Table 2.

Comparison between macronodular and micronodular bilateral adrenocortical hyperplasia.

	Macronodular Bilateral Adrenocortical Hyperplasia	Micronodular Bilateral Adrenocortical Hyperplasia
Size	Bilateral benign adrenal macronodules >1 cm.	Bilateral adrenal nodules <1 cm in diameter. Primary pigmented nodular adrenal disease is the most frequent form.
Cortisol secretion degree/clinical presentation	Associated with variable degree of cortisol excess. Responsible for less than 2% of all cases of Cushing’s syndrome.	Clinically overt cortisol excess (Cushing’s syndrome).
Age of onset	Late median age in sporadic cases (around 55 years).	Diagnosis is often made before the age of 30 years, with 50% of patients being less than 15 years.
Syndromic cases	Rarely may be part of hereditary familial tumor syndromes including multiple endocrine neoplasia type 1 (MEN1), familial adenomatous polyposis (APC) and hereditary leiomyomatosis and renal cell cancer syndrome (fumarate hydrogenase, FH).	Primary pigmented nodular adrenal disease can be the presenting manifestation of Carney complex (PRKAR1A mutations).
Familial cases	Related to germline mutations of the Armadillo Repeat Containing 5 (ARMC5). A mutation of ARMC5 gene is found in around 20–25% of all bilateral macronodular adrenocortical hyperplasia cases (40% in patients with overt Cushing’s syndrome and 11% in patients with mHC).	Isolated micronodular bilateral adrenocortical hyperplasia can be related to germline PRKA1RA mutation (c.709-7del6 is the most frequent form).
Sporadic cases	Cortisol secretion is in part regulated by the expression of multiple aberrant G protein-coupled receptors (GPCRs). Many of these aberrant receptors stimulate the cAMP/PKA pathway, as does ACTH in normal adrenals.	Micronodular bilateral adrenocortical hyperplasia can be sporadic or familial.