemaitre X, Benecke A, Meatchi T, Zennaro MC. Adrenal cortex remodeling and functional zona glomerulosa hyperplasia in primary aldosteronism. Hypertension 2010; 56: 885-892
- 52 Dekkers T, ter Meer M, Lenders JW, Hermus AR, Schultze Kool L, Langenhuijsen JF, Nishimoto K, Ogishima T, Mukai K, Azizan EA, Tops B, Deinum J, Kusters B. Adrenal nodularity and somatic mutations in primary aldosteronism: one node is the culprit?. J Clin Endocrinol Metab 2014; 99: E1341-E1351
- 53 Fernandes-Rosa FL, Giscos-Duriez I, Amar L, Gomez-Sanchez CE, Meatchi T, Boulkroun S, Zennaro MC. Different somatic mutations in multinodular adrenals with aldosterone producing adenoma. Hypertension. 2015 in press
- 54 Nishimoto K, Tomlins SA, Kuick R, Cani AK, Giordano TJ, Hovelson DH, Liu CJ, Sanjanwala AR, Edwards MA, Gomez-Sanchez CE, Nanba K, Rainey WE. Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands. Proc Natl Acad Sci USA 2015; 112: E4591-E4599
- 55 Boulkroun S, Samson-Couterie B, Golib-Dzib JF, Amar L, Plouin PF, Sibony M, Lefebvre H, Louiset E, Jeunemaitre X, Meatchi T, Benecke A, Lalli E, Zennaro MC. Aldosterone-producing adenoma formation in the adrenal cortex involves expression of stem/progenitor cell markers. Endocrinology 2011; 152: 4753-4763