Cushing's syndrome due to primary pigmented nodular adrenocortical disease
- André Lacroix, MD
André Lacroix, MD
- Section Editor — Adrenal Disease
- Professor of Medicine
- University of Montreal, Quebec, Canada
Among the causes of Cushing's syndrome are three rare types of nodular adrenocortical diseases that are usually bilateral:
●Corticotropin (ACTH)-dependent bilateral macronodular hyperplasia secondary to long-term adrenal stimulation in patients with Cushing's disease (pituitary ACTH-secreting tumor) or ectopic ACTH syndrome
●Primary bilateral macronodular adrenal hyperplasia (BMAH)
●ACTH-independent micronodular hyperplasia or dysplasia and its most frequent variant, primary pigmented nodular adrenocortical disease (PPNAD), which may be sporadic or familial (as part of the Carney complex [CNC])
PPNAD and other micronodular adrenocortical disease will be reviewed here. Cushing's disease and BMAH are discussed separately. (See "Causes and pathophysiology of Cushing's syndrome" and "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia".)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- 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.
- Horvath A, Mericq V, Stratakis CA. Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia. N Engl J Med 2008; 358:750.
- Carney JA, Young WF Jr. Primary pigmented nodular adrenocortical disease and its associated conditions. Endocrinologist 1992; 2:6.
- Larsen JL, Cathey WJ, Odell WD. Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing's syndrome. Case report and review of the literature. Am J Med 1986; 80:976.
- Young WF Jr, Carney JA, Musa BU, et al. Familial Cushing's syndrome due to primary pigmented nodular adrenocortical disease. Reinvestigation 50 years later. N Engl J Med 1989; 321:1659.
- Bertherat J, Horvath A, Groussin L, et al. Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab 2009; 94:2085.
- Ruder HJ, Loriaux DL, Lipsett MB. Severe osteopenia in young adults associated with Cushing's syndrome due to micronodular adrenal disease. J Clin Endocrinol Metab 1974; 39:1138.
- Carson DJ, Sloan JM, Cleland J, et al. Cyclical Cushing's syndrome presenting as short stature in a boy with recurrent atrial myxomas and freckled skin pigmentation. Clin Endocrinol (Oxf) 1988; 28:173.
- Gunther DF, Bourdeau I, Matyakhina L, et al. Cyclical Cushing syndrome presenting in infancy: an early form of primary pigmented nodular adrenocortical disease, or a new entity? J Clin Endocrinol Metab 2004; 89:3173.
- Braithwaite SS, Collins S, Prinz RA, et al. Decreased dehydroepiandrosterone sulfate in pigmented nodular adrenal dysplasia. Clin Chem 1989; 35:2216.
- Stratakis CA, Sarlis N, Kirschner LS, et al. Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med 1999; 131:585.
- Louiset E, Stratakis CA, Perraudin V, et al. The paradoxical increase in cortisol secretion induced by dexamethasone in primary pigmented nodular adrenocortical disease involves a glucocorticoid receptor-mediated effect of dexamethasone on protein kinase A catalytic subunits. J Clin Endocrinol Metab 2009; 94:2406.
- Bourdeau I, Lacroix A, Schürch W, et al. Primary pigmented nodular adrenocortical disease: paradoxical responses of cortisol secretion to dexamethasone occur in vitro and are associated with increased expression of the glucocorticoid receptor. J Clin Endocrinol Metab 2003; 88:3931.
- Louiset E, Gobet F, Libé R, et al. ACTH-independent Cushing's syndrome with bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma. J Clin Endocrinol Metab 2010; 95:18.
- Caticha O, Odell WD, Wilson DE, et al. Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia. J Clin Endocrinol Metab 1993; 77:494.
- Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985; 64:270.
- Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 2001; 86:4041.
- Doppman JL, Travis WD, Nieman L, et al. Cushing syndrome due to primary pigmented nodular adrenocortical disease: findings at CT and MR imaging. Radiology 1989; 172:415.
- Stratakis CA, Jenkins RB, Pras E, et al. Cytogenetic and microsatellite alterations in tumors from patients with the syndrome of myxomas, spotty skin pigmentation, and endocrine overactivity (Carney complex). J Clin Endocrinol Metab 1996; 81:3607.
- Stratakis CA, Courcoutsakis NA, Abati A, et al. Thyroid gland abnormalities in patients with the syndrome of spotty skin pigmentation, myxomas, endocrine overactivity, and schwannomas (Carney complex). J Clin Endocrinol Metab 1997; 82:2037.
- Almeida MQ, Stratakis CA. Carney complex and other conditions associated with micronodular adrenal hyperplasias. Best Pract Res Clin Endocrinol Metab 2010; 24:907.
- Anselmo J, Medeiros S, Carneiro V, et al. A large family with Carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer. J Clin Endocrinol Metab 2012; 97:351.
- Morin E, Mete O, Wasserman JD, et al. Carney complex with adrenal cortical carcinoma. J Clin Endocrinol Metab 2012; 97:E202.
- 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.
- 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.
- 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.
- Casey M, Vaughan CJ, He J, et al. Mutations in the protein kinase A R1alpha regulatory subunit cause familial cardiac myxomas and Carney complex. J Clin Invest 2000; 106:R31.
- Veugelers M, Wilkes D, Burton K, et al. Comparative PRKAR1A genotype-phenotype analyses in humans with Carney complex and prkar1a haploinsufficient mice. Proc Natl Acad Sci U S A 2004; 101:14222.
- Groussin L, Kirschner LS, Vincent-Dejean C, et al. Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet 2002; 71:1433.
- Nadella KS, Kirschner LS. Disruption of protein kinase a regulation causes immortalization and dysregulation of D-type cyclins. Cancer Res 2005; 65:10307.
- Groussin L, Horvath A, Jullian E, et al. A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds. J Clin Endocrinol Metab 2006; 91:1943.
- Pereira AM, Hes FJ, Horvath A, et al. Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families. J Clin Endocrinol Metab 2010; 95:338.
- Groussin L, Jullian E, Perlemoine K, et al. Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab 2002; 87:4324.
- D'Andrea MR, Qiu Y, Haynes-Johnson D, et al. Expression of PDE11A in normal and malignant human tissues. J Histochem Cytochem 2005; 53:895.
- Boikos SA, Horvath A, Heyerdahl S, et al. Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions. Horm Metab Res 2008; 40:347.
- Horvath A, Giatzakis C, Robinson-White A, et al. 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 2006; 66:11571.
- Libé R, Fratticci A, Coste J, et al. Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors. Clin Cancer Res 2008; 14:4016.
- Veugelers M, Bressan M, McDermott DA, et al. Mutation of perinatal myosin heavy chain associated with a Carney complex variant. N Engl J Med 2004; 351:460.
- Tadjine M, Lampron A, Ouadi L, et al. Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD). Clin Endocrinol (Oxf) 2008; 69:367.
- Gaujoux S, Tissier F, Groussin L, et al. Wnt/beta-catenin and 3',5'-cyclic adenosine 5'-monophosphate/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors. J Clin Endocrinol Metab 2008; 93:4135.
- Beuschlein F, Fassnacht M, Assié G, et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. N Engl J Med 2014; 370:1019.
- Bleasel NR, Stapleton KM. Carney complex: in a patient with multiple blue naevi and lentigines, suspect cardiac myxoma. Australas J Dermatol 1999; 40:158.
- Rockall AG, Babar SA, Sohaib SA, et al. CT and MR imaging of the adrenal glands in ACTH-independent cushing syndrome. Radiographics 2004; 24:435.
- Vezzosi D, Tenenbaum F, Cazabat L, et al. Hormonal, Radiological, NP-59 Scintigraphy, and Pathological Correlations in Patients With Cushing's Syndrome Due to Primary Pigmented Nodular Adrenocortical Disease (PPNAD). J Clin Endocrinol Metab 2015; 100:4332.
- Powell AC, Stratakis CA, Patronas NJ, et al. Operative management of Cushing syndrome secondary to micronodular adrenal hyperplasia. Surgery 2008; 143:750.
- Sarlis NJ, Chrousos GP, Doppman JL, et al. Primary pigmented nodular adrenocortical disease: reevaluation of a patient with carney complex 27 years after unilateral adrenalectomy. J Clin Endocrinol Metab 1997; 82:1274.
- CLINICAL PRESENTATION
- Sporadic or familial
- Cushing's syndrome
- Carney complex (CNC)
- Initial evaluation
- Adrenal imaging
- Sequential low-dose-high-dose dexamethasone suppression test (Liddle's test)
- Pharmacologic therapy
- SOCIETY GUIDELINE LINKS
- SUMMARY AND RECOMMENDATIONS