Genetic basis of Cushing’s disease in children and targeted therapeutic future perspectives
https://doi.org/10.14341/probl12676
Abstract
Cushing’s disease (CD) is a multisystem disorder of a cortisol excess caused by ACTH -secreting pituitary tumor (corticotropinoma). CD in children is due to somatic or germline mutations with the late onset causing multiple endocrine tumors. If not treated, hypercortisolism leads to severe decrease in quality of life and life-threating conditions. The first-line treatment for CD is pituitary surgery, which might be followed by complications and relapse with necessity of additional surgery or initiations of second-line treatment. Recent studies of molecular basis of corticotropinoma development made it possible to employ medical therapy in CD. Understanding of corticotropinoma etiology and pathogenesis is an important part of education for pediatric endocrinologists since we need to keep in mind possibility of multisystem disorder in case of CD in children and because medical therapy might gain more important role for CD treatment in future.
The most actual genetic aspects of corticotroph adenomas growth and the medical treatment opportunities are present in this review.
About the Authors
E. A. Yanar
Endocrinology Research Centre
Russian Federation
Competing Interests: No
Russian Federation
Eda A. Yanar.
11 Dm. Ulyanova street, 117036 Moscow.
eLibrary SPIN: 3104-6767
Competing Interests: No
N. V. Makazan
Endocrinology Research Centre
Russian Federation
Competing Interests: No
Russian Federation
Nadezhda V. Makazan - MD, PhD.
11 Dm. Ulyanova street, 117036 Moscow.
eLibrary SPIN: 7156-6517
Competing Interests: No
E. M. Orlova
Endocrinology Research Centre
Russian Federation
Competing Interests: No
Russian Federation
Elizaveta M. Orlova - MD, Associate Professor.
11 Dm. Ulyanova street, 117036 Moscow.
eLibrary SPIN: 5221-4235
Competing Interests: No
M. А. Kareva
Endocrinology Research Centre
Russian Federation
Competing Interests: No
Russian Federation
Maria A. Kareva – MD.
11 Dm. Ulyanova street, 117036 Moscow.
eLibrary SPIN: 5089-0310
Competing Interests: No
References
1. Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;7:281-293. Published 2015 Apr 17. doi: 10.2147/CLEP.S44336
2. Stratakis CA. An update on Cushing syndrome in pediatrics. Ann Endocrinol (Paris). 2018;79(3):125-131. doi: 10.1016/j.ando.2018.03.010
3. Storr HL, Savage MO. Management of endocrine disease: Paediatric Cushing’s disease. Eur J Endocrinol. 2015;173(1):R35-R45. doi: 10.1530/EJE-15-0013
4. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing’s Disease. Endocr Rev. 2015;36(4):385-486. doi: 10.1210/er.2013-1048
5. Lapshlna AM, Abrosimov AYu, Marova YI. The clinical and morphofunctional characteristics of adrenocorticotropic hormone-producing tumors. Problems of Endocrinology. 2008;54(4):49-54. (In Russ.). doi: 10.14341/probl200854449-54.
6. Maira M, Couture C, Le Martelot G, et al. The T-box factor Tpit recruits SRC/p160 co-activators and mediates hormone action. J Biol Chem. 2003;278(47):46523-32. doi: 10.1074/jbc.m305626200.
7. Du L, Bergsneider M, Mirsadraei L, et al. Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease. Proceedings of the National Academy of Sciences of the United States of America. 2013 May;110(21):8555-8560. doi: 10.1073/pnas.1306182110.
8. Kirschke E, Goswami D, Southworth D, et al. Glucocorticoid receptor function regulated by coordinated action of the Hsp90 and Hsp70 chaperone cycles. Cell. 2014;157(7):1685-1697. doi: 10.1016/j.cell.2014.04.038
9. Bilodeau S, Vallette-Kasic S, Gauthier Y, et al. Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. Genes Dev. 2006;20(20):2871-2886. doi: 10.1101/gad.1444606.
10. Albani A, Theodoropoulou M, Reincke M. Genetics of Cushing’s disease. Clin Endocrinol (Oxf). 2018;88(1):3-12. doi: 10.1111/cen.13457
11. Tritos NA, Biller BMK. Medical Management of Cushing Disease. Neurosurg Clin N Am. 2019;30(4):499-508. doi: 10.1016/j.nec.2019.05.007
12. Herman V, Fagin J, Gonsky R, et al. Clonal origin of pituitary adenomas. J Clin Endocrinol Metab. 1990;71(6):1427-1433. doi: 10.1210/jcem-71-6-1427
13. Hernández-Ramírez LC, Stratakis CA. Genetics of Cushing’s Syndrome. Endocrinol Metab Clin North Am. 2018;47(2):275-297. doi: 10.1016/j.ecl.2018.02.007
14. Huizenga NA, de Lange P, Koper JW, et al. Human adrenocorticotropin-secreting pituitary adenomas show frequent loss of heterozygosity at the glucocorticoid receptor gene locus. J Clin Endocrinol Metab. 1998;83(3):917-921. doi: 10.1210/jcem.83.3.4648
15. Tateno T, Izumiyama H, Doi M, et al. Differential gene expression in ACTH -secreting and non-functioning pituitary tumors. Eur J Endocrinol. 2007;157(6):717-724. doi: 10.1530/EJE-07-0428
16. Evang JA, Borota OC, Melum E, et al. HDAC2 expression and variable number of repeats in exon 1 of the HDAC2 gene in corticotroph adenomas. Clin Endocrinol (Oxf). 2010;73(2):229-235. doi: 10.1111/j.1365-2265.2010.03805.x
17. Tabuchi Y, Kitamura T, Fukuhara A, et al. Nur77 gene expression levels were involved in different ACTH-secretion autonomy between Cushing’s disease and subclinical Cushing’s disease. Endocr J. 2016;63(6):545-554. doi: 10.1507/endocrj.EJ15-0695
18. Korbonits M, Bujalska I, Shimojo M, et al. Expression of 11 beta-hydroxysteroid dehydrogenase isoenzymes in the human pituitary: induction of the type 2 enzyme in corticotropinomas and other pituitary tumors. J Clin Endocrinol Metab. 2001;86(6):2728-2733. doi: 10.1210/jcem.86.6.7563
19. Wells AD, Morawski PA. New roles for cyclin-dependent kinases in T cell biology: linking cell division and differentiation. Nat Rev Immunol. 2014;14(4):261-270. doi: 10.1038/nri3625
20. Jordan S, Lidhar K, Korbonits M, et al. Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur J Endocrinol. 2000;143(1):R1-R6. doi: 10.1530/eje.0.143r001
21. Roussel-Gervais A, Bilodeau S, Vallette S, et al. Cooperation between cyclin E and p27(Kip1) in pituitary tumorigenesis. Mol Endocrinol. 2010;24(9):1835-1845. doi: 10.1210/me.2010-0091
22. Roussel-Gervais A, Couture C, Langlais D, et al. The Cables1 Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease. J Clin Endocrinol Metab. 2016;101(2):513-522. doi: 10.1210/jc.2015-3324
23. Hernández-Ramírez LC, Gam R, Valdés N, et al. Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing’s disease. Endocr Relat Cancer. 2017;24(8):379-392. doi: 10.1530/ERC-17-0131
24. Theodoropoulou M, Arzberger T, Gruebler Y, et al. Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells. J Endocrinol. 2004;183(2):385-394. doi: 10.1677/joe.1.05616
25. Qian ZR, Sano T, Asa SL, et al. Cytoplasmic expression of fibroblast growth factor receptor-4 in human pituitary adenomas: relation to tumor type, size, proliferation, and invasiveness. J Clin Endocrinol Metab. 2004;89(4):1904-1911. doi: 10.1210/jc.2003-031489
26. Reincke M, Sbiera S, Hayakawa A, et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat Genet. 2015;47(1):31-38. doi: 10.1038/ng.3166
27. Renner U, Ciato D, Stalla GK. Recent advances in understanding corticotroph pituitary tumor initiation and progression. F1000Res. 2018;7:F1000 Faculty Rev-1354. Published 2018 Aug 29. doi: 10.12688/f1000research.14789.1
28. Hayashi K, Inoshita N, Kawaguchi K, et al. The USP8 mutational status may predict drug susceptibility in corticotroph adenomas of Cushing’s disease. Eur J Endocrinol. 2016;174(2):213-226. doi: 10.1530/EJE-15-0689
29. Faucz FR, Tirosh A, Tatsi C, et al. Somatic USP8 Gene Mutations Are a Common Cause of Pediatric Cushing Disease. J Clin Endocrinol Metab. 2017;102(8):2836-2843. doi: 10.1210/jc.2017-00161
30. Cohen M, Persky R, Stegemann R, et al. Germline USP8 Mutation Associated With Pediatric Cushing Disease and Other Clinical Features: A New Syndrome. J Clin Endocrinol Metab. 2019;104(10):4676-4682. doi: 10.1210/jc.2019-00697
31. Buckley N, Bates AS, Broome JC, et al. p53 Protein accumulates in Cushings adenomas and invasive non-functional adenomas. J Clin Endocrinol Metab. 1994;79(5):1513-1516. doi: 10.1210/jcem.79.5.7962351
32. Tadjine M, Lampron A, Ouadi L, Bourdeau I. Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas. Clin Endocrinol (Oxf). 2008;68(2):264-270. doi: 10.1111/j.1365-2265.2007.03033.x
33. Murat CB, Braga PB, Fortes MA, et al. Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas. Braz J Med Biol Res. 2012;45(9):851-855. doi: 10.1590/s0100-879x2012007500115
34. Simonds WF, Varghese S, Marx SJ, Nieman LK. Cushing’s syndrome in multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf). 2012;76(3):379-386. doi: 10.1111/j.1365-2265.2011.04220.x
35. de Laat JM, Dekkers OM, Pieterman CR, et al. Long-Term Natural Course of Pituitary Tumors in Patients With MEN1: Results From the DutchMEN1 Study Group (DMSG). J Clin Endocrinol Metab. 2015;100(9):3288-3296. doi: 10.1210/JC.2015-2015
36. Bilezikjian LM, Vale WW. The Local Control of the Pituitary by Activin Signaling and Modulation. Open Neuroendocrinol J. 2011;4:90-101. doi: 10.2174/1876528901104010090
37. Trouillas J, Labat-Moleur F, Sturm N, et al. Pituitary tumors and hyperplasia in multiple endocrine neoplasia type 1 syndrome (MEN1): a case-control study in a series of 77 patients versus 2509 non-MEN1 patients. Am J Surg Pathol. 2008;32(4):534-543. doi: 10.1097/PAS.0b013e31815ade45
38. Chasseloup F, Pankratz N, Lane J, et al. Germline CDKN1B Loss-of-Function Variants Cause Pediatric Cushing’s Disease With or Without an MEN4 Phenotype. J Clin Endocrinol Metab. 2020;105(6):1983-2005. doi: 10.1210/clinem/dgaa160
39. Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing’s disease: multiple endocrine neoplasia, type 2. Medicine (Baltimore). 1968;47(5):371-409. doi: 10.1097/00005792-196809000-00001
40. Kasturi K, Fernandes L, Quezado M, et al. Cushing Disease in a patient with Multiple Endocrine Neoplasia type 2B. J Clin Transl Endocrinol Case Rep. 2017;4:1-4. doi: 10.1016/j.jecr.2017.02.001
41. Naziat A, Karavitaki N, Thakker R, et al. Confusing genes: a patient with MEN2A and Cushing’s disease. Clin Endocrinol (Oxf). 2013;78(6):966-968. doi: 10.1111/cen.12072
42. Daly AF, Jaffrain-Rea ML, Ciccarelli A, et al. Clinical characterization of familial isolated pituitary adenomas. J Clin Endocrinol Metab. 2006;91(9):3316-3323. doi: 10.1210/jc.2005-2671
43. Beckers A, Aaltonen LA, Daly AF, Karhu A. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr Rev. 2013;34(2):239-277. doi: 10.1210/er.2012-1013
44. Song MS, Rossi JJ. Molecular mechanisms of Dicer: endonuclease and enzymatic activity. Biochem J. 2017;474(10):1603-1618. Published 2017 May 4. doi: 10.1042/BCJ20160759
45. Lania A, Mantovani G, Spada A. cAMP pathway and pituitary tumorigenesis. Ann Endocrinol (Paris). 2012;73(2):73-75. doi: 10.1016/j.ando.2012.03.027
46. Correa R, Salpea P, Stratakis CA. Carney complex: an update. Eur J Endocrinol. 2015;173(4):M85-M97. doi: 10.1530/EJE-15-0209
47. Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000;26(1):89-92. doi: 10.1038/79238
48. Kiefer FW, Winhofer Y, Iacovazzo D, et al. PRKAR1A mutation causing pituitary-dependent Cushing disease in a patient with Carney complex. Eur J Endocrinol. 2017;177(2):K7-K12. doi: 10.1530/EJE-17-0227
49. Pack SD, Qin LX, Pak E, et al. Common genetic changes in hereditary and sporadic pituitary adenomas detected by comparative genomic hybridization. Genes Chromosomes Cancer. 2005;43(1):72-82. doi: 10.1002/gcc.20162
50. Hernández-Ramírez LC, Tatsi C, Lodish MB, et al. Corticotropinoma as a Component of Carney Complex. J Endocr Soc. 2017;1(7):918-925. Published 2017 May 30. doi: 10.1210/js.2017-00231
51. Petersenn S, Beckers A, Ferone D, et al. Therapy of endocrine disease: outcomes in patients with Cushing’s disease undergoing transsphenoidal surgery: systematic review assessing criteria used to define remission and recurrence. Eur J Endocrinol. 2015;172(6):R227-R239. doi: 10.1530/EJE-14-0883
52. Theodoropoulou M, Reincke M. Tumor-Directed Therapeutic Targets in Cushing Disease. J Clin Endocrinol Metab. 2019;104(3):925-933. doi: 10.1210/jc.2018-02080
53. Marova E.I., Arapova S.D. Sovremennye vozmozhnosti lechenija bolezni Icenko-Kushinga. Jeffektivnaja farmakoterapija. 2010(37):54-60. (In Russ.).
54. Lapshina A.M. Klinicheskaja i morfo-funkcional’naja harakteristika opuholej, producirujushhih adrenokortikotropnyj gormon. Diss. … VAK RF 14.00.03 kand. med. nauk. — M.; 2009. Доступно по: https://www.dissercat.com/content/klinicheskaya-i-morfo-funktsionalnaya-kharakteristika-opukholei-produtsiruyushchikh-adrenoko. Ссылка активна на 07.12.2020.
55. Ji Y, Vogel RI, Lou E. Temozolomide treatment of pituitary carcinomas and atypical adenomas: systematic review of case reports. Neurooncol Pract. 2016;3(3):188-195. doi: 10.1093/nop/npv059
56. Zhang D, Bergsneider M, Wang MB, Heaney AP. Targeting the ERK pathway for the treatment of Cushing’s disease. Oncotarget. 2016;7(43):69149-69158. doi: 10.18632/oncotarget.12381
Supplementary files
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1. Figure 1. Scheme of regulation of the hypothalamic-pituitary-adrenal axis and the synthesis of proopiomelanocortin. | |
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2. Figure 2. Disorders of negative feedback mechanisms, regulation of POMC transcription and cell proliferation, described in Itsenko-Cushing's disease. | |
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3. Figure 3. Prospects for targeted therapy in Itsenko-Cushing's disease. | |
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Yanar E.A., Makazan N.V., Orlova E.M., Kareva M.А. Genetic basis of Cushing’s disease in children and targeted therapeutic future perspectives. Problems of Endocrinology. 2020;66(6):39-49. (In Russ.) https://doi.org/10.14341/probl12676
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