Table 1.

Adrenocortical causes of cushing syndrome

Adrenocortical lesions	Age group	Histopathology	Genetics	Gene/locus
I. BENIGN
1. Common adenoma	all ages	adenoma of the zona fasciculata	MEN 1, FAP, MAS, HLRCS, CNC, Carney triad, other;	menin, APC, GNAS, FH, PRKAR1A; 2p16, 9q34, other;
2. Macronodular hyperplasias (multiple nodules more than 1 cm each)
Bilateral macro-adenomatous hyperplasia (BMAH	middle age	distinct adenomas (usually 2 or 3) with internodular atrophy	MEN 1, FAP, MAS, HLRCS, other; isolated (AD); other	menin, APC GNAS, FH, ectopic GPCRs
BMAH of childhood (c-BMAH)	infants, very young children	as above; occasional microadenomas	McCune-Albright syndrome (MAS)	GNAS
ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), also known as massive macronodular adrenocortical disease (MMAD) (AIMAH/MMAD)	middle age	Adenomatous hyperplasia (multiple) with internodular hyperplasia of the zona fasciculata	Isolated, AD	ectopic GPCRs; WISP-2 & Wnt-signaling; 17q22-24, other
3. Micronodular hyperplasias (multiple nodules less than 1 cm each)
Isolated primary pigmented nodular adrenocortical disease (i-PPNAD)	children; young adults	micro-adenomatous hyperplasia with (mostly) internodular atrophy and nodular pigment (lipofuscin)	Isolated; AD	PRKAR1A, PDE11A; 2p16; other
Carney complex (CNC) -associated primary pigmented nodular adrenocortical disease (c-PPNAD)	children; young and middle ages	micro-adenomatous hyperplasia with (mostly) internodular atrophy and (mainly nodular) pigment (lipofuscin)	CNC (AD)	PRKAR1A, 2p16; other
Isolated micro-nodular adrenocortical disease (i-MAD)	mostly children; young adults	micro-adenomatous with hyperplasia of the surrounding zona fasciculata and limited or absent pigment	isolated, AD; other;	PDE11A, other; 2p12-p16, 5q, other
II. MALIGNANT
1. Cancer (sporadic)	all ages	mitotic figures, atypia of cortical cells; capsular invasion; metastases	isolated	TP53, β-catenin, INHA; 2p, 2q, 9q, 11q, other
2. Cancer (syndromic)	children; young adults	as above	LFS (AD); BWS, RTS, other	TP53, CHK22, IGF2, other
3. Brazil variant	children; young adults	as above; milder clinical course	AD; other	TP53, INHA, SF1; 9q34 amplification; other

^*Abbreviations: MEN 1=multiple endocrine neoplasia type 1; FAP=familial adenomatous polyposis (polyposis coli); MAS=McCune-Albright syndrome; HLRCS=hereditary leiomyomatosis and renal cancer syndrome; FH=fumarate hydratase; AD=autosomal dominant; CNC=Carney complex; GPCR=G-protein coupled receptors; LFS=Li-Fraumeni syndrome; BWS=Beckwith-Widemann syndrome; RTS=Rubinstein-Taybi syndrome