Subscribe to RSS
DOI: 10.1055/a-1061-7349
Update of Genetic and Molecular Causes of Adrenocortical Hyperplasias Causing Cushing Syndrome
![](https://www.thieme-connect.de/media/hmr/202008/lookinside/thumbnails/10.1055-a-1061-7349-1.jpg)
Abstract
Bilateral hyperplasias of the adrenal cortex are rare causes of chronic endogenous hypercortisolemia also called Cushing syndrome. These hyperplasias have been classified in two categories based on the adrenal nodule size: the micronodular types include Primary Pigmented Nodular Adrenocortical Disease (PPNAD) and isolated Micronodular Adrenal Disease (iMAD) and the macronodular also named Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH). This review discusses the genetic and molecular causes of these different forms of hyperplasia that involve mutations and dysregulation of various regulators of the cAMP/protein kinase A (PKA) pathway. PKA signaling is the main pathway controlling cortisol secretion in adrenocortical cells under ACTH stimulation. Although mutations of the regulatory subunit R1α of PKA (PRKAR1A) is the main cause of familial and sporadic PPNAD, inactivation of two cAMP-binding phosphodiesterases (PDE11A and PDE8B) are associated with iMAD even if they are also found in PPNAD and PBMAH cases. Interestingly, PBMAH that is observed in multiple familial syndrome such as APC, menin, fumarate hydratase genes, has initially been associated with the aberrant expression of G-protein coupled receptors (GPCR) leading to an activation of cAMP/PKA pathway. However, more recently, the discovery of germline mutations in Armadillo repeat containing protein 5 (ARMC5) gene in 25–50% of PBMAH patients highlights its importance in the development of PBMAH. The potential relationship between ARMC5 mutations and aberrant GPCR expression is discussed as well as the potential other causes of PBMAH.
Publication History
Received: 07 September 2019
Accepted: 05 November 2019
Article published online:
25 February 2020
© Georg Thieme Verlag KG
Stuttgart · New York
-
References
- 1 Lacroix A, Bourdeau I, Lampron A. et al. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol (Oxf) 2010; 73: 1-15
- 2 Lodish M. Cushingʼs syndrome in childhood: Update on genetics, treatment, and outcomes. Curr Opin Endocrinol Diabetes Obes 2015; 22: 48-54
- 3 Stratakis CA, Boikos SA. Genetics of adrenal tumors associated with Cushingʼs syndrome: A new classification for bilateral adrenocortical hyperplasias. Nat Clin Pract Endocrinol Metab 2007; 3: 748-757
- 4 Horvath A, Boikos S, Giatzakis C. et al. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet 2006; 38: 794-800
- 5 Kamilaris CDC, Faucz FR, Voutetakis A. et al. Carney complex. Exp Clin Endocrinol Diabetes 2019; 127: 156-164
- 6 Stratakis CA. Clinical genetics of multiple endocrine neoplasias, Carney complex and related syndromes. J Endocrinol Invest 2001; 24: 370-383
- 7 Horvath A, Bertherat J, Groussin L. et al. Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): An update. Hum Mutat 2010; 31: 369-379
- 8 Stratakis CA, Carney JA, Lin JP. et al. Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2. J Clin Invest 1996; 97: 699-705
- 9 Casey M, Mah C, Merliss AD. et al. Identification of a novel genetic locus for familial cardiac myxomas and Carney complex. Circulation 1998; 98: 2560-2566
- 10 Kirschner LS, Carney JA, Pack SD. et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet 2000; 26: 89-92
- 11 Bertherat J, Horvath A, Groussin L. et al. Mutations in regulatory subunit type 1A of cyclic adenosine 5ʼ-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab 2009; 94: 2085-2091
- 12 Horvath A, Bertherat J, Groussin L. et al. Mutations and polymorphisms in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A): An update. Hum Mutat 2010; 31: 369-379
- 13 Kirschner LS, Sandrini F, Monbo J. et al. Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the carney complex. Hum Mol Genet 2000; 9: 3037-3046
- 14 Amieux PS, McKnight GS. The essential role of RI alpha in the maintenance of regulated PKA activity. Ann NY Acad Sci 2002; 968: 75-95
- 15 Bertherat J, Groussin L, Sandrini F. et al. Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity. Cancer Res 2003; 63: 5308-5319
- 16 Sahut-Barnola I, de Joussineau C, Val P. et al. Cushingʼs syndrome and fetal features resurgence in adrenal cortex-specific Prkar1a knockout mice. PLoS Genet 2010; 6: e1000980
- 17 Dumontet T, Sahut-Barnola I, Septier A. et al. PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal. JCI Insight 2018; 3: e98394
- 18 de Joussineau C, Sahut-Barnola I, Tissier F. et al. mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD). Hum Mol Genet 2014; 23: 5418-5428
- 19 Mavrakis M, Lippincott-Schwartz J, Stratakis CA. et al. Depletion of type IA regulatory subunit (RIalpha) of protein kinase A (PKA) in mammalian cells and tissues activates mTOR and causes autophagic deficiency. Hum Mol Genet 2006; 15: 2962-2971
- 20 de Joussineau C, Sahut-Barnola I, Tissier F. et al. mTOR pathway is activated by PKA in adrenocortical cells and participates in vivo to apoptosis resistance in primary pigmented nodular adrenocortical disease (PPNAD). Hum Mol Genet 2014; 23: 5418-5428
- 21 Almeida MQ, Stratakis CA. Carney complex and other conditions associated with micronodular adrenal hyperplasias. Best Pract Res Clin Endocrinol Metab 2010; 24: 907-914
- 22 Stratakis CA. cAMP/PKA signaling defects in tumors: genetics and tissue-specific pluripotential cell-derived lesions in human and mouse. Molecular and Cellular Endocrinology 2013; 371: 208-220
- 23 Wayman C, Phillips S, Lunny C. et al. Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. Int J Impot Res 2005; 17: 216-223
- 24 Ceyhan O, Birsoy K, Hoffman CS. Identification of biologically active PDE11-selective inhibitors using a yeast-based high-throughput screen. Chem Biol 2012; 19: 155-163
- 25 Horvath A, Giatzakis C, Tsang K. et al. A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: A novel PDE8B isoform in human adrenal cortex. Eur J Hum Genet 2008; 16: 1245-1253
- 26 Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 2010; 59: 367-374
- 27 Rothenbuhler A, Horvath A, Libe R. et al. Identification of novel genetic variants in phosphodiesterase 8B (PDE8B), a cAMP-specific phosphodiesterase highly expressed in the adrenal cortex, in a cohort of patients with adrenal tumours. Clin Endocrinol 2012; 77: 195-199
- 28 Tsai LC, Shimizu-Albergine M, Beavo JA. The high-affinity cAMP-specific phosphodiesterase 8B controls steroidogenesis in the mouse adrenal gland. Mol Pharmacol 2011; 79: 639-648
- 29 Vezzosi D, Libe R, Baudry C. et al. Phosphodiesterase 11A (PDE11A) gene defects in patients with acth-independent macronodular adrenal hyperplasia (AIMAH): Functional variants may contribute to genetic susceptibility of bilateral adrenal tumors. J Clin Endocrinol Metab 2012; 97: E2063-E2069
- 30 Wilmot Roussel H, Vezzosi D, Rizk-Rabin M. et al. Identification of gene expression profiles associated with cortisol secretion in adrenocortical adenomas. J Clin Endocrinol Metab 2013; 98: E1109-E1121
- 31 Szarek E, Stratakis CA. Phosphodiesterases and adrenal Cushing in mice and humans. Horm Metab Res 2014; 46: 863-868
- 32 Louiset E, Duparc C, Young J. et al. Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia. N Eng. J Med 2013; 369: 2115-2125
- 33 Lacroix A. Heredity and cortisol regulation in bilateral macronodular adrenal hyperplasia. N Eng. J Med 2013; 369: 2147-2149
- 34 Lacroix A. ACTH-independent macronodular adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009; 23: 245-259
- 35 Hsiao HP, Kirschner LS, Bourdeau I. et al. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J Clin Endocrinol Metab 2009; 94: 2930-2937
- 36 Libe R, Coste J, Guignat L. et al. Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushingʼs syndrome. Eur J Endocrinol 2010; 163: 129-138
- 37 Espiard S, Ragazzon B, Bertherat J. Protein kinase A alterations in adrenocortical tumors. Horm Metab Res 2014; 46: 869-875
- 38 Swords FM, Noon LA, King PJ. et al. Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene. Mol Cell Endocrinol 2004; 213: 149-154
- 39 Swords FM, Baig A, Malchoff DM. et al. Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity. Mol Endocrinol 2002; 16: 2746-2753
- 40 St-Jean M, Ghorayeb NE, Bourdeau I. et al. Aberrant G-protein coupled hormone receptor in adrenal diseases. Best Pract Res Clin Endocrinol Metab 2018; 32: 165-187
- 41 El Ghorayeb N, Bourdeau I, Lacroix A. Multiple aberrant hormone receptors in Cushingʼs syndrome. Eur J Endocrinol 2015; 173: M45-M60
- 42 Lecoq AL, Stratakis CA, Viengchareun S. et al. Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushingʼs syndrome. JCI Insight 2017; 2
- 43 Candida Barisson Villares Fragoso M, Pontes Cavalcante I, Meneses Ferreira A. et al. Genetics of primary macronodular adrenal hyperplasia. Presse Med 2018; 47: e139-e149
- 44 Fragoso MC, Domenice S, Latronico AC. et al. Cushingʼs syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. J Clin Endocrinol Metab 2003; 88: 2147-2151
- 45 Almeida MQ, Azevedo MF, Xekouki P. et al. Activation of cyclic AMP signaling leads to different pathway alterations in lesions of the adrenal cortex caused by germline PRKAR1A defects vs. those due to somatic GNAS mutations. J Clin Endocrinol Metab 2012; 97: E687-E693
- 46 Villares Fragoso MC, Wanichi IQ, Cavalcante IP. et al. The Role of gsp Mutations on the Development of Adrenocortical Tumors and Adrenal Hyperplasia. Front Endocrinol (Lausanne) 2016; 7: 104
- 47 Hsiao HP, Kirschner LS, Bourdeau I. et al. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J Clin Endocrinol Metab 2009; 94: 2930-2937
- 48 Gaujoux S, Pinson S, Gimenez-Roqueplo AP. et al. Inactivation of the APC gene is constant in adrenocortical tumors from patients with familial adenomatous polyposis but not frequent in sporadic adrenocortical cancers. Clin Cancer Res 2010; 16: 5133-5141
- 49 Heaton JH, Wood MA, Kim AC. et al. Progression to adrenocortical tumorigenesis in mice and humans through insulin-like growth factor 2 and beta-catenin. Am J Pathol 2012; 181: 1017-1033
- 50 Berthon A, Martinez A, Bertherat J. et al. Wnt/beta-catenin signalling in adrenal physiology and tumour development. Mol Cell Endocrinol 2012; 351: 87-95
- 51 Concolino P, Costella A, Capoluongo E. Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years. Cancer Genet 2016; 209: 36-41
- 52 Crabtree JS, Scacheri PC, Ward JM. et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci USA 2001; 98: 1118-1123
- 53 Harding B, Lemos MC, Reed AA. et al. Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia. Endocr Relat Cancer 2009; 16: 1313-1327
- 54 Drougat L, Espiard S, Bertherat J. Genetics of primary bilateral macronodular adrenal hyperplasia: A model for early diagnosis of Cushingʼs syndrome?. Eur J Endocrinol 2015; 173: M121-M131
- 55 Gatta-Cherifi B, Chabre O, Murat A. et al. Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe dʼetude des Tumeurs Endocrines database. Eur J Endocrinol 2012; 166: 269-279
- 56 Shuch B, Ricketts CJ, Vocke CD. et al. Adrenal nodular hyperplasia in hereditary leiomyomatosis and renal cell cancer. J Urol 2013; 189: 430-435
- 57 Assie G, Libe R, Espiard S. et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushingʼs syndrome. N Eng J Med 2013; 369: 2105-2114
- 58 Alencar GA, Lerario AM, Nishi MY. et al. ARMC5 Mutations are a frequent cause of primary macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2014; jc20134237
- 59 Faucz FR, Zilbermint M, Lodish MB. et al. Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) Gene: A clinical and genetic investigation. J Clin Endocrinol Metab 2014; 99: E1113-E1119
- 60 Espiard S, Drougat L, Libe R. ARMC5 mutations in a large cohort of primary macronodular adrenal hyperplasia: Clinical and functional consequences. J Clin Endocrinol Metab 2015; 100: E926-E935
- 61 Elbelt U, Trovato A, Kloth M. et al. Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma. J Clin Endocrinol Metab 2015; 100: E119-E128
- 62 Gagliardi L, Schreiber AW, Hahn CN. et al. Armc5 mutations are common in familial bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2014; jc20141265
- 63 Albiger NM, Regazzo D, Rubin B. et al. A multicenter experience on the prevalence of ARMC5 mutations in patients with primary bilateral macronodular adrenal hyperplasia: From genetic characterization to clinical phenotype. Endocrine 2017; 55: 959-968
- 64 Bourdeau I, Oble S, Magne F. et al. ARMC5 mutations in a large French-Canadian family with cortisol-secreting beta-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia. Eur J Endocrinol 2016; 174: 85-96
- 65 Correa R, Zilbermint M, Berthon A. et al. The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia. Eur J Endocrinol 2015; 173: 435-440
- 66 Yu L, Zhang J, Guo X. et al. ARMC5 mutations in familial and sporadic primary bilateral macronodular adrenal hyperplasia. PLoS One 2018; 13: e0191602
- 67 Berthon A, Hannah-Shmouni F, Maria AG. et al. High expression of adrenal P450 aromatase (CYP19A1) in association with ARMC5-primary bilateral macronodular adrenocortical hyperplasia. J Steroid Biochem Mol Biol 2019; 191: 105316
- 68 Gagliardi L, Schreiber AW, Hahn CN. et al. ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2014; 99: E1784-E1792
- 69 Rego T, Fonseca F, Espiard S. et al. ARMC5 mutation in a Portuguese family with primary bilateral macronodular adrenal hyperplasia (PBMAH). Endocrinol Diabetes Metab Case Rep 2017; pii 16-0135 DOI: 10.1530/EDM-16-0135.
- 70 Suzuki S, Tatsuno I, Oohara E. et al. Germline deletion of Armc5 in familial primary macronodular adrenal hyperplasia. Endocr Pract 2015; 21: 1152-1160
- 71 Cavalcante IP, Nishi M, Zerbini MCN. et al. The role of ARMC5 in human cell cultures from nodules of primary macronodular adrenocortical hyperplasia (PMAH). Mol Cell Endocrinol 2018; 460: 36-46
- 72 Berthon A, Faucz FR, Espiard S. et al. Age-dependent effects of Armc5 haploinsufficiency on adrenocortical function. Hum Mol Genet 2017; 26: 3495-3507
- 73 Hu Y, Lao L, Mao J. et al. Armc5 deletion causes developmental defects and compromises T-cell immune responses. Nat Commun 2017; 8: 13834
- 74 Thomas M, Keramidas M, Monchaux E. et al. Dual hormonal regulation of endocrine tissue mass and vasculature by adrenocorticotropin in the adrenal cortex. Endocrinology 2004; 145: 4320-4329
- 75 Bonnet-Serrano F, Bertherat J. Genetics of tumors of the adrenal cortex. Endocr Relat Cancer 2018; 25: R131-R152
- 76 Beuschlein F, Fassnacht M, Assie G. et al. Constitutive activation of PKA catalytic subunit in adrenal Cushingʼs syndrome. N Eng. J Med 2014; 370: 1019-1028
- 77 Lodish MB, Yuan B, Levy I. et al. Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: Molecular mechanisms and clinical presentations. Eur J Endocrinol 2015; 172: 803-811
- 78 Carney JA, Lyssikatos C, Lodish MB. et al. Germline PRKACA amplification leads to Cushing syndrome caused by 3 adrenocortical pathologic phenotypes. Hum Pathol 2015; 46: 40-49
- 79 Stratakis CA. E pluribus unum? The main protein kinase A catalytic subunit (PRKACA), a likely oncogene, and cortisol-producing tumors. J Clin Endocrinol Metab 2014; 99: 3629-3633
- 80 Collier LS, Suyama K, Anderson JH. et al. Drosophila Costal1 mutations are alleles of protein kinase A that modulate hedgehog signaling. Genetics 2004; 167: 783-796