Abstract
Adrenocortical causes of Cushing's syndrome include the following: common cortisol-producing adenomas, which are usually isolated (without associated tumors) and sporadic (without a family history); rare, but often clinically devastating, adrenocortical carcinomas; and a spectrum of adrenocorticotropin-independent, and almost always bilateral, hyperplasias, which are not rare, and are the most recently recognized cause. The majority of benign lesions of the adrenal cortex seem to be linked to abnormalities of the cyclic AMP signaling pathway, whereas cancer is linked to aberrant expression of insulin-like growth factor II, tumor protein p53 and related molecules. In this article, we propose a new clinical classification and nomenclature for the various forms of adrenocorticotropin-independent adrenocortical hyperplasias that is based on their histologic and genetic features. We also review the molecular genetics of adrenocortical tumors, including recent discoveries relating to the role of phosphodiesterase 11A. This is a timely Review because of recent advances in the clinical and molecular understanding of these diseases.
Key Points
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Hyperplasias cause Cushing's syndrome more frequently than was previously thought, and they include an expanding list of diverse diseases
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The WNT (wingless-type MMTV integration site family) pathway is an important molecular pathway involved in both adrenocortical development and tumor formation
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Inhibin A and tumor protein p53 (the products of the INHA and TP53 genes, respectively) are involved in the formation of malignant adrenocortical tumors
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An overactive cyclic AMP signaling pathway is involved in most adrenocortical hyperplasias and occasionally in sporadic adenomas
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Insulin-like growth factor II mediates the most important signaling pathway in adrenal cancer
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Genetic defects of phosphodiesterases might be a frequent cause of adrenal and, possibly, other tumors
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References
Stratakis CA and Kirschner LS (1998) Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm Metab Res 30: 456–463
Grumbach MM et al. (2003) Management of the clinically inapparent adrenal mass (“incidentaloma”). Ann Intern Med 138: 424–429
Stratakis CA (2003) Genetics of adrenocortical tumors: gatekeepers, landscapers and conductors in symphony. Trends Endocrinol Metab 14: 404–410
Lack EE (1997) Tumors of the adrenal gland and extra-adrenal paraganglia. In Atlas of Tumor Pathology, 3rd series, fascicle 19, 184–187 (Eds Saenger W et al.) Washington, DC: Armed Forces Institute of Pathology
Mochizuki Y et al. (1995) The difference in autofluorescence features of lipofuscin between brain and adrenal. Zoolog Sci 12: 283–288
Gunther DF et al. (2004) Cyclical Cushing syndrome presenting in infancy: an early form of primary pigmented nodular adrenocortical disease, or a new entity? J Clin Endocrinol Metab 89: 3173–3182
Schteingart DE (2001) Current perspective in the diagnosis and treatment of adrenocortical carcinoma. Rev Endocr Metab Disord 2: 323–333
Wajchenberg BL et al. (2000) Adrenocortical carcinoma: clinical and laboratory observations. Cancer 88: 711–736
Lee SB and Haber DA (2001) Wilms tumor and the WT1 gene. Exp Cell Res 264: 74–99
Kreidberg JA et al. (1993) WT-1 is required for early kidney development. Cell 74: 679–691
Heikkila M et al. (2002) Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology 143: 4358–4365
Suwa T et al. (2003) Zonal expression of dickkopf-3 and components of the Wnt signalling pathways in the human adrenal cortex. J Endocrinol 178: 149–158
Horvath A et al. (2006) Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation. J Clin Endocrinol Metab 91: 584–596
Rainey WE et al. (2001) Gene profiling of human fetal and adult adrenals. J Endocrinol 171: 209–215
Bourdeau I et al. (2004) Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators. Oncogene 23: 1575–1585
Giordano TJ et al. (2003) Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am J Pathol 162: 521–531
de Fraipont F et al. (2005) Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic acid microarrays identifies several candidate genes as markers of malignancy. J Clin Endocrinol Metab 90: 1819–1829
West AN et al. (2007) Gene expression profiling of childhood adrenocortical tumors. Cancer Res 67: 600–608
Bornstein SR and Hornsby PJ (2005) What can we learn from gene expression profiling for adrenal tumor management? J Clin Endocrinol Metab 90: 1900–1902
Tissier F et al. (2005) Mutations of β-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 65: 7622–7627
Bourdeau I et al. (2005) Mutations and interstitial deletions involving exon 3 of the β-catenin gene are detected in sporadic adrenocortical tumors. Presented at the 55th Annual Meeting of the American Society of Human Genetics: 2005 October 26–29; Salt Lake City, UT
Hammer GD et al. (2005) Transcriptional regulation of adrenocortical development. Endocrinology 146: 1018–1024
Matzuk MM et al. (1996) Transgenic models to study the roles of inhibins and activins in reproduction, oncogenesis, and development. Recent Prog Horm Res 51: 123–154
Matzuk MM et al. (1994) Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. Proc Natl Acad Sci USA 91: 8817–8821
Kananen K et al. (1996) Gonadectomy permits adrenocortical tumorigenesis in mice transgenic for the mouse inhibin α-subunit promoter/simian virus 40 T-antigen fusion gene: evidence for negative autoregulation of the inhibin α-subunit gene. Mol Endocrinol 10: 1667–1677
Hofland J et al. (2006) Expression of activin and inhibin subunits, receptors and binding proteins in human adrenocortical neoplasms. Clin Endocrinol (Oxf) 65: 792–799
Longui CA et al. (2004) Inhibin a-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers. J Med Genet 41: 354–359
Stratakis CA and Bossis I (2004) Genetics of the adrenal gland. Rev Endocr Metab Disord 5: 53–68
Figueiredo BC et al. (1999) Comparative genomic hybridization analysis of adrenocortical tumors of childhood. J Clin Endocrinol Metab 84: 1116–1121
Figueiredo BC et al. (2005) Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors. J Clin Endocrinol Metab 90: 615–619
Merke DP and Stratakis CA (2006) The adrenal life cycle: the fetal and adult cortex and the remaining questions. J Pediatr Endocrinol Metab 19: 1299–1302
Clark AJ and Metherell LA (2006) Mechanisms of disease: the adrenocorticotropin receptor and disease. Nat Clin Pract Endocrinol Metab 2: 282–290
Swords FM et al. (2002) Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity. Mol Endocrinol 16: 2746–2753
Boston BA et al. (1994) Activating mutation in the stimulatory guanine nucleotide-binding protein in an infant with Cushing's syndrome and nodular adrenal hyperplasia. J Clin Endocrinol Metab 79: 890–893
Fragoso MC et al. (2003) Cushing's syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene. J Clin Endocrinol Metab 88: 2147–2151
Bourdeau I and Stratakis CA (2002) Cyclic AMP-dependent signaling aberrations in macronodular adrenal disease. Ann NY Acad Sci 968: 240–255
Stratakis CA (2002) Mutations of the gene encoding the protein kinase A type I-α regulatory subunit (PRKAR1A) in patients with the “complex of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas” (Carney complex). Ann NY Acad Sci 968: 3–21
Bertherat J et al. (2003) 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 63: 5308–5319
Lacroix A et al. (1992) Gastric inhibitory polypeptide-dependent cortisol hypersecretion—a new cause of Cushing's syndrome. N Engl J Med 327: 974–980
Lacroix A et al. (2001) Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome. Endocr Rev 22: 75–110
Groussin L et al. (2002) The ectopic expression of the gastric inhibitory polypeptide receptor is frequent in adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia, but rare in unilateral tumors. J Clin Endocrinol Metab 87: 1980–1985
Louiset E et al. (2006) Expression of serotonin 7 receptor and coupling of ectopic receptors to protein kinase A and ionic currents in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome. J Clin Endocrinol Metab 91: 4578–4586
Vezzosi D et al. (2007) Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors. Eur J Endocrinol 156: 21–31
Mazzuco TL et al. (2007) Aberrant GPCR expression is a sufficient genetic event to trigger adrenocortical tumorigenesis. Mol Cell Endocrinol 265–266: 23–28
Mazzuco TL et al. (2006) Aberrant expression of human luteinizing hormone receptor by adrenocortical cells is sufficient to provoke both hyperplasia and Cushing's syndrome features. J Clin Endocrinol Metab 91: 196–203
White PC (1994) Genetic diseases of steroid metabolism. Vitam Horm 49: 131–195
Pang S et al. (1981) Adrenocortical tumor in a patient with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 68: 242–246
Lack EE and Travis WD (1995) Diagnostic problems in surgical pathology of the adrenal glands. Mod Pathol 8: 312–332
Libe R and Bertherat J (2005) Molecular genetics of adrenocortical tumours, from familial to sporadic diseases. Eur J Endocrinol 153: 477–487
Shi Z et al. (2007) Primary pigmented nodular adrenocortical disease reveals insulin-like growth factor binding protein-2 regulation by protein kinase A. Growth Horm IGF Res 17: 113–121
Baker J et al. (1993) Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75: 73–82
Hertel NT et al. (2003) Late relapse of adrenocortical carcinoma in Beckwith–Wiedemann syndrome. Clinical, endocrinological and genetic aspects. Acta Paediatr 92: 439–443
Matyakhina L et al. (2005) Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical Cushing syndrome: a clinical and molecular genetic investigation. J Clin Endocrinol Metab 90: 3773–3779
Varley JM (2003) Germline TP53 mutations and Li–Fraumeni syndrome. Hum Mutat 21: 313–320
Ribeiro RC et al. (2001) An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 98: 9330–9335
DiGiammarino EL et al. (2002) A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol 9: 12–16
Vahteristo P et al. (2001) p53, CHK2, and CHK1 genes in Finnish families with Li–Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res 61: 5718–5722
Kirschner LS et al. (2000) Mutations of the gene encoding the protein kinase A type I-α regulatory subunit in patients with the Carney complex. Nat Genet 26: 89–92
Stratakis CA et al. (2001) Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 86: 4041–4046
Groussin L et al. (2002) Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab 87: 4324–4329
Kirschner LS et al. (2000) Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex. Hum Mol Genet 9: 3037–3046
Horvath A et al. (2006) A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet 38: 794–800
Loughney K et al. (2005) 3′, 5′-cyclic nucleotide phosphodiesterase 11A: localization in human tissues. Int J Impot Res 17: 320–325
D'Andrea MR et al. (2005) Expression of PDE11A in normal and malignant human tissues. J Histochem Cytochem 53: 895–903
Yuasa K et al. (2001) Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains. Eur J Biochem 268: 168–178
Horvath A et al. (2006) Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population. Cancer Res 66: 11571–11575
Kawamura M et al. (2002) Phyllodulcin, a constituent of “Amacha”, inhibits phosphodiesterase in bovine adrenocortical cells. Pharmacol Toxicol 90: 106–108
Young WF Jr (2007) Clinical practice. The incidentally discovered adrenal mass. N Engl J Med 356: 601–610
Acknowledgements
This work was supported by the National Institute of Child Health and Human Development (NICHD), National Institutes for Health (NIH) intramural project Z01-HD-000642-04 to CA Stratakis and NICHD clinical protocols 95CH0059 and 00CH160. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.
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Stratakis, C., Boikos, S. Genetics of adrenal tumors associated with Cushing's syndrome: a new classification for bilateral adrenocortical hyperplasias. Nat Rev Endocrinol 3, 748–757 (2007). https://doi.org/10.1038/ncpendmet0648
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DOI: https://doi.org/10.1038/ncpendmet0648
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