| H01431 | |
| H number | H01431 |
| Name | Cushing syndrome |
| Description | 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). |
| Category | Endocrine and metabolic disease DIS_PATHWAY hsa04934 Cushing syndrome |
| Network | nt06310 CRH-ACTH-cortisol signaling nt06360 Cushing syndrome |
| Gene | (MEN1) MEN1 [HSA:4221] [KO:K14970] (MEN4) CDKN1B [HSA:1027] [KO:K06624] (CNC1) PRKAR1A [HSA:5573] [KO:K04739] (PITA1) AIP [HSA:9049] [KO:K17767] (PITA2) GPR101 [HSA:83550] [KO:K08423] (PITA3) GNAS [HSA:2778] [KO:K04632] (PITA4) USP8 [HSA:9101] [KO:K11839] (PITA5) CDH23 [HSA:64072] [KO:K06813] (AIMAH2) ARMC5 [HSA:79798] [KO:K22499] (PPNAD1) PRKAR1A [HSA:5573] [KO:K04739] (PPNAD2) PDE11A [HSA:50940] [KO:K13298] (PPNAD3) PDE8B [HSA:8622] [KO:K18437] (PPNAD4) PRKACA [HSA:5566] [KO:K04345] RASD1 [HSA:51655] [KO:K07843] |
| Pathogen | - |
| Env factor | - |
| Carcinogen | - |
| Drug | Pasireotide diaspartate [DR:D10497] Pasireotide pamoate [DR:D10566] Osilodrostat phosphate [DR:D11062] Levoketoconazole [DR:D10950] |
| Comment | - |
| Other DBs | ICD-11: 5A70 ICD-10: E24 MeSH: D003480 OMIM: 131100 610755 160980 102200 300943 617686 219090 617540 219080 615954 610489 610475 614190 615830 |
| Reference | PMID:26004339 AUTHORS Lacroix A, Feelders RA, Stratakis CA, Nieman LK TITLE Cushing's syndrome. JOURNAL Lancet 386:913-27 (2015) DOI:10.1016/S0140-6736(14)61375-1 PMID:25350067 AUTHORS Lecoq AL, Kamenicky P, Guiochon-Mantel A, Chanson P TITLE Genetic mutations in sporadic pituitary adenomas--what to screen for? JOURNAL Nat Rev Endocrinol 11:43-54 (2015) DOI:10.1038/nrendo.2014.181 PMID:28850717 AUTHORS Albani A, Theodoropoulou M, Reincke M TITLE Genetics of Cushing's disease. JOURNAL Clin Endocrinol (Oxf) 88:3-12 (2018) DOI:10.1111/cen.13457 PMID:12791038 (MEN1) AUTHORS Park JH, Kim IJ, Kang HC, Lee SH, Shin Y, Kim KH, Lim SB, Kang SB, Lee K, Kim SY, Lee MS, Lee MK, Park JH, Moon SD, Park JG TITLE Germline mutations of the MEN1 gene in Korean families with multiple endocrine neoplasia type 1 (MEN1) or MEN1-related disorders. JOURNAL Clin Genet 64:48-53 (2003) DOI:10.1034/j.1399-0004.2003.00091.x PMID:17030811 (CDKN1B) AUTHORS Pellegata NS, Quintanilla-Martinez L, Siggelkow H, Samson E, Bink K, Hofler H, Fend F, Graw J, Atkinson MJ TITLE Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. JOURNAL Proc Natl Acad Sci U S A 103:15558-63 (2006) DOI:10.1073/pnas.0603877103 PMID:12812976 (PRKAR1A) AUTHORS Robinson-White A, Hundley TR, Shiferaw M, Bertherat J, Sandrini F, Stratakis CA TITLE Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2. JOURNAL Hum Mol Genet 12:1475-84 (2003) DOI:10.1093/hmg/ddg160 PMID:16728643 (AIP) AUTHORS Vierimaa O, Georgitsi M, Lehtonen R, Vahteristo P, Kokko A, Raitila A, Tuppurainen K, Ebeling TM, Salmela PI, Paschke R, Gundogdu S, De Menis E, Makinen MJ, Launonen V, Karhu A, Aaltonen LA TITLE Pituitary adenoma predisposition caused by germline mutations in the AIP gene. JOURNAL Science 312:1228-30 (2006) DOI:10.1126/science.1126100 PMID:25470569 (GPR101) AUTHORS Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH, Castermans E, Villa C, Dimopoulos A, Chittiboina P, Xekouki P, Shah N, Metzger D, Lysy PA, Ferrante E, Strebkova N, Mazerkina N, Zatelli MC, Lodish M, Horvath A, de Alexandre RB, Manning AD, Levy I, Keil MF, Sierra Mde L, Palmeira L, Coppieters W, Georges M, Naves LA, Jamar M, Bours V, Wu TJ, Choong CS, Bertherat J, Chanson P, Kamenicky P, Farrell WE, Barlier A, Quezado M, Bjelobaba I, Stojilkovic SS, Wess J, Costanzi S, Liu P, Lupski JR, Beckers A, Stratakis CA TITLE Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. JOURNAL N Engl J Med 371:2363-74 (2014) DOI:10.1056/NEJMoa1408028 PMID:7737262 (GNAS) AUTHORS Williamson EA, Ince PG, Harrison D, Kendall-Taylor P, Harris PE TITLE G-protein mutations in human pituitary adrenocorticotrophic hormone-secreting adenomas. JOURNAL Eur J Clin Invest 25:128-31 (1995) DOI:10.1111/j.1365-2362.1995.tb01537.x PMID:25485838 (USP8) AUTHORS Reincke M, Sbiera S, Hayakawa A, Theodoropoulou M, Osswald A, Beuschlein F, Meitinger T, Mizuno-Yamasaki E, Kawaguchi K, Saeki Y, Tanaka K, Wieland T, Graf E, Saeger W, Ronchi CL, Allolio B, Buchfelder M, Strom TM, Fassnacht M, Komada M TITLE Mutations in the deubiquitinase gene USP8 cause Cushing's disease. JOURNAL Nat Genet 47:31-8 (2015) DOI:10.1038/ng.3166 PMID:28413019 (CDH23) AUTHORS Zhang Q, Peng C, Song J, Zhang Y, Chen J, Song Z, Shou X, Ma Z, Peng H, Jian X, He W, Ye Z, Li Z, Wang Y, Ye H, Zhang Z, Shen M, Tang F, Chen H, Shi Z, Chen C, Chen Z, Shen Y, Wang Y, Lu S, Zhang J, Li Y, Li S, Mao Y, Zhou L, Yan H, Shi Y, Huang C, Zhao Y TITLE Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas. JOURNAL Am J Hum Genet 100:817-823 (2017) DOI:10.1016/j.ajhg.2017.03.011 PMID:24601692 (ARMC5) AUTHORS Faucz FR, Zilbermint M, Lodish MB, Szarek E, Trivellin G, Sinaii N, Berthon A, Libe R, Assie G, Espiard S, Drougat L, Ragazzon B, Bertherat J, Stratakis CA TITLE Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation. JOURNAL J Clin Endocrinol Metab 99:E1113-9 (2014) DOI:10.1210/jc.2013-4280 PMID:12213893 (PRKAR1A) AUTHORS Groussin L, Jullian E, Perlemoine K, Louvel A, Leheup B, Luton JP, Bertagna X, Bertherat J TITLE Mutations of the PRKAR1A gene in Cushing's syndrome due to sporadic primary pigmented nodular adrenocortical disease. JOURNAL J Clin Endocrinol Metab 87:4324-9 (2002) DOI:10.1210/jc.2002-020592 PMID:16767104 (PDE11A) AUTHORS Horvath A, Boikos S, Giatzakis C, Robinson-White A, Groussin L, Griffin KJ, Stein E, Levine E, Delimpasi G, Hsiao HP, Keil M, Heyerdahl S, Matyakhina L, Libe R, Fratticci A, Kirschner LS, Cramer K, Gaillard RC, Bertagna X, Carney JA, Bertherat J, Bossis I, Stratakis CA TITLE A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. JOURNAL Nat Genet 38:794-800 (2006) DOI:10.1038/ng1809 PMID:18272904 (PDE8B) AUTHORS Horvath A, Mericq V, Stratakis CA TITLE Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia. JOURNAL N Engl J Med 358:750-2 (2008) DOI:10.1056/NEJMc0706182 PMID:24571724 (PRKACA) AUTHORS Beuschlein F, Fassnacht M, Assie G, Calebiro D, Stratakis CA, Osswald A, Ronchi CL, Wieland T, Sbiera S, Faucz FR, Schaak K, Schmittfull A, Schwarzmayr T, Barreau O, Vezzosi D, Rizk-Rabin M, Zabel U, Szarek E, Salpea P, Forlino A, Vetro A, Zuffardi O, Kisker C, Diener S, Meitinger T, Lohse MJ, Reincke M, Bertherat J, Strom TM, Allolio B TITLE Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome. JOURNAL N Engl J Med 370:1019-28 (2014) DOI:10.1056/NEJMoa1310359 PMID:28487882 (RASD1) AUTHORS 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 TITLE Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma. JOURNAL Cold Spring Harb Mol Case Stud 3:a001602 (2017) DOI:10.1101/mcs.a001602 |