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Cushing syndrome due to primary pigmented nodular adrenocortical disease

Cushing syndrome due to primary pigmented nodular adrenocortical disease
Literature review current through: Jan 2024.
This topic last updated: Nov 30, 2023.

INTRODUCTION — Among the causes of Cushing 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 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 disease and BMAH are discussed separately. (See "Causes and pathophysiology of Cushing syndrome" and "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia".)

CLINICAL PRESENTATION — Primary pigmented nodular adrenocortical disease (PPNAD) is the most common form of corticotropin (ACTH)-independent micronodular hyperplasia or dysplasia. Other less frequent forms of bilateral hyperplasia in which the micronodules are not pigmented (so-called nonpigmented forms) are associated with phosphodiesterase 11A isoform 4 (PDE11A gene) [1] or phosphodiesterase 8B (PDE8B gene) [2] mutations.

Sporadic or familial — It may occur as a sporadic disorder (approximately 33 percent) or it may be familial (approximately 66 percent), either as part of Carney complex (CNC) or as isolated PPNAD. In one series of 88 patients with PPNAD, 40 occurred as part of CNC. (See 'Carney complex (CNC)' below.)

Cushing syndrome — PPNAD can cause Cushing syndrome. However, it is a rare disorder; among patients with Cushing syndrome, PPNAD is diagnosed in fewer than 1 percent. The hypercortisolism is due to multiple, pigmented, ACTH-independently functioning adrenocortical nodules. Patients with PPNAD may present with the typical signs and symptoms of hypercortisolism including weight gain, obesity, hypertension, and menstrual cycle disorders. A number of clinical features help characterize this disorder including:

Patients present at a young age: before age 30 years and before age 15 years in 50 percent of cases [3-6].

Sex and/or puberty modify the expression of Cushing syndrome in PPNAD: after adolescence, PPNAD is more common in females than males; by the age of 40 years, over 70 percent of female carriers of PRKAR1A defects develop PPNAD, compared with 45 percent of males [7].

Osteoporosis is a prominent feature [3], and avascular hip necrosis has been reported [8].

In many patients with PPNAD, the signs and symptoms of hypercortisolism are subtle and develop slowly over years [3]. In others, the hypercortisolism may be irregular [8] or cyclic [9,10], with either progressive or rapidly appearing Cushing habitus, followed by periods of remission. In patients with mild or periodic hypercortisolism, establishing the diagnosis of Cushing syndrome may be challenging, because plasma ACTH levels may be incompletely suppressed. (See 'Diagnosis' below and "Establishing the diagnosis of Cushing syndrome".)

In children with cyclic hypercortisolism, the typical growth failure observed with most children with Cushing syndrome may be absent.

Serum dehydroepiandrosterone sulfate concentrations are decreased in this as in other forms of ACTH-independent Cushing syndrome [11]. There is usually only poor stimulation of cortisol following stimulation with Cortrosyn [3].

A paradoxical increase in urinary free cortisol in response to dexamethasone (low dose (2 mg) and high-dose (8 mg) six-day dexamethasone suppression tests) has been observed in patients with PPNAD [12].

In one patient with transient Cushing syndrome during pregnancy and oral contraceptive use, cortisol secretion in PPNAD nodules was stimulated in vitro by estrogens [13].

Pathology — Histologically, most nodules are less than 4 mm, unencapsulated, but sharply demarcated from the adjacent atrophic cortex, which lacks the usual adrenal zonation [3,4,14-16]. The cells in the PPNAD nodules are large and globular with eosinophilic or clear cytoplasm; many of these cells contain coarsely granular brown pigment, identified as lipofuscin [3]. High synaptophysin expression in PPNAD nodules suggests a neuroendocrine phenotype of these cells [3,15,17]. The adrenal glands are normal or slightly enlarged and weigh between 4 and 17 grams [3].

Carney complex (CNC) — PPNAD may occur as part of Carney complex or syndrome, an autosomal dominantly inherited multiple neoplasia syndrome characterized by spotty skin pigmentation, endocrine tumors, and nonendocrine tumors (including atrial myxomas, cutaneous myxomas) (table 1). Definite diagnosis of CNC requires two or more major manifestations. A number of related clinical components may suggest the diagnosis of CNC, but are not considered diagnostic of the disease [9,11]. Diagnosis may also be made if one major criterion is present and a first-degree relative has CNC or an inactivating mutation of the gene encoding PKA regulatory 1-alpha subunit (PRKAR1A) [18]. (table 1)

Carney complex is reviewed in detail separately. (See "Carney complex".)

In the series of 88 patients with PPNAD noted above, 40 cases occurred as part of CNC [3]. Of these, 32 (80 percent) had pigmented skin lesions or cutaneous myxomas, 29 (72 percent) had one or more cardiac myxomas, and 18 (45 percent) had Cushing syndrome. Breast masses or testicular tumors were seen in 10 females (42 percent of the female patients) and nine males (56 percent of the male patients, respectively). Data from other studies suggest that two-thirds of the cases of CNC are familial, and although males and females are about equally affected, transmission occurs through an affected female in 80 percent of cases, perhaps in part because of decreased fertility caused by the Sertoli-cell tumors, which are found in one-third of affected males [15].

Overt Cushing syndrome caused by PPNAD occurs in 25 to 45 percent of all patients with the CNC; subclinical, atypical, or periodic Cushing syndrome occurs in others, and histological changes in the adrenal cortex are found at autopsy in almost every patient [3,15]. In other familial forms, micronodular hyperplasia or PPNAD and Cushing syndrome occur without any other features of CNC.

Heterogeneity in pathological and clinical features later became evident. In some patients with micronodular adrenal disease (MAD), no lipofuscin pigment was present in the nodules and the Cushing syndrome tended to manifest at an early age (two to seven years old). In most of these patients, MAD was isolated without other tumors or conditions; most patients were female and sporadic, but autosomal dominant inheritance was found in one kindred [1].

Two cases of adrenal carcinoma were reported in a patient with PPNAD by the PRKAR1A mutation [19] and in another with a PRKAR1 frame shift mutation resulting in a premature stop codon and a heterozygous p53 polymorphic [20]. Although it cannot be proven that the adrenal cancer was caused by the mutation, this observation has potential implications for counseling patients and families with CNC.

Patients with PPNAD who are diagnosed with CNC need annual monitoring with echocardiography for cardiac myxomas [15]. Additional baseline testing for testicular, thyroid, and breast tumors is also suggested [15].

GENETICS — Linkage analysis has isolated three genetic loci for the Carney complex (CNC), at 2p16 (CNC2), 17q22-24 (CNC1), and 17p12-13.1 [21,22]. To date, four responsible disease genes have been identified: protein kinase A regulatory 1-alpha subunit (PRKAR1A), phosphodiesterase 11A isoform 4 gene (PDE11A), phosphodiesterase 8B gene (PDE8B), and myosin heavy chain gene (MYH8).

PRKAR1A – In families with the CNC mapping to 17q22-24, heterozygous inactivating mutations have been identified in PRKAR1A, an apparent tumor suppressor gene that encodes the PRKAR1A [23,24]. In two series of patients with primary pigmented nodular adrenocortical disease (PPNAD) with CNC, 65 to 82 percent had PRKAR1A mutations [25,26]. In a third report of 353 cases with PPNAD or CNC, 73 percent carried 80 different PRKAR1A mutations, but this percentage was only 62 percent when analysis was restricted to index cases [7]. Patients with PRKAR1A mutations had more pigmented skin lesions, myxomas, thyroid and gonadal tumors with earlier onset of disease; PPNAD occurred more often in females while other tumors did not have sex predilection. Mutations occurring in exons were more often associated with acromegaly, myxomas, lentigines, and schwannomas. Patients with non-expressed PRKAR1A mutations had less severe disease.

These mutations code for a truncated protein that is not produced, and the loss of this protein leads to increased protein kinase A (PKA) activation by cyclic adenosine monophosphate (cAMP). In the mouse, knockout of PRKAR1A leads to up-regulation of D-type cyclins, suggesting a mechanism for tumorigenesis in the syndrome [27]. One mutation, a small intronic deletion of PRKAR1A, is associated with low penetrance and a mild phenotype (isolated PPNAD, but not the CNC) [28]. A mutation in the initiation codon of PRKAR1A, M1V, has also been associated with a mild phenotype (PPNAD only, with mild atypical Cushing syndrome) [29].

Inactivating germ-line mutations of PRKAR1A also appear to be common in sporadic and isolated cases of PPNAD [30].

PDE11A – Inactivating mutations in PDE11A located on chromosome 2q31-35, have been identified in three kindreds with non-pigmented micronodular hyperplasia without PPKAR1A mutations [1]. PDE11A is a dual-specificity phosphodiesterase (PDE) catalyzing the hydrolysis of both cAMP and cyclic guanosine monophosphate (cGMP); it is expressed in several endocrine tissues, but only the A4 splice variant is expressed in adrenal tissue [31,32]. Decreased PDE11A expression results in increased adrenocortical levels cAMP and cAMP-responsive element (CREB) phosphorylation presumably causing adrenal hyperplasia [32]. PDE11A-inactivating mutations have also been identified in the general population suggesting that these mutations may contribute to a predisposition to other tumors, in addition to their association with adrenocortical hyperplasias [33]. PDE11A was sequenced in 117 adrenocortical tumors and 192 control subjects: while missense germ line variants were present in 5.7 percent of controls it was found in 18.8 percent of adrenocortical tumors and were present in adrenocortical carcinomas, adenomas and bilateral macronodular adrenal hyperplasia (BMAH) cases [34].

PDE8B – In one kindred with nonpigmented micronodular adrenal disease (MAD), a single base substitution (c.914A>T or H305P) in PDE8B was identified in a young girl with Cushing syndrome; her father carried the same mutation and was found to have hypertension, abnormal midnight cortisol levels, and mild adrenal hyperplasia on computed tomography (CT) scan [2]. Transfection of the mutant PDE8B in cell lines produced increased cAMP levels, confirming the impaired ability of the mutant protein to degrade cAMP.

MYH8 – A variant of the CNC including atrial myxomas and distal arthrogryposis (multiple joint contractures), but no adrenal involvement, was described in a large family. Arthrogryposis manifested primarily as trismus and pseudocamptodactyly (contracture of the fourth and fifth fingers). In this family, the disease mapped to the 17p12-13.1 locus [35]. A mutation was identified in the perinatal MYH8 at this locus; this mutation was also identified in two families with isolated arthrogryposis without atrial myxomas.

B-catenin mutations – In addition to germ line PRKAR1A mutations, somatic beta-catenin mutations have been found in larger nodules of patients with PPNAD, suggesting that secondary events in the Wnt/beta-catenin signaling pathway can contribute to tumorigenesis in PPNAD [36,37]. No somatic mutations were found in the micronodules, but diffuse and focal nuclear accumulation of beta-catenin was present in nodules of all sizes as well as in the internodular atrophic adrenals.

In rare cases of PPNAD without previously identified mutations, germline duplications of the catalytic subunit of protein kinase A (PRKACA) gene have been found to increase adrenal tissue PKA activity and cause a PPNAD-like histology and clinical presentation [38].

DIAGNOSIS — Establishing the diagnosis of primary pigmented nodular adrenocortical disease (PPNAD) may be difficult, in particular when it occurs without other clinical manifestations (not as part of Carney complex [CNC]), or when there are no other affected family members. In addition, patients with PPNAD or micronodular adrenal disease (MAD) may have cyclic or episodic hypercortisolism, and radiologic imaging may be normal or show only subtle nodularity. However, the diagnostic steps are the same as for any patient with suspected Cushing syndrome, including confirming hypercortisolism, determining whether the hypercortisolism is corticotropin (ACTH)-dependent or ACTH-independent, and identifying the cause of the hypercortisolism.

Initial evaluation — The evaluation will differ when one is investigating family members of patients with PPNAD or CNC as compared with isolated cases. The first step in evaluation of sporadic cases is to confirm the presence of hypercortisolism. There are a number of available tests, including 24-hour urinary free cortisol excretion, 1 mg overnight dexamethasone suppression test, and evening salivary cortisol. Cortisol excretion should be unequivocally and reproducibly increased. (See "Establishing the diagnosis of Cushing syndrome".)

In members of families affected by PPNAD or other forms of micronodular disease, subclinical adrenal disease can be identified even in patients with normal urinary free cortisol levels by using dexamethasone suppression tests. In these patients, even subtle changes of cortisol secretion (ie, non-suppressibility with dexamethasone) are abnormal (plasma cortisol >1.8 mcg/dL [50 nmol/L] following Liddle's test). (See 'Sequential low-dose-high-dose dexamethasone suppression test (Liddle's test)' below.)

The second step is to determine whether the hypercortisolism is ACTH-dependent or independent by measuring plasma ACTH. A low plasma ACTH concentration [<5 pg/mL (1.1 pmol/L)] in a patient with a high serum cortisol concentration [>15 mcg/dL (415 nmol/L)] is evidence of ACTH-independent disease.

Adrenal imaging — In patients with ACTH-independent Cushing syndrome, adrenal computed tomography (CT) without contrast is the next diagnostic step to determine if the hypercortisolism is due to a unilateral adrenal tumor or to bilateral hyperplasia or nodular disease [39]. The appearance of the adrenal glands on imaging in patients with PPNAD is often initially interpreted as normal, which is different from other ACTH-independent disorders where relatively large tumors are seen [3,12,16]. In PPNAD, the overall size of the adrenal gland is often not enlarged, but instead is occupied by several small black or brown nodules spread in an otherwise atrophic cortex; this can be seen as a string of beads on thin-section high resolution CT scan (image 1).

This was illustrated in a series of 88 patients with proven PPNAD, 33 of whom had undergone adrenal imaging. The adrenals appeared normal in 45 percent and bilaterally enlarged in 27 percent [3]. A unilateral mass was seen in 15 percent and bilateral nodularity was seen in only 12 percent. Adrenal scintigraphy with iodine-131 (131-I)-labeled cholesterol (NP-59) was done in 18 patients, showing bilateral uptake in 16, unilateral uptake in one, and no uptake in one [3]. In a French cohort of 17 patients, adrenal CT scan findings varied with either normal adrenal, micro, or macronodules. NP-59 scintigraphy was particularly useful in identifying the bilateral nature of the disease, but more than half of the patients with PPNAD had asymmetrical adrenal uptake related to the presence of macronodules [40]. Of note, adrenal scintigraphy is not widely available in many countries presently.

In a review of 34 patients with micronodular adrenal hyperplasia/PPNAD who underwent surgery at a single institution, only nine (26 percent) had normal appearing adrenals on CT, while the majority was found to have some abnormality detected, mostly small, irregular micronodular hyperplasia or "beads-on-a-string" appearance [41].

Sequential low-dose-high-dose dexamethasone suppression test (Liddle's test) — One test that may distinguish patients with PPNAD from other primary adrenocortical lesions is the sequential low dose and high dose dexamethasone suppression test (Liddle's test), which is primarily used to distinguish hypercortisolism due to pituitary ACTH-producing adenomas from ectopic ACTH. In practice, patients with primary adrenal disease would already have been identified as having ACTH-independent Cushing syndrome and would not undergo this test. (See "Establishing the cause of Cushing syndrome".)

The test consists of 24-hour urine collections for the determination of cortisol excretion at baseline (two days), and during dexamethasone administration at doses of 0.5 mg every six hours for two days and 2 mg every six hours for another two days.

In contrast to the majority of patients with primary adrenocortical disease, who demonstrate no change in urinary cortisol, 69 to 75 percent of patients with PPNAD have a paradoxical rise in urinary cortisol excretion [12,42]. In the first study noted above, an increase of 50 percent or more in urinary free cortisol levels on day six of the Liddle's test identified 9 of 13 patients (69.2 percent) with primary pigmented nodular adrenocortical disease. In addition, it excluded all patients with macronodular adrenocortical disease, but was present in 3 of the 15 patients with single adrenocortical adenomas (20 percent). An increase in urinary free cortisol excretion of 100 percent or more on day six identified only patients with primary pigmented nodular adrenocortical disease.

Genetic testing — Given the rarity of this disorder, we suggest that patients with possible PPNAD or CNC (and their family members) undergo their diagnostic and genetic testing at a tertiary referral center with expertise in this area. In addition, patients with suspected CNC should undergo echocardiography to exclude the presence of cardiac myxomas, which may cause significant morbidity and mortality [43]

TREATMENT

Bilateral adrenalectomy — We recommend bilateral adrenalectomy in patients with either the sporadic or familial (Carney syndrome) form of bilateral micronodular adrenal hyperplasia with Cushing syndrome. This approach is uniformly effective since this disorder is a primary adrenal disease [3,14,41,44].

Adrenalectomy causes permanent adrenal insufficiency. However, unlike those with Cushing disease, patients with primary adrenocortical Cushing syndrome are not at risk for Nelson syndrome (corticotroph tumor progression), because the pituitary is intrinsically normal. Therefore, pituitary radiation to prevent Nelson syndrome is unnecessary. (See "Medical therapy of hypercortisolism (Cushing's syndrome)".)

Subtotal or unilateral adrenalectomy should not be performed, except in the very rare occurrence of a large unilateral functional adrenal nodule with contralateral normal-sized gland. In one patient who was reevaluated 27 years after unilateral adrenalectomy, the diurnal rhythm of serum cortisol was abnormal and clinical manifestations of cortisol excess were present [45]. Surgical adrenalectomy, including surgical approach and postoperative hormone replacement is discussed in greater detail separately.

Pharmacologic therapy — Medical treatment does not cure corticotropin (ACTH)-independent primary pigmented nodular adrenocortical disease (PPNAD). However, the adrenal enzyme inhibitors (ketoconazole or metyrapone), have been used to reduce cortisol secretion and improve the physical condition of patients with severe Cushing syndrome before adrenal surgery [41].

Unlike patients with Cushing disease, ACTH secretion will not increase and override the pharmacologic blockade if the pharmacologic blockade is incomplete. (See "Medical therapy of hypercortisolism (Cushing's syndrome)".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of Cushing syndrome".)

SUMMARY AND RECOMMENDATIONS

Primary pigmented nodular adrenocortical disease (PPNAD) is a corticotropin (ACTH)-independent disorder that results in Cushing syndrome. It is a rare disorder; among patients with Cushing syndrome, PPNAD is diagnosed in fewer than 1 percent. The hypercortisolism is due to multiple pigmented functioning adrenocortical nodules. It may occur as a sporadic disorder (33 percent), or it may be familial (66 percent), either as part of Carney complex (CNC) or as isolated PPNAD. (See 'Clinical presentation' above.)

Carney complex or syndrome is an autosomal dominantly inherited multiple neoplasia syndrome characterized by spotty pigmentation, endocrine tumors (most commonly PPNAD), and non-endocrine tumors (table 1). (See 'Carney complex (CNC)' above.)

Cushing syndrome in PPNAD presents at an unusually young age. In some patients, the hypercortisolism develops very slowly. In others, the hypercortisolism may be cyclic or irregular, with progressive or rapidly appearing Cushing habitus, followed by periods of remission. The diagnosis of Cushing syndrome may be challenging in some of these cases. (See 'Cushing syndrome' above.)

One test that may distinguish patients with PPNAD from other primary adrenocortical lesions is the sequential low dose and high dose dexamethasone suppression test (Liddle's test), as 69 to 75 percent of patients with PPNAD have a paradoxical rise in urinary cortisol excretion in response to dexamethasone. (See 'Sequential low-dose-high-dose dexamethasone suppression test (Liddle's test)' above.)

It is often difficult to distinguish patients with PPNAD from other ACTH-independent causes of Cushing syndrome. Adrenal imaging with computed tomography (CT) or magnetic resonance imaging (MRI) may be apparently normal in many cases as the overall adrenal size is often not enlarged. (See 'Adrenal imaging' above.)

In patients with PPNAD, screening for other tumors of the CNC should be performed. (See 'Carney complex (CNC)' above.)

Mutations of protein kinase A regulatory 1-alpha subunit (PRKAR1A) is the most frequent genetic cause of PPNAD, either familial forms with or without CNC or in sporadic forms. In the nonpigmented forms of micronodular hyperplasia, inactivating mutations in phosphodiesterase 11A isoform 4 gene (PDE11A) or of phosphodiesterase 8B gene (PDE8B) have also been identified. (See 'Genetics' above.)

We recommend bilateral adrenalectomy in patients with either the sporadic or familial (Carney syndrome) form of bilateral micronodular adrenal hyperplasia with Cushing syndrome (Grade 1B). (See 'Bilateral adrenalectomy' above.)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

  1. 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.
  2. Horvath A, Mericq V, Stratakis CA. Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia. N Engl J Med 2008; 358:750.
  3. Carney JA, Young WF Jr. Primary pigmented nodular adrenocortical disease and its associated conditions. Endocrinologist 1992; 2:6.
  4. 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.
  5. 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.
  6. Maillet M, Bourdeau I, Lacroix A. Update on primary micronodular bilateral adrenocortical diseases. Curr Opin Endocrinol Diabetes Obes 2020; 27:132.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. Braithwaite SS, Collins S, Prinz RA, et al. Decreased dehydroepiandrosterone sulfate in pigmented nodular adrenal dysplasia. Clin Chem 1989; 35:2216.
  12. 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.
  13. 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.
  14. Carney JA, Gordon H, Carpenter PC, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985; 64:270.
  15. 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.
  16. 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.
  17. 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.
  18. Almeida MQ, Stratakis CA. Carney complex and other conditions associated with micronodular adrenal hyperplasias. Best Pract Res Clin Endocrinol Metab 2010; 24:907.
  19. 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.
  20. Morin E, Mete O, Wasserman JD, et al. Carney complex with adrenal cortical carcinoma. J Clin Endocrinol Metab 2012; 97:E202.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. Nadella KS, Kirschner LS. Disruption of protein kinase a regulation causes immortalization and dysregulation of D-type cyclins. Cancer Res 2005; 65:10307.
  28. 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.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. Libé R, Fratticci A, Coste J, et al. Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors. Clin Cancer Res 2008; 14:4016.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. 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.
  41. Powell AC, Stratakis CA, Patronas NJ, et al. Operative management of Cushing syndrome secondary to micronodular adrenal hyperplasia. Surgery 2008; 143:750.
  42. 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.
  43. Bleasel NR, Stapleton KM. Carney complex: in a patient with multiple blue naevi and lentigines, suspect cardiac myxoma. Australas J Dermatol 1999; 40:158.
  44. Liu X, Zhang S, Guo Y, et al. Treatment of Primary Pigmented Nodular Adrenocortical Disease. Horm Metab Res 2022; 54:721.
  45. 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.
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