MEN syndromes are relatively rare.
Estimated prevalence is between 1 to 3 in 100,000.[8]Al-Salameh A, Cadiot G, Calender A, et al. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021 Apr;17(4):207-24.
https://www.doi.org/10.1038/s41574-021-00468-3
http://www.ncbi.nlm.nih.gov/pubmed/33564173?tool=bestpractice.com
Around 90% of patients develop primary hyperparathyroidism (PHPT) and this is often diagnosed at a younger age (20 to 25 years) compared to sporadic forms of PHPT.[3]Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep;97(9):2990-3011.
https://academic.oup.com/jcem/article/97/9/2990/2536740
http://www.ncbi.nlm.nih.gov/pubmed/22723327?tool=bestpractice.com
Approximately 40% to 70% of patients with MEN1 have pancreatic neuroendocrine tumors (NETs), which may be functioning (e.g., gastrinomas, insulinomas, glucagonomas, vasoactive intestinal polypeptidomas [VIPomas]), or nonfunctioning.[3]Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep;97(9):2990-3011.
https://academic.oup.com/jcem/article/97/9/2990/2536740
http://www.ncbi.nlm.nih.gov/pubmed/22723327?tool=bestpractice.com
Due to routine screening in MEN1 families, nonfunctioning pancreatic NETs are now the most common type of pancreatic NET in the setting of MEN1.[3]Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep;97(9):2990-3011.
https://academic.oup.com/jcem/article/97/9/2990/2536740
http://www.ncbi.nlm.nih.gov/pubmed/22723327?tool=bestpractice.com
[8]Al-Salameh A, Cadiot G, Calender A, et al. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021 Apr;17(4):207-24.
https://www.doi.org/10.1038/s41574-021-00468-3
http://www.ncbi.nlm.nih.gov/pubmed/33564173?tool=bestpractice.com
Gastrinomas are the most common functioning duodenopancreatic NETs in MEN1, affecting 21% to 70% of patients.[8]Al-Salameh A, Cadiot G, Calender A, et al. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021 Apr;17(4):207-24.
https://www.doi.org/10.1038/s41574-021-00468-3
http://www.ncbi.nlm.nih.gov/pubmed/33564173?tool=bestpractice.com
Around 30% to 40% of patients with MEN1 have pituitary adenomas.[3]Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep;97(9):2990-3011.
https://academic.oup.com/jcem/article/97/9/2990/2536740
http://www.ncbi.nlm.nih.gov/pubmed/22723327?tool=bestpractice.com
Prolactinomas are the most common and occur in 65% of patients with MEN1-related pituitary adenomas.[8]Al-Salameh A, Cadiot G, Calender A, et al. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021 Apr;17(4):207-24.
https://www.doi.org/10.1038/s41574-021-00468-3
http://www.ncbi.nlm.nih.gov/pubmed/33564173?tool=bestpractice.com
Growth hormone-secreting (somatotroph) pituitary adenomas and nonfunctioning adenomas are the next most common MEN1-related pituitary adenomas.[8]Al-Salameh A, Cadiot G, Calender A, et al. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021 Apr;17(4):207-24.
https://www.doi.org/10.1038/s41574-021-00468-3
http://www.ncbi.nlm.nih.gov/pubmed/33564173?tool=bestpractice.com
Adrenocorticotrophic hormone-secreting tumors are less common, occurring in <5% of patients with MEN1-related pituitary adenomas.[8]Al-Salameh A, Cadiot G, Calender A, et al. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021 Apr;17(4):207-24.
https://www.doi.org/10.1038/s41574-021-00468-3
http://www.ncbi.nlm.nih.gov/pubmed/33564173?tool=bestpractice.com
Thyroid-stimulating hormone-secreting tumors and gonadotroph secreting tumors are rare (<1%) MEN1-related pituitary adenomas.[8]Al-Salameh A, Cadiot G, Calender A, et al. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021 Apr;17(4):207-24.
https://www.doi.org/10.1038/s41574-021-00468-3
http://www.ncbi.nlm.nih.gov/pubmed/33564173?tool=bestpractice.com
Thymic and bronchial neuroendocrine tumors (NETs) each occur in 2% of patients with MEN1.[3]Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep;97(9):2990-3011.
https://academic.oup.com/jcem/article/97/9/2990/2536740
http://www.ncbi.nlm.nih.gov/pubmed/22723327?tool=bestpractice.com
Thymic NETs show a marked male predominance in European patients with MEN1 and are associated with a high mortality.[8]Al-Salameh A, Cadiot G, Calender A, et al. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol. 2021 Apr;17(4):207-24.
https://www.doi.org/10.1038/s41574-021-00468-3
http://www.ncbi.nlm.nih.gov/pubmed/33564173?tool=bestpractice.com
Bronchial NETs have a more indolent course.[3]Thakker RV, Newey PJ, Walls GV, et al; Endocrine Society. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012 Sep;97(9):2990-3011.
https://academic.oup.com/jcem/article/97/9/2990/2536740
http://www.ncbi.nlm.nih.gov/pubmed/22723327?tool=bestpractice.com
[9]de Laat JM, Pieterman CR, van den Broek MF, et al. Natural course and survival of neuroendocrine tumors of thymus and lung in MEN1 patients. J Clin Endocrinol Metab. 2014 Sep;99(9):3325-33.
http://www.ncbi.nlm.nih.gov/pubmed/24915123?tool=bestpractice.com
[10]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 Jun 11;10:339.
https://www.doi.org/10.3389/fendo.2019.00339
http://www.ncbi.nlm.nih.gov/pubmed/31263451?tool=bestpractice.com
Reported in approximately 1000 families worldwide in 2001.[5]Wells SA Jr, Pacini F, Robinson BG, et al. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013 Aug;98(8):3149–64.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399478
http://www.ncbi.nlm.nih.gov/pubmed/23744408?tool=bestpractice.com
Most cases are MEN2A.
Medullary thyroid cancer presents in nearly all genetic carriers of MEN2 by adulthood if not treated with prophylactic thyroidectomy, and is the commonest presenting feature of MEN2.[5]Wells SA Jr, Pacini F, Robinson BG, et al. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013 Aug;98(8):3149–64.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399478
http://www.ncbi.nlm.nih.gov/pubmed/23744408?tool=bestpractice.com
Pheochromocytoma occurs in about 50% of MEN2A patients. Pheochromocytoma is the first manifestation of MEN2 in 25% of patients.[5]Wells SA Jr, Pacini F, Robinson BG, et al. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013 Aug;98(8):3149–64.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399478
http://www.ncbi.nlm.nih.gov/pubmed/23744408?tool=bestpractice.com
[11]Petri BJ, van Eijck CH, de Herder WW, et al. Phaeochromocytomas and sympathetic paragangliomas. Br J Surg. 2009 Dec;96(12):1381-92.
http://onlinelibrary.wiley.com/doi/10.1002/bjs.6821/full
http://www.ncbi.nlm.nih.gov/pubmed/19918850?tool=bestpractice.com
Multigland parathyroid adenomas develop in up to 30% of MEN2A patients.[5]Wells SA Jr, Pacini F, Robinson BG, et al. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013 Aug;98(8):3149–64.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399478
http://www.ncbi.nlm.nih.gov/pubmed/23744408?tool=bestpractice.com
[12]Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med. 1988 Feb 25;318(8):478-84.
http://www.ncbi.nlm.nih.gov/pubmed/2893259?tool=bestpractice.com
[13]Easton DF, Ponder MA, Cummings T, et al. The clinical and screening age-at-onset distribution for the MEN-2 syndrome. Am J Hum Genet. 1989 Feb;44(2):208-15.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1715408/pdf/ajhg00112-0034.pdf
http://www.ncbi.nlm.nih.gov/pubmed/2563193?tool=bestpractice.com
[14]Ponder BA, Ponder MA, Coffey R, et al. Risk estimation and screening in families of patients with medullary thyroid carcinoma. Lancet. 1988 Feb 20;1(8582):397-401.
http://www.ncbi.nlm.nih.gov/pubmed/2893198?tool=bestpractice.com
PHPT is found in smaller subsets of MEN2A patients.[15]Schuffenecker I, Virally-Monod M, Brohet R, et al. Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe d'etude des Tumeurs a Calcitonine. J Clin Endocrinol Metab. 1998 Feb;83(2):487-91.
http://jcem.endojournals.org/cgi/content/full/83/2/487
http://www.ncbi.nlm.nih.gov/pubmed/9467562?tool=bestpractice.com
Rare variants of MEN2A include Hirschsprung disease and cutaneous lichen amyloidosis.[16]Donovan DT, Levy ML, Furst EJ, et al. Familial cutaneous lichen amyloidosis in association with multiple endocrine neoplasia type 2A: a new variant. Henry Ford Hosp Med J. 1989;37(3-4):147-50.
http://www.ncbi.nlm.nih.gov/pubmed/2576950?tool=bestpractice.com
[17]Verdy M, Weber AM, Roy CC, et al. Hirschsprung's disease in a family with multiple endocrine neoplasia type 2. J Pediatr Gastroenterol Nutr. 1982;1(4):603-7.
http://www.ncbi.nlm.nih.gov/pubmed/6136579?tool=bestpractice.com
MEN2B is quite rare (prevalence: 0.9 to 1.6 per million individuals) and, compared with MEN2A, is notable for more aggressive pheochromocytoma and medullary thyroid cancer presenting at earlier ages.[6]Castinetti F, Waguespack SG, Machens A, et al. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. Lancet Diabetes Endocrinol. 2019 Mar;7(3):213-20.
https://www.doi.org/10.1016/S2213-8587(18)30336-X
http://www.ncbi.nlm.nih.gov/pubmed/30660595?tool=bestpractice.com
[18]Castinetti F, Moley J, Mulligan L, et al. A comprehensive review on MEN2B. Endocr Relat Cancer. 2018 Feb;25(2):T29-T39.
https://www.doi.org/10.1530/ERC-17-0209
http://www.ncbi.nlm.nih.gov/pubmed/28698189?tool=bestpractice.com