Cushing syndrome

Pituitary adenoma [DS:H01102]
Non-pituitary tumor
CRH-producing tumor
Adrenocortical tumor
McCane Albright
Birateral macronodular adrenal hyperplasia [DS:H02049]
Primary pigmented nodular adrenal disease [DS:H00260]

Cushing syndrome (CS) is a rare disorder resulting from prolonged exposure to excess glucocorticoids via exogenous and endogenous sources. The typical clinical features of CS are related to hypercortisolism and include accumulation of central fat, moon facies, neuromuscular weakness, osteoporosis or bone fractures, metabolic complications, and mood changes. Traditionally, endogenous CS is classified as adrenocorticotropic hormone (ACTH)-dependent (about 80%) or ACTH- independent (about 20%). Among ACTH-dependent forms, pituitary corticotroph adenoma (Cushing's disease) is most common. Most pituitary tumors are sporadic, resulting from monoclonal expansion of a single mutated cell. Recently recurrent activating somatic driver mutations in the ubiquitin-specific protease 8 gene (USP8) were identified in almost half of corticotroph adenoma. Germline mutations in MEN1 (encoding menin), AIP (encoding aryl-hydrocarbon receptor-interacting protein), PRKAR1A (encoding cAMP-dependent protein kinase type I alpha regulatory subunit) and CDKN1B (encoding cyclin-dependent kinase inhibitor 1B; also known as p27 Kip1) have been identified in familial forms of pituitary adenomas. However, the frequency of familial pituitary adenomas is less than 5% in patients with pituitary adenomas. Among ACTH-independent CS, adrenal adenoma is most common. Rare adrenal causes of CS include primary bilateral macronodular adrenal hyperplasia (BMAH) or primary pigmented nodular adrenocortical disease (PPNAD).

Endocrine and metabolic disease

nt06310  CRH-ACTH-cortisol signaling
nt06360  Cushing syndrome

MEN1 [HSA:4221] [KO:K14970]
CDKN1B [HSA:1027] [KO:K06624]
PRKAR1A [HSA:5573] [KO:K04739]
AIP [HSA:9049] [KO:K17767]
GPR101 [HSA:83550] [KO:K08423]
GNAS [HSA:2778] [KO:K04632]
USP8 [HSA:9101] [KO:K11839]
PIK3CA [HSA:5290] [KO:K00922]
DICER1 [HSA:23405] [KO:K11592]
RASD1 [HSA:51655] [KO:K07843]
ARMC5 [HSA:79798] [KO:K22499]
FH [HSA:2271] [KO:K01679]
PDE11A [HSA:50940] [KO:K13298]
APC [HSA:324] [KO:K02085]
MC2R [HSA:4158] [KO:K04200]
PRKACA [HSA:5566] [KO:K04345]
PRKAR1A [HSA:5573] [KO:K04739]
PDE11A [HSA:50940] [KO:K13298]
PDE8B [HSA:8622] [KO:K18437]

Pasireotide diaspartate [DR:D10497]
Pasireotide pamoate [DR:D10566]
Osilodrostat phosphate [DR:D11062]

PMID:26004339

Lacroix A, Feelders RA, Stratakis CA, Nieman LK

Cushing's syndrome.

Lancet 386:913-27 (2015)
DOI:10.1016/S0140-6736(14)61375-1

PMID:25350067

Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P

Genetic mutations in sporadic pituitary adenomas--what to screen for?

Nat Rev Endocrinol 11:43-54 (2015)
DOI:10.1038/nrendo.2014.181

PMID:28850717

Albani A, Theodoropoulou M, Reincke M

Genetics of Cushing's disease.

Clin Endocrinol (Oxf) 88:3-12 (2018)
DOI:10.1111/cen.13457

PMID:28487882

Uzilov AV, Cheesman KC, Fink MY, Newman LC, Pandya C, Lalazar Y, Hefti M, Fowkes M, Deikus G, Lau CY, Moe AS, Kinoshita Y, Kasai Y, Zweig M, Gupta A, Starcevic D, Mahajan M, Schadt EE, Post KD, Donovan MJ, Sebra R, Chen R, Geer EB

Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.

Cold Spring Harb Mol Case Stud 3:a001602 (2017)
DOI:10.1101/mcs.a001602