Sandbox MEN
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]
Synonyms and keywords:
Overview
Historical Perspective
- In 1903 Erdheim described the case of an acromegalic patient with a pituitary adenoma and three enlarged parathyroid glands.
- In 1953 Underdahl et al. reported a case series of 8 patients with a syndrome of pituitary, parathyroid, and pancreatic islet adenomas.
- In 1954 Wermer noted that this syndrome was transmitted as a dominant trait.
- In 1959 Hazard et al. described medullary (solid) thyroid carcinoma.
- In 1961 Sipple described a combination of a pheochromocytoma, medullary thyroid carcinoma and parathyroid adenoma.
- In 1966 Williams et al. described the combination of mucosal neuromas, pheochromocytoma and medullary thyroid carcinoma.
- In 1968 Steiner et al. introduced the term "multiple endocrine neoplasia" (MEN) to describe disorders featuring combinations of endocrine tumors and proposed the terms 'Wermer syndrome' for MEN 1 and 'Sipple syndrome' for MEN 2.
- In 1974 Sizemore et al. showed that the MEN 2 category included two groups of patients with MTC and pheochromocytoma: one with parathyroid disease and a normal appearance (MEN 2A) and the other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B).
- In 1988 the MEN1 locus was assigned to Chromosome 11 (11q13).
- In 1993 mutations in the RET oncogene were shown to be the cause of MEN 2A by Lois Mulligan, working in the laboratory of Dr Bruce Ponder in Cambridge.[1]
- In 1998 the MEN1 gene was cloned[2]
Classification
MEN type 1
Type 1 is also known as Wermer's syndrome after Dr Paul Wermer, who described it in 1954:[3]
- Parathyroid hyperplasia/tumour causing hyperparathyroidism.
- Pancreatic islet cell tumours causing hypoglycaemia (insulinoma) and Zollinger-Ellison syndrome (gastrinoma).
- Pituitary adenoma which may cause pituitary hormone excess.
The causative mutation is in the MEN1 gene at 11q13 which encodes a nuclear protein called menin that is believed to act as a tumor suppressor. Most cases of multiple endocrine neoplasia type 1 are inherited in an autosomal dominant pattern.
MEN type 2
MEN type 2/type 2a
MEN syndrome types 2 and 3 have their basis in molecular genetics. Individuals can be tested for this genetic disorder reliably even when asymptomatic. The mutation is in the RET proto-oncogene. Most cases of multiple endocrine neoplasia types 2 and 3 are inherited in an autosomal dominant pattern.
Type 2 is also known as Sipple syndrome (after the American Dr John H. Sipple, who described it in 1961)[4] and used to be called type 2A:
- Medullary carcinoma of the thyroid which is associated with increased calcitonin secretion. A test for elevated calcitonin should be done after pentagastrin injection and/or calcium infusion, to ensure that all affected patients are detected.
- Pheochromocytoma
- Parathyroid hyperplasia/tumour causing hyperparathyroidism.
MEN type 3/type 2b
This syndrome has no eponym; it was described by Schimke et al in 1968.[5] Originally thought to be a third MEN, then considered a variant of II (especially after linkage to RET was confirmed), it is now considered its own syndrome.
- Pheochromocytoma
- Medullary carcinoma of thyroid which is associated with increased calcitonin secretion. A test for elevated calcitonin should be done after pentagastrin injection and/or calcium infusion, to ensure that all affected patients are detected.
- Mucosal neuromas which are usually situated in the gastrointestinal tract.
- Marfanoid habitus
Comparison
Percentages in table below refer to how large fraction of people with the MEN type develop the neoplasia type.
| Feature | MEN 1 | MEN 2 | ||
|---|---|---|---|---|
| MEN 2A | MEN 2B | FMTC | ||
| Eponym | Wermer syndrome | Sipple syndrome | (multiple) | (none) |
| OMIM | Template:OMIM4 | Template:OMIM4 | Template:OMIM4 | Template:OMIM4 |
| Pancreatic tumors | gastrinoma (50%[6]), insulinoma (20%[6]), vipoma, glucagonoma, PPoma |
- | - | - |
| Pituitary adenoma | 66%[6] | - | - | - |
| Angiofibroma | 64%*[7] | - | - | - |
| Lipoma | 17%*[7] | - | - | - |
| Parathyroid hyperplasia | 90%[6] | 50%[6] | - | - |
| Medullary thyroid carcinoma | - | 100%[6] | 85%[6] | 100% |
| Pheochromocytoma | - | >33%[6] | 50% | - |
| Marfanoid body habitus | - | - | 80% | - |
| Mucosal neuroma | - | - | 100%[6] | - |
| Gene(s) | MEN1 (Template:OMIM4) | RET (Template:OMIM4) | RET (Template:OMIM4) | RET (Template:OMIM4), NTRK1 (Template:OMIM4) |
| Approx. prevalence | 1 in 35,000 (1 in 20,000 to 1 in 40,000)[8] |
1 in 40,000[9] | 1 in 1,000,000 (1 in 600,000[10] to 1 in 4,000,000[11])[12] |
|
| Initial description (year) | 1954[13] | 1961[14] | 1965 | |
*- of patients with MEN1 and gastrinoma
FMTC = familial medullary thyroid cancer
- Multiple endocrine neoplasia type 2b|MEN 2B is sometimes known as MEN 3 and the designation varies by institution (c.f. www.ClinicalReview.com).
- Although a variety of additional eponyms have been proposed for MEN2B (e.g. Williams-Pollock syndrome, Gorlin-Vickers syndrome, and Wagenmann–Froboese syndrome), none ever gained sufficient traction to merit continued use and, indeed, are all but abandoned in the medical literature. Another early report was Schimke et al. in 1968.[15]
- OMIM also includes a fourth form of multiple endocrine neoplasia ("MEN4"), associated with CDKN1B.[16] The presentation is believed to overlap that of MEN1 and MEN2.[17]
Pathophysiology
- The term multiple endocrine neoplasia (MEN) encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.
- MEN syndromes are inherited as autosomal dominant disorders.[18]
Associated Conditions
Surgery
- Surgery is the mainstay of treatment of tumors of multiple endocrine neoplasia.
References
- ↑ Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Mulligan LM, Kwok JB, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, et al. Nature 1993 Jun 3;363(6428) 458-60 PMID 8099202
- ↑ Guru SC, Manickam P, Crabtree JS, Olufemi SE, Agarwal SK, Debelenko LV. Identification and characterization of the multiple endocrine neoplasia type 1 (MEN1) gene. J Intern Med 243(6) 433-9
- ↑ Wermer P. Genetic aspect of adenomatosis of endocrine glands. Am J Med 1954;16:363-371. PMID 13138607.
- ↑ Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961;31:163-166.
- ↑ Schimke RN, Hartmann WH, Prout TE, Rimoin DL. Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma and multiple neuromas. A possible regulatory defect in the differentiation of chromaffin tissue. N Engl J Med 1968;279:1-7. PMID 4968712
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 Table 4-7 in:Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-7153-6.
- ↑ 7.0 7.1 Asgharian, B; Turner, ML; Gibril, F; Entsuah, LK; Serrano, J; Jensen, RT (November 2004). "Cutaneous tumors in patients with multiple endocrine neoplasm type 1 (MEN1) and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity for MEN1". The Journal of Clinical Endocrinology and Metabolism. 89 (11): 5328–36. doi:10.1210/jc.2004-0218. PMID 15531478.
- ↑ [1] 123I labeled metaiodobenzylguanidine for diagnosis of neuroendocrine tumors. Jiang L, Schipper ML, Li P, Cheng Z, Reports in Medical Imaging. 2009: 2 79-89
- ↑ Dora JM, Siqueira DR, Meyer EL, Puñales MK, Maia AL (November 2008). "Pancreatitis as the first manifestation of multiple endocrine neoplasia type 2A". Arq Bras Endocrinol Metabol. 52 (8): 1332–6. doi:10.1590/S0004-27302008000800021. PMID 19169490.
- ↑ Marx, Stephen J (2011). "Chapter 41: Multiple endocrine neoplasia". In Melmed, Shlomo. Williams Textbook of Endocrinology, 12th ed. pp. 1728–1767.
- ↑ Moline J, Eng C. (2011). "Multiple endocrine neoplasia type 2: An overview". Genetics in Medicine. 13 (9): 755–764. doi:10.1097/GIM.0b013e318216cc6d. PMID 21552134.
- ↑ Martino Ruggieri (2005). Neurocutaneous Disorders : The Phakomatoses. Berlin: Springer. ISBN 3-211-21396-1. - Chapter: Multiple Endocrine Neoplasia Type 2B by Electron Kebebew, Jessica E. Gosnell and Emily Reiff. Pages 695-701. [2] This reference quotes a prevalence of 1 in 40,000, but this figure is inconsistent with the same reference's calculated incidence of 4 per 100 million per year for MEN2B.
- ↑ Wermer P (1954). "Genetic aspects of adenomatosis of endocrine glands". Am. J. Med. 16 (3): 363–71. doi:10.1016/0002-9343(54)90353-8. PMID 13138607.
- ↑ Sipple JH (1961). "The association of pheochromocytoma with carcinoma of the thyroid gland". Am. J. Med. 31: 163–6. doi:10.1016/0002-9343(61)90234-0.
- ↑ Schimke RN, Hartmann WH, Prout TE, Rimoin DL (1968). "Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma and multiple neuromas. A possible regulatory defect in the differentiation of chromaffin tissue". N. Engl. J. Med. 279 (1): 1–7. doi:10.1056/NEJM196807042790101. PMID 4968712.
- ↑ Online Mendelian Inheritance in Man (OMIM) MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV; MEN4 -610755
- ↑ Pellegata NS, Quintanilla-Martinez L, Siggelkow H; Quintanilla-Martinez; Siggelkow; Samson; Bink; Hofler; Fend; Graw; Atkinson; et al. (Oct 2006). "Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans". Proc. Natl. Acad. Sci. U.S.A. 103 (42): 15558–63. Bibcode:2006PNAS..10315558P. doi:10.1073/pnas.0603877103. PMC 1622862. PMID 17030811.
- ↑ Template:DorlandsDict