Table 1.

Causes of endogenous Cushing’s syndrome and their genetic bases

Origin	Lesion type	General molecular mechanisms	Clinical presentation	Known genetic causes
Cushing’s disease (60–70% of cases)	Corticotropinoma	Resistance to glucocorticoid negative feedback, cell cycle dysregulation, overexpression of membrane receptors (arginine-vasopressin receptors, epidermal growth factor receptor)	Sporadic Cushing’s disease, no associated manifestations	Somatic USP8 GOF hotspot mutations
				Somatic GNAS GOF mutations (codon 201 or 227)
				Somatic RASD1 LOF mutation
			Carney complex	Germline PRKAR1A LOF mutations/deletions, uncharacterized defect in 2p16, PRKACB amplification
			Familial isolated pituitary adenoma	Germline AIP LOF mutations/deletions, unknown genetic defect in 80% of cases
			Familial CD with very low penetrance?	Germline CABLES1 LOF mutations
			Multiple endocrine neoplasia type 1	Germline MEN1 LOF mutations/deletions
			Multiple endocrine neoplasia type 2	Germline RET LOF mutations/deletions
			Pheocromocytoma/paraganglioma and pituitary adenoma
			Multiple endocrine neoplasia type 4	Germline CDKN1B LOF mutations/deletions
			Tuberous sclerosis	Germline TSC1 or TSC2 LOF mutations
Ectopic ACTH secretion (5–10% of cases) and ectopic CRH secretion (very rare)	Medullary thyroid carcinoma	Production of ACTH or CRH by tumoral neuroendocrine tissue	Isolated medullary thyroid carcinoma	RET LOF mutations
			Multiple endocrine neoplasia type 2
	Other malignant neuroendocrine tumors (bronchial endocrine tumor, small cell lung cancer, others)		Isolated small cell lung cancer	Loss of 3p23-p21, somatic TP53 and RB1 LOF mutation, others
			Multiple endocrine neoplasia type 1	Germline MEN1 LOF mutations/deletions
	Benign neuroendocrine tumors (pheochromocytoma, others)		Multiple endocrine neoplasia type 2	Germline RET LOF mutations/deletions
			Neurofibromatosis type 1	Germline NF1 LOF mutations
			Von Hippel-Lindau disease	Germline VHL LOF mutations
			Isolated paraganglioma/pheochromocytoma	SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, MAX, TMEM127 LOF mutations
Adrenal (primary) (20–30% of cases)	Cortisol-producing adenoma	Overactivation of the cAMP and WNT/CTNNB1 pathways, overexpression of steroidogenic enzymes	Sporadic Cushing’s syndrome, no associated manifestations	Somatic PRKACA GOF hotspot mutations, somatic CTNNB1 LOF mutations
			Multiple endocrine neoplasia type 1	MEN1 LOF mutations/deletions
			Familial adenomatous polyposis and Gardner’s syndrome	Germline APC LOF mutations
	Primary multinodular adrenal hyperplasia (PMAH)	Ectopic GPCR and ACTH expression, overactivation of the cAMP and WNT/CTNNB1 pathways, overexpression of steroidogenic enzymes	Sporadic Cushing’s syndrome, no associated manifestations	Germline and somatic ARMC5 LOF mutations
				Somatic GIPR amplification
				Somatic MC2R mutations
				Germline PRKACA amplification
	Primary pigmented nodular adrenocortical disease (PPNAD)	Overactivation of the cAMP pathway	Sporadic Cushing’s syndrome, no associated manifestations (isolated PPNAD)	Germline PRKAR1A LOF mutations/deletions, uncharacterized defect in 2p16, germline PDE11A LOF mutations
			Carney complex	Germline PRKAR1A LOF mutations/deletions, uncharacterized defect in 2p16, PRKACB amplification
	Isolated micronodular adrenal disease (iMAD)		Sporadic Cushing’s syndrome, no associated manifestations	Germline PDE8B LOF mutation
				Germline PDE11A LOF mutations
				Germline PRKACA amplifications
	Primary bimorphic adrenocortical disease		McCune-Albright syndrome	Mosaic GNAS GOF mutation (codon 201)
	Adrenocortical carcinoma	Impaired TP53/RB1 signaling and chromatin remodeling, overactivation of the WNT/CTNNB1 pathway	Familial adenomatous polyposis	Germline APC LOF mutations
			Sporadic Cushing’s syndrome, no associated manifestations	Somatic ZNRF3, APC, CTNNB1, CDKN2A, CDK4, RB1, MDM2, TP53, MEN1, DAXX, and ATRX mutations
			Beckwith-Wiedemann syndrome	11p15.5 maternal rearrangements, paternal uniparental disomy, abnormal methylation, germline CDKN1C and WTX LOF mutations
			Li-Fraumeni syndrome	Germline TP53 LOF mutations
			Multiple endocrine neoplasia type 1	MEN1 LOF mutations/deletions
			Rubinstein-Taybi syndrome	Germline CREBBP or EP300 LOF mutations

See references in text. GOF, gain-of-function; GPCR, G protein-coupled receptor; LOF, loss-of-function.