Characteristics of Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A

Abstract

Objective: Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominantly inherited tumour syndrome and primary hyperparathyroidism (pHPT) is one of the major components of MEN2A. Our study evaluated the features of MEN2A-related hyperparathyroidism Material and Methods: Records of 49 patients with MEN2A followed up at Istanbul Faculty of Medicine were retrospectively reviewed. Results: This study included 25 females and 24 males, and 55% of the patients had RET 634 variants. The median follow-up duration was 12 years. Medullary thyroid cancer (MTC) was present in 44 patients, and the mean age at diagnosis was 30.8±14 years. Pheochromocytoma was detected in 61% of patients, and the mean age at diagnosis was 36.4±12.6 years. Twelve patients (F/M=1) had pHPT, and the mean age at diagnosis was 40±15.7 years. The frequency of pHPT was 6% in the ATA moderate-risk category and 33.3% in the high-risk category (RET 634 variants). pHPT developed in 3 of 4 patients carrying the RET C634R variant. The most common symptoms were nephrolithiasis and osteoporosis, and 67% of patients had normocalcemic pHPT. Selective surgery was performed in 9 patients and subtotal parathyroidectomy in 1 patient. The median follow-up duration after the diagnosis of pHPT was 10.5 years, and persistent disease developed in 1 patient. Recurrent hyperparathyroidism occurred in 1 patient 12 years after the first operation. Five patients developed permanent hypoparathyroidism. Conclusion: The RET mutation at codon 634 is associated with a high frequency of pHPT, usually accompanied by normocalcemia or, less frequently, mild hypercalcemia.

Keywords

• Multiple Endocrine Neoplasia type Type 2A
• MEN2A
• Primary Hyperparathyroidism

References

1. Takaya K, Yoshimasa T, Arai H, Tamura N, Miyamoto Y, Itoh H, et al. Expression of the RET proto-oncogene in normal human tissues, pheochromocytomas, and other tumors of neural crest origin. J Mol Med (Berl) 1996;74(10):617-21. google scholar
2. Opsahl EM, Brauckhoff M, Schlichting E, Helset K, Svartberg J, Brauckhoff K, et al. A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma. Thyroid 2016;26(9):1225-38. google scholar
3. Mathiesen JS, Kroustrup JP, Vestergaard P, Stochholm K, Poulsen PL, Rasmussen ÂK, et al. Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark 1901-2014: a nationwide study. Clin Epidemiol 2018;10:1479-87. google scholar
4. Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015;25(6):567-610. google scholar
5. Quayle FJ, Fialkowski EA, Benveniste R, Moley JF. Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery 2007;142(6):800-5. google scholar
6. Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metab 2013;98(2):E336-45. google scholar
7. Iacobone M, Carnaille B, Palazzo FF, Vriens M. Hereditary hyperparathyroidism--a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbecks Arch Surg 2015;400(8):867-86. google scholar
8. Raue F, Kraimps JL, Dralle H, Cougard P, Proye C, Frilling A, et al. Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med 1995;238(4):369-73. google scholar

9. Larsen LV, Mirebeau-Prunier D, Imai T, Alvarez-Escola C, Hasse-Lazar K, Censi S, et al. Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study. Endocr Connect 2020;9(6):489-97. google scholar
10. van Treijen MJC, de Vries LH, Hertog D, Vriens MR, Verrijn Stuart AA, van Nesselrooij BPM, et al. Multiple Endocrine Neoplasia Type 2. [Updated 2022 Jan 2]. In: Feingold KR, Anawalt B, Blackman MR, et al., Endotext South Dartmouth (MA): MDText.com, Inc.; 2000-. https://www.ncbi.nlm.nih.gov/books/NBK481898/ google scholar
11. Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000;88(5):1139-48. google scholar
12. Siqueira DR, Ceolin L, Ferreira CV, Romitti M, Maia SC, Maciel LM, et al. Role of RET genetic variants in MEN2-associated pheochromocytoma. Eur J Endocrinol 2014;170(6):821-8. google scholar
13. Holm M, Vestergaard P, Poulsen MM, Rasmussen ÂK, Feldt-Rasmussen U, Bay M, et al. Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 2A in Denmark 1930-2021: A Nationwide Population-Based Retrospective Study. Cancers (Basel) 2023;15(7):2125. google scholar
14. Machens A, Gimm O, Hinze R, Hoppner W, Boehm BO, Dralle H. Genotype-phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endoc Metabol 2001;86:1104-9. google scholar
15. Mulligan LM, Eng C, Healey CS, Clayton D, Kwok JB, Gardner E, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994;6(1):70-4. google scholar
16. Frank-Raue K, Höppner W, Frilling A, Kotzerke J, Dralle H, Haase R, et al. Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German Medullary Thyroid Carcinoma Study Group. J Clin Endocrinol Metab 1996;81(5):1780-3. google scholar
17. Herfarth KK, Bartsch D, Doherty GM, Wells Jr SA, Lairmore TC. Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery 1996;120:966-73. google scholar