Subscribe to RSS
DOI: 10.1055/a-2359-8051
From the First Case Reports to KDM1A Identification: 35 Years of Food (GIP)-Dependent Cushing’s Syndrome
Abstract
Food-dependent Cushing’s syndrome (FDCS) is a rare presentation of hypercortisolism from adrenal origin, mostly observed in primary bilateral macronodular adrenal hyperplasia (PBMAH) but also in some cases of unilateral adrenocortical adenoma. FDCS is mediated by the aberrant expression of glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) in adrenocortical cells. GIP, secreted by duodenal K cells after food intake, binds to its ectopic adrenal receptor, and stimulates cortisol synthesis following meals. FDCS was first described more than 35 years ago, and its genetic cause in PBMAH has been recently elucidated: KDM1A inactivation by germline heterozygous pathogenic variants is constantly associated with a loss-of-heterozygosity of the short arm of chromosome 1, containing the KDM1A locus. This causes biallelic inactivation of KDM1A, resulting in the GIPR overexpression in the adrenal cortex. These new insights allow us to propose the KDM1A genetic screening to all PBMAH patients with signs of FDCS (low fasting cortisol that increases after a mixed meal or oral glucose load) and to all first-degree relatives of KDM1A variant carriers. Given that KDM1A is a tumor suppressor gene that has also been associated with monoclonal gammopathy of uncertain significance and multiple myeloma, the investigation of FDCS in the diagnostic management of patients with PBMAH and further genetic testing and screening for malignancies should be encouraged.
Publication History
Received: 12 February 2024
Received: 14 June 2024
Accepted: 27 June 2024
Article published online:
26 July 2024
© 2024. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 Lacroix A, Ndiaye N, Tremblay J. et al. Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocr Rev 2001; 22: 75-110 DOI: 10.1210/edrv.22.1.0420.
- 2 Hamet P, Larochelle P, Franks DJ. et al. Cushing syndrome with food-dependent periodic hormonogenesis. Clin Invest Med 1987; 10: 530-533
- 3 Vaczlavik A, Bouys L, Violon F. et al. KDM1A inactivation causes hereditary food-dependent Cushing syndrome. Genet Med 2022; 24: 374-383 DOI: 10.1016/j.gim.2021.09.018.
- 4 Chasseloup F, Bourdeau I, Tabarin A. et al. Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing’s syndrome: A multicentre, retrospective, cohort study. Lancet Diabetes Endocrinol 2021; 9: 813-824 DOI: 10.1016/S2213-8587(21)00236-9.
- 5 Marks V. The early history of GIP 1969–2000: From enterogastrone to major metabolic hormone. Peptides 2020; 125: 170276 DOI: 10.1016/j.peptides.2020.170276.
- 6 Brown JC, Pederson RA, Jorpes E. et al. Preparation of highly active enterogastrone. Can J Physiol Pharmacol 1969; 47: 113-114 DOI: 10.1139/y69-020.
- 7 Turner DS, Shabaan A, Etheridge L. et al. The effect of an intestinal polypeptide fraction on insulin release in the rat in vitro and in vivo. Endocrinology 1973; 93: 1323-1328 DOI: 10.1210/endo-93-6-1323.
- 8 Mcintyre N, Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet 1964; 2: 20-21 DOI: 10.1016/s0140-6736(64)90011-x.
- 9 Dupre J. An intestinal hormone affecting glucose disposal in man. Lancet 1964; 2: 672-673 DOI: 10.1016/s0140-6736(64)92481-x.
- 10 Laughton NB, Macallum AB, Macallum AB. The relation of the duodenal mucosa to the internal secretion of the pancreas. Proc R Soc Lond B 1997; 111: 37-46 DOI: 10.1098/rspb.1932.0042.
- 11 Turner DS, Etheridge L, Marks V. et al. Effectiveness of the intestinal polypeptides, IRP, GIP, VIP and motilin on insulin release in the rat. Diabetologia 1974; 10: 459-463 DOI: 10.1007/BF01221638.
- 12 Dupre J, Ross SA, Watson D. et al. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab 1973; 37: 826-828 DOI: 10.1210/jcem-37-5-826.
- 13 Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J Diabetes Investig 2010; 1: 8-23 DOI: 10.1111/j.2040-1124.2010.00022.x.
- 14 Yamada Y, Hayami T, Nakamura K. et al. Human gastric inhibitory polypeptide receptor: Cloning of the gene (GIPR) and cDNA. Genomics 1995; 29: 773-776 DOI: 10.1006/geno.1995.9937.
- 15 Volz A, Göke R, Lankat-Buttgereit B. et al. Molecular cloning, functional expression, and signal transduction of the GIP-receptor cloned from a human insulinoma. FEBS Lett 1995; 373: 23-29 DOI: 10.1016/0014-5793(95)01006-z.
- 16 Gremlich S, Porret A, Hani EH. et al. Cloning, functional expression, and chromosomal localization of the human pancreatic islet glucose-dependent insulinotropic polypeptide receptor. Diabetes 1995; 44: 1202-1208 DOI: 10.2337/diab.44.10.1202.
- 17 Mayendraraj A, Rosenkilde MM, Gasbjerg LS. GLP-1 and GIP receptor signaling in beta cells - A review of receptor interactions and co-stimulation. Peptides 2022; 151: 170749 DOI: 10.1016/j.peptides.2022.170749.
- 18 Lacroix A, Bolté E, Tremblay J. et al. Gastric inhibitory polypeptide-dependent cortisol hypersecretion--a new cause of Cushing’s syndrome. N Engl J Med 1992; 327: 974-980 DOI: 10.1056/NEJM199210013271402.
- 19 Reznik Y, Allali-Zerah V, Chayvialle JA. et al. Food-dependent Cushing’s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide. N Engl J Med 1992; 327: 981-986 DOI: 10.1056/NEJM199210013271403.
- 20 Bertagna X. New Causes of Cushing’s Syndrome. New England Journal of Medicine 1992; 327: 1024-1025 DOI: 10.1056/NEJM199210013271410.
- 21 Schorr I, Ney RL. Abnormal hormone responses of an adrenocortical cancer adenyl cyclase. J Clin Invest 1971; 50: 1295-1300 DOI: 10.1172/JCI106608.
- 22 Schorr I, Rathnam P, Saxena BB. et al. Multiple specific hormone receptors in the adenylate cyclase of an adrenocortical carcinoma. J Biol Chem 1971; 246: 5806-5811
- 23 Hingshaw HT, Ney RL, McKerns KW. Abnormal control in the neoplastic adrenal cortex. Hormones and Cancer 1974; 309-327
- 24 de Herder WW, Hofland LJ, Usdin TB. et al. Food-dependent Cushing’s syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells. J Clin Endocrinol Metab 1996; 81: 3168-3172 DOI: 10.1210/jcem.81.9.8784063.
- 25 Luton JP, Bertherat J, Kuhn JM. et al Aberrant expression of the GIP (Gastric Inhibitory Polypeptide) receptor in an adrenal cortical adenoma responsible for a case of food-dependent Cushing’s syndrome. Bull Acad Natl Med 1998; 182: 1839-1849 discussion 1849-1850
- 26 N’Diaye N, Tremblay J, Hamet P. et al. Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing’s syndrome. J Clin Endocrinol Metab 1998; 83: 2781-2785 DOI: 10.1210/jcem.83.8.5038.
- 27 Mazzuco TL, Chabre O, Feige JJ. et al. Aberrant GPCR expression is a sufficient genetic event to trigger adrenocortical tumorigenesis. Mol Cell Endocrinol 2007; 265–266: 23-28 DOI: 10.1016/j.mce.2006.12.034.
- 28 Lacroix A, Tremblay J, Touyz RM. et al. Abnormal adrenal and vascular responses to vasopressin mediated by a V1-vasopressin receptor in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia, Cushing’s syndrome, and orthostatic hypotension. J Clin Endocrinol Metab 1997; 82: 2414-2422 DOI: 10.1210/jcem.82.8.4140.
- 29 Mune T, Murase H, Yamakita N. et al. Eutopic overexpression of vasopressin v1a receptor in adrenocorticotropin-independent macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2002; 87: 5706-5713 DOI: 10.1210/jc.2002-020067.
- 30 Louiset E, Contesse V, Groussin L. et al. Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing’s syndrome: Molecular, immunohistochemical and pharmacological correlates. J Endocrinol 2008; 196: 1-9 DOI: 10.1677/JOE-07-0413.
- 31 Lacroix A, Tremblay J, Rousseau G. et al. Propranolol therapy for ectopic beta-adrenergic receptors in adrenal Cushing’s syndrome. N Engl J Med 1997; 337: 1429-1434 DOI: 10.1056/NEJM199711133372004.
- 32 Lacroix A, Hamet P, Boutin JM. Leuprolide acetate therapy in luteinizing hormone--dependent Cushing’s syndrome. N Engl J Med 1999; 341: 1577-1581 DOI: 10.1056/NEJM199911183412104.
- 33 Cartier D, Lihrmann I, Parmentier F. et al. Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing’s syndrome. J Clin Endocrinol Metab 2003; 88: 248-254 DOI: 10.1210/jc.2002-021107.
- 34 Mannelli M, Ferruzzi P, Luciani P. et al. Cushing’s syndrome in a patient with bilateral macronodular adrenal hyperplasia responding to cisapride: An in vivo and in vitro study. J Clin Endocrinol Metab 2003; 88: 4616-4622 DOI: 10.1210/jc.2002-021949.
- 35 Contesse V, Reznik Y, Louiset E. et al. Abnormal sensitivity of cortisol-producing adrenocortical adenomas to serotonin: In vivo and in vitro studies. J Clin Endocrinol Metab 2005; 90: 2843-2850 DOI: 10.1210/jc.2004-2476.
- 36 Vezzosi D, Cartier D, Régnier C. et al. Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors. Eur J Endocrinol 2007; 156: 21-31 DOI: 10.1530/eje.1.02324.
- 37 Plöckinger U, Chrusciel M, Doroszko M. et al. Functional implications of LH/hCG receptors in pregnancy-induced Cushing syndrome. J Endocr Soc 2017; 1: 57-71 DOI: 10.1210/js.2016-1021.
- 38 Hsiao H-P, Kirschner LS, Bourdeau I. et al. Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. J Clin Endocrinol Metab 2009; 94: 2930-2937 DOI: 10.1210/jc.2009-0516.
- 39 Libé R, Coste J, Guignat L. et al. Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: A frequent finding in a prospective study of 32 patients with overt or subclinical Cushing’s syndrome. Eur J Endocrinol 2010; 163: 129-138 DOI: 10.1530/EJE-10-0195.
- 40 Hofland J, Hofland LJ, van Koetsveld PM. et al. ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11β-hydroxylase. Orphanet J Rare Dis 2013; 8: 142 DOI: 10.1186/1750-1172-8-142.
- 41 Mircescu H, Jilwan J, N’Diaye N. et al. Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing’s syndrome?. J Clin Endocrinol Metab 2000; 85: 3531-3536 DOI: 10.1210/jcem.85.10.6865.
- 42 Lacroix A. Extensive expertise in endocrinology: Glucose-dependent insulinotropic peptide-dependent Cushing’s syndrome. Eur J Endocrinol 2023; 188: R56-R72 DOI: 10.1093/ejendo/lvad026.
- 43 Faucz FR, Zilbermint M, Lodish MB. et al. Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: A clinical and genetic investigation. J Clin Endocrinol Metab 2014; 99: E1113-E1119 DOI: 10.1210/jc.2013-4280.
- 44 Espiard S, Drougat L, Libé R. et al. ARMC5 mutations in a large cohort of primary macronodular adrenal hyperplasia: Clinical and functional consequences. J Clin Endocrinol Metab 2015; 100: E926-E935 DOI: 10.1210/jc.2014-4204.
- 45 Bouys L, Vaczlavik A, Jouinot A. et al. Identification of predictive criteria for pathogenic variants of primary bilateral macronodular adrenal hyperplasia (PBMAH) gene ARMC5 in 352 unselected patients. Eur J Endocrinol 2022; 187: 123-134 DOI: 10.1530/EJE-21-1032.
- 46 Bertherat J, Bourdeau I, Bouys L. et al. Clinical, pathophysiologic, genetic, and therapeutic progress in primary bilateral macronodular adrenal hyperplasia. Endocr Rev 2023; 44: 567-628 DOI: 10.1210/endrev/bnac034.
- 47 Bouys L, Chiodini I, Arlt W. et al. Update on primary bilateral macronodular adrenal hyperplasia (PBMAH). Endocrine 2021; 71: 595-603 DOI: 10.1007/s12020-021-02645-w.
- 48 Lacroix A, Mircescu H, Harriet P. Clinical evaluation of the presence of abnormal hormone receptors in adrenal Cushing’s syndrome. The Endocrinologist 1999; 9: 9
- 49 Debillon E, Velayoudom-Cephise F-L, Salenave S. et al. Unilateral adrenalectomy as a first-line treatment of Cushing’s syndrome in patients with primary bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2015; 100: 4417-4424 DOI: 10.1210/jc.2015-2662.
- 50 Meloche-Dumas L, Mercier F, Lacroix A. Role of unilateral adrenalectomy in bilateral adrenal hyperplasias with Cushing’s syndrome. Best Pract Res Clin Endocrinol Metab 2021; 35: 101486 DOI: 10.1016/j.beem.2021.101486.
- 51 N’Diaye N, Hamet P, Tremblay J. et al. Asynchronous development of bilateral nodular adrenal hyperplasia in gastric inhibitory polypeptide-dependent Cushing’s syndrome. J Clin Endocrinol Metab 1999; 84: 2616-2622 DOI: 10.1210/jcem.84.8.5930.
- 52 Lebrethon MC, Avallet O, Reznik Y. et al. Food-dependent Cushing’s syndrome: Characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients. J Clin Endocrinol Metab 1998; 83: 4514-4519 DOI: 10.1210/jcem.83.12.5336.
- 53 Albiger NM, Occhi G, Mariniello B. et al. Food-dependent Cushing’s syndrome: From molecular characterization to therapeutical results. Eur J Endocrinol 2007; 157: 771-778 DOI: 10.1530/EJE-07-0253.
- 54 Preumont V, Mermejo LM, Damoiseaux P. et al. Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP-dependent Cushing’s syndrome. Horm Metab Res 2011; 43: 287-291 DOI: 10.1055/s-0030-1270523.
- 55 Larose S, Bondaz L, Mermejo LM. et al. Coexistence of myelolipoma and primary bilateral macronodular adrenal hyperplasia with GIP-dependent Cushing’s syndrome. Front Endocrinol (Lausanne) 2019; 10: 618 DOI: 10.3389/fendo.2019.00618.
- 56 Assié G, Libé R, Espiard S. et al. ARMC5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome. N Engl J Med 2013; 369: 2105-2114 DOI: 10.1056/NEJMoa1304603.
- 57 Alencar GA, Lerario AM, Nishi MY. et al. ARMC5 mutations are a frequent cause of primary macronodular adrenal Hyperplasia. J Clin Endocrinol Metab 2014; 99: E1501-E1509 DOI: 10.1210/jc.2013-4237.
- 58 Bourdeau I, Oble S, Magne F. et al. ARMC5 mutations in a lar French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia. Eur J Endocrinol 2016; 174: 85-96 DOI: 10.1530/EJE-15-0642.
- 59 Drougat L, Espiard S, Bertherat J. Genetics of primary bilateral macronodular adrenal hyperplasia: A model for early diagnosis of Cushing’s syndrome?. Eur J Endocrinol 2015; 173: M121-M131 DOI: 10.1530/EJE-15-0532.
- 60 Faillot S, Foulonneau T, Néou M. et al. Genomic classification of benign adrenocortical lesions. Endocr Relat Cancer 2021; 28: 79-95 DOI: 10.1530/ERC-20-0128.
- 61 Antonini SR, N’Diaye N, Baldacchino V. et al. Analysis of the putative regulatory region of the gastric inhibitory polypeptide receptor gene in food-dependent Cushing’s syndrome. J Steroid Biochem Mol Biol 2004; 91: 171-177 DOI: 10.1016/j.jsbmb.2004.03.120.
- 62 Lecoq A-L, Stratakis CA, Viengchareun S. et al Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing’s syndrome. JCI Insight 2017; 2: e92184 92184 DOI: 10.1172/jci.insight.92184.
- 63 Correa R, Zilbermint M, Berthon A. et al. The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia. Eur J Endocrinol 2015; 173: 435-440 DOI: 10.1530/EJE-15-0205.
- 64 Violon F, Bouys L, Berthon A. et al. Impact of morphology in the genotype and phenotype correlation of bilateral macronodular adrenocortical disease (BMAD): A series of clinicopathologically well-characterized 35 cases. Endocr Pathol 2023; 34: 179-199 DOI: 10.1007/s12022-023-09751-7.
- 65 Shi Y, Lan F, Matson C. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004; 119: 941-953 DOI: 10.1016/j.cell.2004.12.012.
- 66 Vinckier NK, Patel NA, Geusz RJ. et al. LSD1-mediated enhancer silencing attenuates retinoic acid signalling during pancreatic endocrine cell development. Nat Commun 2020; 11: 2082 DOI: 10.1038/s41467-020-16017-x.
- 67 Wang J, Scully K, Zhu X. et al. Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 2007; 446: 882-887 DOI: 10.1038/nature05671.
- 68 Laurent B, Ruitu L, Murn J. et al. A specific LSD1/KDM1A isoform regulates neuronal differentiation through H3K9 demethylation. Mol Cell 2015; 57: 957-970 DOI: 10.1016/j.molcel.2015.01.010.
- 69 Bertherat J, Contesse V, Louiset E. et al. In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing’s syndrome: Identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism. J Clin Endocrinol Metab 2005; 90: 1302-1310 DOI: 10.1210/jc.2004-1256.
- 70 Wei X, Calvo-Vidal MN, Chen S. et al. Germline lysine-specific demethylase 1 (LSD1/KDM1A) mutations confer susceptibility to multiple myeloma. Cancer Res 2018; 78: 2747-2759 DOI: 10.1158/0008-5472.CAN-17-1900.
- 71 Karakaidos P, Verigos J, Magklara A. LSD1/KDM1A, a gate-keeper of cancer stemness and a promising therapeutic target. Cancers 2019; 11: 1821 DOI: 10.3390/cancers11121821.
- 72 Hage M, Chaligné R, Viengchareun S. et al. Hypermethylator phenotype and ectopic GIP receptor in GNAS mutation-negative somatotropinomas. J Clin Endocrinol Metab 2019; 104: 1777-1787 DOI: 10.1210/jc.2018-01504.
- 73 Regazzo D, Losa M, Albiger NM. et al. The GIP/GIPR axis is functionally linked to GH-secretion increase in a significant proportion of GSP- somatotropinomas. Eur J Endocrinol 2017; 176: 543-553 DOI: 10.1530/EJE-16-0831.
- 74 Occhi G, Losa M, Albiger N. et al. The glucose-dependent insulinotropic polypeptide receptor is overexpressed amongst GNAS1 mutation-negative somatotropinomas and drives growth hormone (GH)-promoter activity in GH3 cells. J Neuroendocrinol 2011; 23: 641-649 DOI: 10.1111/j.1365-2826.2011.02155.x.
- 75 Hage M, Janot C, Salenave S. et al. Management of endocrine disease: Etiology and outcome of acromegaly in patients with a paradoxical GH response to glucose. Eur J Endocrinol 2021; 184: R261-R268 DOI: 10.1530/EJE-20-1448.
- 76 Chasseloup F, Regazzo D, Tosca L. et al. KDM1A genotyping and expression in 146 sporadic somatotroph pituitary adenomas. Eur J Endocrinol 2024; 190: 173-181 DOI: 10.1093/ejendo/lvae013.
- 77 Cavalcante IP, Berthon A, Fragoso MC. et al. Primary bilateral macronodular adrenal hyperplasia: Definitely a genetic disease. Nat Rev Endocrinol 2022; 18: 699-711 DOI: 10.1038/s41574-022-00718-y.
- 78 Metzger E, Wissmann M, Yin N. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 2005; 437: 436-439 DOI: 10.1038/nature04020.
- 79 Adamo A, Sesé B, Boue S. et al. LSD1 regulates the balance between self-renewal and differentiation in human embryonic stem cells. Nat Cell Biol 2011; 13: 652-659 DOI: 10.1038/ncb2246.