A combination of endogenous hypercortisolism and primary hyperparathyroidism: clinical and genetic characteristics

BACKGROUND: A combination of endogenous hypercortisolism and primary hyperparathyroidism (PHPT) occurs rarely, few clinical cases are described in the literature. The causes of the development of such combination are poorly investigated. AIM: To study clinical and genetic characteristics of a combination of endogenous hypercortisolism and PHPT.

MATERIALS AND METHODS: A retrospective, single-center, cross-sectional, observational study was performed. Clinical characteristics of patients with a combination of endogenous hypercortisolism and PHPT were analyzed. All patients had previously undergone genetic testing as follows: MEN1 Sanger sequencing (n=10), next-generation sequencing of a panel of genes including MEN1 and CDKN1B (n=3), whole-exome sequencing (n=8).

RESULTS: 21 patients (17 females, 4 males) were included in the study: 17 with Cushing’s disease (CD) and PHPT, 3 patients with Cushing’s syndrome (CS) and PHPT, and one patient with ACTH-ectopic syndrome (ACTH-ES) and PHPT. Among patients with CD and PHPT ten had MEN1 mutations (multiple endocrine neoplasia type 1 syndrome (MEN1)), and seven did not have MEN1 mutations (MEN1 phenocopies). In patients with MEN1 the debut of both CD and PHPT occurred at younger age in comparison to MEN1 phenocopies (p=0,015 and p=0,0006). In 60% of MEN1 CD occured in infancy, and in all children CD was the first manifestation. In 75% of adult MEN1 patients CD was diagnosed after PHPT, whereas in all MEN1 phenocopies PHPT was diagnosed after or during investigation with regard to CD. The majority of MEN1 patients also had gastro-entero- pancreatic neuroendocrine tumors (NETs), and some had lung NETs, whereas patients with MEN1 phenocopies did not have NETs. One patient with CS (bilateral lesions) and PHPT had ARMC5 mutation. In a patient with ACTH-ES and PHPT no mutations were found.

CONCLUSION: A combination of endogenous hypercortisolism and PHPT occurs more frequently in females. In children with MEN1 and in MEN1 phenocopies the first manifestation is more frequently CD, while PHPT is diagnosed accidentally during evaluation, whereas in adults with MEN1 the first manifestation is more frequently PHPT. MEN1 mutations can be the cause of a combination of these two endocrine tumor diseases, and, possibly, ARMC5 mutations in cases of CS and PHPT, though in the majority of cases the cause remains unknown. Identification of causes of endogenous hypercortisolism and PHPT co-occurrence can expand our understanding of the mechanisms of endocrine tumor development.

1. Mel’nichenko GA, Dedov II, Belaja Zh. Cushing’s disease: the clinical features, diagnostics, differential diagnostics, and methods of treatment. Problemy endocrinologii. 2015;61(2):55–77. (In Russ). doi: https://doi.org/10.14341/probl201561255-77

2. Lacroix A, Feelders R A, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015; 386(9996):913–927. doi: https://doi.org/10.1016/S0140-6736(14)61375-1

3. Lodish M, Stratakis CA. A genetic and molecular update on adrenocortical causes of Cushing syndrome. Nat Rev Endocrinol. 2016;12(5):255-62. doi: https://doi.org/10.1038/nrendo.2016.24

4. Mamedova EO, Mokrysheva NG, Pigarova EA, Voronkova IA, Kuznetsov SN, et al. Molecular and genetic features of primary hyperparathyroidism in young patients. Problems of Endocrinology. 2016;62(2):4-11. (In Russ). doi: https://doi.org/10.14341/probl20166224-11

5. Simonds WF. Expressions of Cushing’s syndrome in multiple endocrine neoplasia type 1. Front Endocrinol (Lausanne). 2023;14:1183297. Published 2023 Jun 20. doi: https://doi.org/10.3389/fendo.2023.1183297

6. Singeisen H, Renzulli MM, Pavlicek V, et al. Multiple endocrine neoplasia type 4: a new member of the MEN family. Endocr Connect. 2023;12(2):e220411. Published 2023 Jan 24. doi: https://doi.org/10.1530/EC-22-0411

7. 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

8. Mamedova EO, Mokrysheva NG, Pigarova EA, Przhiyalkovskaya EG, Vasilyev EV, et al. Phenocopies of multiple endocrine neoplasia type 1: role of the genes, associated with the development of pituitary adenomas. Problems of Endocrinology. 2016;62(4):4-10. (In Russ.) doi: https://doi.org/10.14341/probl20166244-10

9. Mamedova EO, Mokrysheva NG, Przhiialkovskaia EG, Pigarova EA, Rozhinskaia LIa, Tiul’pakov AN. Multiple endocrine neoplasia type 1 variants and phenocopies. Therapeutic Archive. 2014;86(10):87-91. (In Russ.)

10. Mamedova EO, Vasilyev E, Petrov V.M, Izmailova NS, Buryakina SA, et al. Hereditary Cushing’s syndrome caused by primary bilateral macronodular adrenal hyperplasia due to ARMC5 mutation with concomitant primary hyperparathyroidism: the first known case in Russia. Problems of Endocrinology. 2019;65(2):89-94. (In Russ.) doi: https://doi.org/10.14341/probl9712

11. Gagliardi L, Schreiber AW, Hahn CN, et al. ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab. 2014;99(9):E1784-E1792. doi: https://doi.org/10.1210/jc.2014-1265

12. Parikh S, Matthews J, Lubitz SE, Schneider S. SAT-193 Clinical Case of ARMC5 Tumor Syndrome: A Rare Case of Cushing’s Syndrome from Primary Bilateral Macronodular Adrenal Hyperplasia Caused by ARMC5 Mutation with Concomitant Presence of Meningiomas and Primary Hyperparathyroidism. J Endocr Soc. 2020;4(Suppl 1):SAT-193. Published 2020 May 8. doi: https://doi.org/10.1210/jendso/bvaa046.662

13. Klinicheskie rekomendatsii «Bolezn Itsenko-Kushinga» (in Russ.) Доступно по: https://www.endocrincentr.ru/sites/default/files/specialists/science/clinic-recomendations/kr84_bolezn_icenkokushinga.pdf. Ссылка активна на 27.09.2025

14. Klinicheskie rekomendatsii «Pervichnii giperparatireoz» (in Russ.) Доступно по: https://cr.minzdrav.gov.ru/view-cr/88_5. Ссылка активна на 27.09.2025

15. Rozhinskaya LY, Khandaeva PM, Lutsenko AS, Lapshina AM, Grigor’ev AY, et al. Relapse of the pituitary adenoma with a change of its hormonal activity in a female patient with multiple endocrine neoplasia syndrome type 1. Almanac of Clinical Medicine. 2018;46(3):270-275 (In Russ.). doi: https://doi.org/10.18786/2072-0505-2018-46-3-270-275

16. RAKER JW, HANNEMAN PH, GRAF WS. Coexisting primary hyperparathyroidism and Cushing’s syndrome. J Clin Endocrinol Metab. 1962;22:273-280. doi: https://doi.org/10.1210/jcem-22-3-273

17. Tajima A, Kawabe K. Cushing’s syndrome masked by primary hyperparathyroidism. J Urol. 1977;118(4):669-670. doi: https://doi.org/10.1016/s0022-5347(17)58147-1

18. Sawano S, Shishiba Y, Shimizu T, et al. Hyperparathyroidism associated with Cushing’s syndrome due to an adrenal cortical adenoma. Endocrinol Jpn. 1990;37(2):255-260. doi: https://doi.org/10.1507/endocrj1954.37.255 19. Newman C, Costello M, Casey M, et al. A case of adrenal Cushing’s syndrome and primary hyperparathyroidism due to an atypical parathyroid adenoma. Ther Adv Endocrinol Metab. 2021;12:20420188211030160. Published 2021 Jul 31. doi: https://doi.org/10.1177/20420188211030160

19. Feldman F, Mitchell W, Soll S. Psychosis, Cushing’s syndrome and hyperparathyroidism. Can Med Assoc J. 1968;98(10):508-511

20. Miyagawa K, Ishibashi M, Kasuga M, Kanazawa Y, Yamaji T, Takaku F. Multiple endocrine neoplasia type I with Cushing’s disease, primary hyperparathyroidism, and insulin-glucagonoma. Cancer. 1988;61(6):1232-1236. doi: https://doi.org/10.1002/1097-0142(19880315)61:6<1232::aid-cncr2820610629>3.0.co;2-4

21. 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: https://doi.org/10.1111/j.1365-2265.2011.04220.x

22. Yanar E.A. Endogennii giperkortitsizm u detei: spektr steroidov, molekulyarnaya genetika i topicheskaya diagnostika v personalizatsii lecheniya: Dis….kand.med.nauk. – Moskva; 2023 (in Russ.) Доступно по: https://www.endocrincentr.ru/sites/default/files/specialists/science/dissertation/yanar_disser_0.pdf. Ссылка активна на 27.09.2025.

23. Wang W, Han R, Ye L, et al. Adrenocortical carcinoma in patients with MEN1: a kindred report and review of the literature. Endocr Connect. 2019;8(3):230-238. doi: https://doi.org/10.1530/EC-18-0526

24. Takagi J, Otake K, Morishita M, et al. Multiple endocrine neoplasia type I and Cushing’s syndrome due to an aggressive ACTH producing thymic carcinoid. Intern Med. 2006;45(2):81-86. doi: https://doi.org/10.2169/internalmedicine.45.1427

25. Yano M, Fukai I, Kobayashi Y, et al. ACTH-secreting thymic carcinoid associated with multiple endocrine neoplasia type 1. Ann Thorac Surg. 2006;81(1):366-368. doi: https://doi.org/10.1016/j.athoracsur.2004.07.084

26. Ghazi AA, Dezfooli AA, Mohamadi F, et al. Cushing syndrome secondary to a thymic carcinoid tumor due to multiple endocrine neoplasia type 1. Endocr Pract. 2011;17(4):e92-e96. doi: https://doi.org/10.4158/EP11038.CR

27. Li X, Su J, Zhao L, et al. Familial Cushing syndrome due to thymic carcinoids in a multiple endocrine neoplasia type 1 kindred. Endocrine. 2014;47(1):183-190. doi: https://doi.org/10.1007/s12020-013-0141-6

28. Rebrova DV, Grigorova SI, Vorokhobina NV, Zgoda EA, Novokshonov KYu, et al. Corticotropin-producing pheochromocytoma in multiple endocrine neoplasia type 1. Problems of Endocrinology. 2023;69(5):55-64. (In Russ.) doi: https://doi.org/10.14341/probl13260

29. Georgitsi M, Raitila A, Karhu A, et al. Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia. J Clin Endocrinol Metab. 2007;92(8):3321-3325. doi: https://doi.org/10.1210/jc.2006-2843

30. 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: https://doi.org/10.1210/clinem/dgaa160

31. Rana HQ, Clifford J, Hoang L, et al. Genotypephenotype associations among panel-based TP53+ subjects. Genet Med. 2019;21(11):2478-2484. doi: https://doi.org/10.1038/s41436-019-0541-y 33. Gagliardi L, Schreiber AW, Hahn CN, et al. ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab. 2014;99(9):E1784-E1792. doi: https://doi.org/10.1210/jc.2014-1265

32. Parikh S, Matthews J, Lubitz SE, Schneider S. SAT-193 Clinical Case of ARMC5 Tumor Syndrome: A Rare Case of Cushing’s Syndrome from Primary Bilateral Macronodular Adrenal Hyperplasia Caused by ARMC5 Mutation with Concomitant Presence of Meningiomas and Primary Hyperparathyroidism. J Endocr Soc. 2020;4(Suppl 1):SAT-193. Published 2020 May 8. doi: https://doi.org/10.1210/jendso/bvaa046.662

33. Komshilova KA, Cheredanova VR, Ershova EV, Mazurina NV, Platonova NM, et al. Experience of surgical treatment of morbid obesity in a patient with hypercortisolism and primary hyperparathyroidism: prioritization. Obesity and metabolism. 2024;21(4):405-411. (In Russ.) doi: https://doi.org/10.14341/omet13143

34. Mamedova EO, Dimitrova DA, Belaya ZhE, Melnichenko GA. The role of non-coding RNAs in the pathogenesis of multiple endocrine neoplasia syndrome type 1. Problems of Endocrinology. 2020;66(2):4-12. (In Russ.) doi: https://doi.org/10.14341/probl12413

35. Truhina DA, Mamedova EO, Belaja ZhE, Mel’nichenko GA. Fenokopii sindroma mnozhestvennyh jendokrinnyh neoplazij 1-go tipa — vozmozhnye prichiny. RMZh. Medicinskoe obozrenie. 2024;8(9):526-530. (In Russ.) doi: https://doi.org/10.32364/2587-6821-2024-8-9-4

36. Trukhina DA, Mamedova EO, Nikitin AG, Koshkin PA, Belaya ZhE, Melnichenko GA. Plasma miRNA expression in patients with genetically confirmed multiple endocrine neoplasia type 1 syndrome and its phenocopies. Problems of Endocrinology. 2023;69(6):70-85. (In Russ.) doi: https://doi.org/10.14341/probl13357

37. Kooblall KG, Stokes VJ, Shariq OA, et al. miR-3156-5p is downregulated in serum of MEN1 patients and regulates expression of MORF4L2. Endocr Relat Cancer. 2022;29(10):557-568. Published 2022 Aug 4. doi: https://doi.org/10.1530/ERC-22-0045

38. Luzi E, Marini F, Giusti F, Galli G, Cavalli L, Brandi ML. The negative feedback-loop between the oncomir Mir-24-1 and menin modulates the Men1 tumorigenesis by mimicking the «Knudson’s second hit». PLoS One. 2012;7(6):e39767. doi: https://doi.org/10.1371/journal.pone.0039767

39. Kohri K, Kataoka K, Iguchi M, Yachiku S, Kurita T, Sonoda T. Relation between parathyroid hormone and adrenocorticotropic hormone in primary hyperparathyroidism. Urol Int. 1984;39(1):1-4. doi: https://doi.org/10.1159/000280932

40. Abou-Samra AB, Jüppner H, Khalifa A, et al. Parathyroid hormone (PTH) stimulates adrenocorticotropin release in AtT-20 cells stably expressing a common receptor for PTH and PTH-related peptide. Endocrinology. 1993;132(2):801-805. doi: https://doi.org/10.1210/endo.132.2.7678801-20

41. Nakayama H, Takahashi T, Oomatsu Y, Nakagawa-Mizuyachi K, Kawashima M. Parathyroid hormone-related peptide directly increases adrenocorticotropic hormone secretion from the anterior pituitary in hens. Poult Sci. 2011;90(1):175-180. doi: https://doi.org/10.3382/ps.2010-00860

42. Nachtigall LB, Guarda FJ, Lines KE, et al. Clinical MEN-1 Among a Large Cohort of Patients With Acromegaly. J Clin Endocrinol Metab. 2020;105(6):e2271-e2281. doi: https://doi.org/10.1210/clinem/dgaa142