Corticotropin-producing pheochromocytoma in multiple endocrine neoplasia type 1

A clinical case of a man 66 y.o. who was diagnosed with hormone-inactive pituitary macroadenoma complicated by corneal erosion and partial atrophy of the optic nerve of the left eye due to exophthalmos. The increase in prolactin level was regarded due to a «stalk-effect». The patient underwent a transnasal pituitary adenomectomy with subsequent regression of symptoms. After 4 years, against the background of a new coronavirus infection, increasing general weakness, headaches, a crisis increase in blood pressure and tachycardia attacks appeared. Computed tomography (CT) accidentally revealed an adrenal incidentaloma, in laboratory tests — hypercortisolism, elevated ACTH levels, hypokalemia, hyperglycemia, increased levels of metanephrine and normetanephrine. The patient developed acute steroid psychosis, after which an adrenalectomy with a tumor was performed, a pheochromocytoma was histologically confirmed. After surgery, there was a regression of symptoms, the development of adrenal insufficiency with reduced levels of ACTH and cortisol. Upon further examination, a polynodose euthyroid goiter was established, the biopsy of the nodes — Hashimoto’s thyroiditis (Bethesda II). Meanwhile, primary hyperparathyroidism was detected. According to ultrasound, scintigraphy with Ts99m-Technetril and CT revealed an increase of left parathyroid gland. A bilateral revision of the neck, removal of the right upper and left upper parathyroid adenomas were performed. In the postoperative period, the levels of calcium and parathyroid hormone were normalized. Given the presence of a combination of multiple tumors of the endocrine system (primary hyperparathyroidism, corticotropin-producing pheochromocytoma, hormone-inactive pituitary macroadenoma, polynodose euthyroid goiter), the MEN1 syndrome was clinically established. The study of 2 and 10 exons of the MEN1 gene revealed no mutations, which does not exclude the presence of a hereditary syndrome. The patient continues observation. In the available literature in Russian and English languages the case of ACTH pheochromocytoma as part of the MEN type 1 syndrome have not been found. Therefore, we consider the presented case to be the first one.

1. Lloyd RV, Osamura RY, Kloppel G, Rosai J. WHO classification of tumors and endocrine organs 4th edition. Geneva: WHO; 2017.

2. Kamilaris CDC, Stratakis CA. Multiple Endocrine Neoplasia Type 1 (MEN1): An update and the significance of early genetic and clinical diagnosis. Front Endocrinol (Lausanne). 2019;(10):339. doi: https://doi.org/10.3389/fendo.2019.00339

3. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for Multiple Endocrine Neoplasia Type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(9):2990-3011. doi: https://doi.org/10.1210/jc.2012-1230

4. Lee M, Pellegata NS. Multiple endocrine neoplasia type 4. Frontiers in Endocrinology. 2013;(10):63-78. doi: https://doi.org/10.1159/000345670

5. Buffet A, Burnichon N, Favier J, Gimenez-Roqueplo A-P. An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2020;34(2):101416. doi: https://doi.org/10.1016/j.beem.2020.101416

6. McDonnell JE, Gild ML, Clifton-Bligh RJ, Robinson BG. Multiple endocrine neoplasia: an update. Intern Med J. 2019;49(8):954-961. doi: https://doi.org/10.1111/imj.14394

7. Viale G, Dell’Orto P, Moro E, et al. Vasoactive intestinal polypeptide-, somatostatin-, and calcitonin-producing adrenal pheochromocytoma associated with the watery diarrhea (WDHH) syndrome. First case report with immunohistochemical findings. Cancer. 1985;55(5):1099-1106. doi: https://doi.org/10.1002/1097-0142(19850301)55:5<1099::AID-CNCR2820550527>3.0.CO;2-3

8. Rebrova DV, Rusakov VF, Fedorov EA, et al. Rare case of pheochromocytoma with calcitonin hypersecretion. Pharmateca. 2021;28(4):90-98. (In Russ.). doi: https://doi.org/10.18565/pharmateca.2021.4.90-98

9. Kuznetsov NS, Marova EI, Latkina NV, et al. ACTH-secreting pheochromocytoma. Case report. Endocrine Surgery. 2012;6(4):43-50. (In Russ.). doi: https://doi.org/10.14341/2306-3513-2012-4-43-50

10. Ctvrtlik F, Tudos Z, Szasz P, et al. Charactericstic CT features of pheochromocytomas - probability model calculation tool based on a multicentric study. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2019;163(3):212-219. doi: https://doi.org/10.5507/bp.2019.047

11. Slattery JMA, Blake MA, Kalra MK, et al. Adrenocortical carcinoma: contrast washout characteristics on CT. AJR Am J Roentgenol. 2006;187(1):W21-24. doi: https://doi.org/10.2214/AJR.04.1751

12. Rusakov VF, Shcherbakov IE, Chinchuk IK, et al. Diagnostic value of ct in examination of patients with adrenal cancer. Problems of Endocrinology. 2022;68(4):13-29. (In Russ.). doi: https://doi.org/10.14341/probl12846

13. Gabi JN, Milhem MM, Tovar YE, et al. Severe Cushing syndrome due to an ACTH-producing pheochromocytoma: a case presentation and review of the literature. J Endocr Soc. 2018;2(7):621-630. doi: https://doi.org/10.1210/js.2018-00086

14. Marova EI, Kuznetsov NS, Rozhinskaya LY, et al. ACTH ectopic syndrome caused by corticomedullary mixed tumor. Problems of Endocrinology. 2016;62(1):50-54. (In Russ.). doi: https://doi.org/10.14341/probl201662150-54

15. Shafigullina ZR, Petrova MM, Shustov SB, et al. Sluchaj sochetanija AKTG-jektopicheskogo sindroma Kushinga i feohromocitomy. Rossijskij semejnyj vrach. 2013;17(4):43-46. (In Russ.).

16. Marova EI, Voronkova IA, Lapshina AM, et al. Adrenocorticotropic hormone-producing pheochromocytoma: analysis of clinical cases. Obesity and metabolism. 2015;12(3):46-52. (In Russ.). doi: https://doi.org/10.14341/omet2015346-52

17. Ryabova TI, Yefimova YV, Zhdanova YL, Denisenko SS. Clinical case of a neuroendocrine tumor – combinations of adrenocorticotropic hormone (ACTH)-ectopic syndrome and pheochromocytoma. Public Heal Far East Peer-reviewed Sci Pract J. 2019;12(2):50-52. (In Russ.). doi: https://doi.org/10.33454/1728-1261-2019-2-50-52

18. Krylov V, Dobreva E, Kharnas S, et al. Adrenocorticotropic hormone-producing pheochromocytoma: A case report. Int J Surg Case Rep. 2020;68(2):59-62. doi: https://doi.org/10.1016/j.ijscr.2020.01.053

19. Geva GA, Gross DJ, Mazeh H, et al. Adrenocorticotropic Hormone Secreting Pheochromocytoma Underlying Glucocorticoid Induced Pheochromocytoma Crisis. Case Rep Endocrinol. 2018;2018:1-4. doi: https://doi.org/10.1155/2018/3963274

20. Zaman S, Patel B, Glynne P, et al. A rare cause of severe Cushing’s syndrome. Endocrinol Diabetes Metab Case Reports. 2020:2020:20-0011. doi: https://doi.org/10.1530/EDM-20-0011

21. Borzouei S, Bahar SHAM, Fereydouni MA, et al. Multiple endocrine neoplasia type IIa associated with Cushing’s syndrome. Arch Iran Med. 2014;17(6):451-454.

22. Mendonсa ВВ, Arnhold IJ, Nicolau W, et al. Cushing’s syndrome due to ectopic ACTH secretion by bilateral pheochromocytomas in multiple endocrine neoplasia type 2A. N Engl J Med. 1988;319(24):1610-1611. doi: https://doi.org/10.1056/NEJM198812153192418

23. Nunes AB, Ezabella MCL, Pereira AC, et al. A novel Val648Ile substitution in RET protooncogene observed in a Cys634Arg multiple endocrine neoplasia type 2A kindred presenting with an adrenocorticotropin-producing pheochromocytoma. J Clin Endocrinol Metab. 2002;87(12):5658-61. doi: https://doi.org/10.1210/jc.2002-020345