Predicting the presence of MEN1 gene mutation based on the clinical phenotype of patients with primary hyperparathyroidism

BACKGROUND: Timely referral of patients for genetic testing to rule out MEN1-associated primary PHPT is important factor in determining treatment strategy and prognosis. In the context of the limited availability of genetic testing, the search for clinical markers indicative of MEN1 gene mutations remains an extremely relevant task.

AIM: To determine the diagnostic value of clinical features of primary PHPT in young patients for predicting the presence of MEN1 gene mutations.

MATERIALS AND METHODS: A single-center, prospective study was conducted at the Endocrinology Research Centre, involving 273 patients with PHPT in the period 2015–2022. Based on the results of genetic and laboratory tests, patients were divided into three groups: those with MEN1 gene mutations (MEN+ group, n=71), those without MEN1 gene mutations — isolated sporadic PHPT (MEN- group, n=158), and patients with PHPT and associated endocrine gland disorders — MEN-1 syndrome phenocopies (PHEN group, n=32). Subgroups of patients younger than 40 years of age were also identified. Comparative analysis was performed among the independent groups and subgroups, and logistic regression analysis was used to develop a mathematical model for predicting the probability of the presence of MEN1 gene mutation.

RESULTS: Patients in the MEN+ and MEN- groups were comparable by gender and age at manifestation, as well as calcium-phosphorus metabolism parameters and PHPT complications. In the PHEN group, PHPT manifested at older age compared to the other groups (p<0.001 for all), with lower total calcium levels and a trend toward lower iPTH concentrations. The MEN+ group had a significantly higher frequency of multiglandular parathyroid (PG) involvement, PHPT recurrence, and positive family history compared to the MEN- and PHEN groups. Histologically, adenomas predominated in the PHEN and MEN- groups (92% and 94%, respectively), whereas hyperplasia of PGs were more common in the MEN+ group (49%). None of the PHEN patients had all three «classic» components of the MEN-1 syndrome, and the clinical course of PHPT was similar to that of the MEN- group. These differences were also observed in the subgroups of patients younger than 40 years, which formed the basis for the development of a mathematical model. The logistic regression equation for predicting the probability of the presence of the MEN1 gene mutation included eight predictors, with a diagnostic sensitivity of 96% and specificity of 98%.

CONCLUSION: Based on the analysis performed, eight hereditary predictors of PHPT within the MEN-1 syndrome were identified. A mathematical model was developed to predict the presence of the MEN1 gene mutation in patients, which demonstrated high classification performance on the training dataset. Further refinement of the model will help improve the quality of medical care for patients with PHPT.

1. Mokrysheva NG, Eremkina AK, Krupinova JA, et al.The clinical practice guidelines for primary hyperparathyroidism, short version. Problems of Endocrinology. 2021;67(4):94-124. (In Russ.). doi: https://doi.org/10.14341/probl12801

2. Cetani F, Saponaro F, Borsari S, Marcocci C. Familial and hereditary forms of primary hyperparathyroidism. Front Horm Res. 2018;(51):40-51. doi: https://doi.org/10.1159/000491037

3. Gorbacheva AM, Eremkina AK, Mokrysheva NG. Hereditary syndromal and nonsyndromal forms of primary hyperparathyroidism. Problems of Endocrinology. 2020;66(1):23-34. (In Russ.). doi: https://doi.org/10.14341/probl10357

4. 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

5. Twigt BA, Scholten A, Valk GD, et al. Differences between sporadic and MEN related primary hyperparathyroidism; Clinical expression, preoperative workup, operative strategy and follow-up. Orphanet J Rare Dis. 2013;8(1):1-8. doi: https://doi.org/10.1186/1750-1172-8-50/FIGURES/1

6. Marini F, Giusti F, Cioppi F, et al. Bone and mineral metabolism phenotypes in MEN1-related and sporadic primary hyperparathyroidism, before and after parathyroidectomy. Cells. 2021;10(8):1895. doi: https://doi.org/10.3390/CELLS10081895

7. Eller‐Vainicher C, Chiodini I, Battista C, et al. Sporadic and MEN1‐related primary hyperparathyroidism: Differences in clinical expression and severity. J Bone Miner Res. 2009;24(8):1404-1410. doi: https://doi.org/10.1359/jbmr.090304

8. Eremkina AK, Sazonova DV, Bibik EE, et al. Severe bone complications of primary hyperparathyroidism in a young patient with the rare verified mutation of MEN1. Problems of Endocrinology. 2022;68(1):81-93. (In Russ.). doi: https://doi.org/10.14341/probl12864

9. 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

10. Pieterman CRC, Hyde SM, Wu SY, et al. Understanding the clinical course of genotype-negative MEN1 patients can inform management strategies. Surgery. 2021;169(1):175-184. doi: https://doi.org/10.1016/J.SURG.2020.04.067

11. de Laat JM, van der Luijt RB, Pieterman CRC, et al. MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. BMC Med. 2016;14(1):1-9. doi: https://doi.org/10.1186/S12916-016-0708-1/FIGURES/3

12. Eller‐Vainicher C, Chiodini I, Battista C, et al. Sporadic and MEN1‐related primary hyperparathyroidism: differences in clinical expression and severity. J Bone Miner Res. 2009;24(8):1404-1410. doi: https://doi.org/10.1359/jbmr.090304

13. Twigt BA, Scholten A, Valk GD, et al. Differences between sporadic and MEN related primary hyperparathyroidism; Clinical expression, preoperative workup, operative strategy and follow-up. Orphanet J Rare Dis. 2013;8(1):1-8. doi: https://doi.org/10.1186/1750-1172-8-50/FIGURES/1

14. Marini F, Giusti F, Cioppi F, et al. Bone and mineral metabolism phenotypes in MEN1-related and sporadic primary hyperparathyroidism, before and after parathyroidectomy. Cells. 2021;10(8):1895. doi: https://doi.org/10.3390/cells10081895

15. Sato M, Miyauchi A, Takahara J. Clinical aspects of hyperparathyroidism in Japanese multiple endocrine neoplasia type 1. Biomed Pharmacother. 2000;(54):86s-89s. doi: https://doi.org/10.1016/S0753-3322(00)80020-7

16. Katai M, Sakurai A, Ikeo Y, Hashizume K. Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1: comparison with sporadic parathyroid adenomas. Horm Metab Res. 2001;33(8):499-503. doi: https://doi.org/10.1055/S-2001-16944

17. Eller‐Vainicher C, Chiodini I, Battista C, et al. Sporadic and MEN1‐related primary hyperparathyroidism: differences in clinical expression and severity. J Bone Miner Res. 2009;24(8):1404-1410. doi: https://doi.org/10.1359/jbmr.090304

18. Lourenço DM, Toledo RA, Mackowiak II, et al. Multiple endocrine neoplasia type 1 in Brazil: MEN1 founding mutation, clinical features, and bone mineral density profile. Eur J Endocrinol. 2008;159(3):259-274. doi: https://doi.org/10.1530/EJE-08-0153

19. Balsalobre Salmeron M, Rodriguez Gonzalez JM, Ríos A, et al. Hiperparatiroidismo primario asociado a neoplasia endocrina múltiple tipo 1 (MEN 1). Experiencia en 71 casos. Cir Esp. 2018;96(10):627-633. doi: https://doi.org/10.1016/J.CIRESP.2018.06.014

20. Wang W, Nie M, Jiang Y, et al. Impaired geometry, volumetric density, and microstructure of cortical and trabecular bone assessed by HR-pQCT in both sporadic and MEN1-related primary hyperparathyroidism. Osteoporosis International. 2019;31(1):165-173. doi: https://doi.org/10.1007/S00198-019-05186-1

21. Marini F, Giusti F, Cioppi F, et al. Bone and mineral metabolism phenotypes in MEN1-related and sporadic primary hyperparathyroidism, before and after parathyroidectomy. Cells. 2021;10(8):1895. doi: https://doi.org/10.3390/CELLS10081895

22. Publishing Ltd B, Mosekilde L. Primary hyperparathyroidism and the skeleton. Clin Endocrinol (Oxf). 2008;69(1):1-19. doi: https://doi.org/10.1111/J.1365-2265.2007.03162.X

23. Gorbacheva A, Eremkina A, Goliusova D, et al. The role of menin in bone pathology. Endocr Connect. 2022;11(3):1404-1410. doi: https://doi.org/10.1530/EC-21-0494

24. Eller‐Vainicher C, Chiodini I, Battista C, et al. Sporadic and MEN1‐related primary hyperparathyroidism: Differences in clinical expression and severity. J Bone Miner Res. 2009;24(8):1404-1410. doi: https://doi.org/10.1359/jbmr.090304

25. Twigt BA, Scholten A, Valk GD, et al. Differences between sporadic and MEN related primary hyperparathyroidism; Clinical expression, preoperative workup, operative strategy and follow-up. Orphanet J Rare Dis. 2013;8(1):1-8. doi: https://doi.org/10.1186/1750-1172-8-50/FIGURES/1

26. Lourenço DM, Coutinho FL, Toledo RA, et al. Early‐onset, progressive, frequent, extensive, and severe bone mineral and renal complications in multiple endocrine neoplasia type 1–associated primary hyperparathyroidism. J Bone Miner Res. 2010;25(11):2382-2391. doi: https://doi.org/10.1002/jbmr.125

27. Thakker R V. Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Mol Cell Endocrinol. 2014;386(1-2):2-15. doi: https://doi.org/10.1016/J.MCE.2013.08.002

28. Bibik EE, Eremkina AK, Knyazeva OA, Mokrysheva NG. Sporadic primary hyperparathyroidism with multiple parathyroid adenomas. Problems of Endocrinology. 2021;67(6):31-38. (In Russ.). doi: https://doi.org/10.14341/probl12798

29. de Laat JM, van der Luijt RB, Pieterman CRC, et al. MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients. BMC Med. 2016;14(1):1-9. doi: https://doi.org/10.1186/S12916-016-0708-1/FIGURES/3

30. Дедов И.И., Мельниченко Г.А., Мокрышева Н.Г., и др. Проект клинических рекомендаций по диагностике и лечению первичного гиперпаратиреоза у взрослых пациентов // Эндокринная хирургия. — 2023. — Т. 16. — №4. — С. 5-54. [Dedov II, Melnichenko GA, Mokrysheva NG, et al. Draft of clinical guidelines for the diagnosis and treatment of primary hyperparathyroidism in adult patients. Endocrine Surgery. 2022;16(4):5-54. (In Russ.)]. doi: https://doi.org/10.14341/serg12790

31. Skandarajah A, Barlier A, Morlet-Barlat N, et al. Should routine analysis of the MEN1 gene be performed in all patients with primary hyperparathyroidism under 40 years of age? World J Surg. 2010;34(6):1294-1298. doi: https://doi.org/10.1007/S00268-009-0388-5

32. De Laat JM, Tham E, Pieterman CRC, et al. Predicting the risk of multiple endocrine neoplasia type 1 for patients with commonly occurring endocrine tumors. Eur J Endocrinol. 2012;167(2):181-187. doi: https://doi.org/10.1530/EJE-12-0210