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== Overview ==
== Overview ==


==Historical Perspective==
* In 1903 Erdheim described the case of an acromegalic patient with a [[pituitary adenoma]] and three enlarged [[parathyroid gland]]s.
* In 1953 Underdahl ''et al.'' reported a case series of 8 patients with a [[syndrome]] of [[pituitary]], [[parathyroid]], and pancreatic islet [[adenoma]]s.
* 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]] [[tumor]]s 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  [[mutation]]s 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.<ref>Germ-line [[mutation]]s of the [[RET]] proto-[[oncogene]] in [[multiple endocrine neoplasia type 2]]A.
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</ref>
* In 1998 the MEN1 gene was cloned<ref name="Guru1998">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</ref>
==Classification==
==Classification==
{{Familytree/start}}
{{Familytree/start}}
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* MEN syndromes are inherited as [[autosomal dominant]] disorders.<ref>{{DorlandsDict|six/000070637|multiple endocrine neoplasia}}</ref>
* MEN syndromes are inherited as [[autosomal dominant]] disorders.<ref>{{DorlandsDict|six/000070637|multiple endocrine neoplasia}}</ref>


==MEN type 1==
===Comparison===
{{main|Multiple endocrine neoplasia type 1}}
#[[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===
{{main|Multiple endocrine neoplasia type 2}}
 
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
 
#[[Medullary thyroid 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.<ref>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</ref> 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]].
#[[Marfan syndrome|Marfanoid]] habitus
 
==MEN type 4==
* A rare and latest addition to the multiple endocrine neoplasia is multiple endocrine neoplasia type 4. It affects pituitary gland and parathyroid glands. So far only 12 index cases have been reported.
==Comparison==
[[File:Multiple endocrine neoplasia.png|thumb|center|500px|Presentations of Multiple endocrine neoplasia.]]
[[File:Multiple endocrine neoplasia.png|thumb|center|500px|Presentations of Multiple endocrine neoplasia.]]
Percentages in table below refer to how large fraction of people with the MEN type develop the [[neoplasia]] type.
Percentages in table below refer to how large fraction of people with the MEN type develop the [[neoplasia]] type.
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|}
|}
<nowiki>*</nowiki>- of patients with MEN1 and gastrinoma
<nowiki>*</nowiki>- 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.<ref>{{cite journal |author=Schimke RN, Hartmann WH, Prout TE, Rimoin DL |title=Syndrome of bilateral pheochromocytoma, medullary thyroid carcinoma and multiple neuromas. A possible regulatory defect in the differentiation of chromaffin tissue |journal=N. Engl. J. Med. |volume=279 |issue=1 |pages=1–7 |year=1968 |pmid=4968712 |doi= 10.1056/NEJM196807042790101|url=}}</ref>
* [[OMIM]] also includes a fourth form of multiple endocrine neoplasia ("MEN4"), associated with CDKN1B.<ref>{{OMIM|610755|MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV; MEN4}}</ref> The presentation is believed to overlap that of MEN1 and MEN2.<ref name="pmid17030811">{{cite journal |author=Pellegata NS, Quintanilla-Martinez L, Siggelkow H, et al. |title=Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=42 |pages=15558–63 |date=Oct 2006 |pmid=17030811 |pmc=1622862 |doi=10.1073/pnas.0603877103 |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=17030811|bibcode=2006PNAS..10315558P |last2=Quintanilla-Martinez |last3=Siggelkow |last4=Samson |last5=Bink |last6=Hofler |last7=Fend |last8=Graw |last9=Atkinson  }}</ref>


=== Associated Conditions===
=== Associated Conditions===

Revision as of 02:00, 1 October 2015

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

Overview

Classification

 
 
 
 
 
 
 
 
 
 
 
 
 
Multiple endocrine neoplasia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multiple endocrine neoplasia type 1
 
 
 
 
 
 
 
Multiple endocrine neoplasia type 2
 
 
 
 
 
 
 
 
 
Multiple endocrine neoplasia type 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multiple endocrine neoplasia type 2A
 
 
 
 
 
 
 
 
 
Multiple endocrine neoplasia type 2B
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multiple endocrine neoplasia type 2A classical
 
Multiple endocrine neoplasia type 2A with cutaneous lichen amyloidosis
 
 
Multiple endocrine neoplasia type 2A with hirschsprung disease
 
Familial medullary cancer without pheochromocytoma or parathyroid hyperplasia
 
 
Medullary thyroid cancer, pheochromocytoma and mucosal neuromas or intestinal ganglioneuromas and marfanoid habitus
 
 
 
 
 
 
 
 
 
 

Pathophysiology

Comparison

Presentations of Multiple endocrine neoplasia.

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%[2]),
insulinoma (20%[2]),
vipoma,
glucagonoma,
PPoma 		- - -
Pituitary adenoma 66%[2] - - -
Angiofibroma 64%*[3] - - -
Lipoma 17%*[3] - - -
Parathyroid hyperplasia 90%[2] 50%[2] - -
Medullary thyroid carcinoma - 100%[2] 85%[2] 100%
Pheochromocytoma - >33%[2] 50% -
Marfanoid body habitus - - 80% -
Mucosal neuroma - - 100%[2] -
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)[4] 		1 in 40,000[5] 1 in 1,000,000
(1 in 600,000[6] to
1 in 4,000,000[7])[8]
Initial description (year) 1954[9] 1961[10] 1965

*- of patients with MEN1 and gastrinoma

Associated Conditions

Surgery

  • Surgery is the mainstay of treatment of tumors of multiple endocrine neoplasia.

References

  1. ↑ Template:DorlandsDict
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 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.
  3. ↑ 3.0 3.1 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.
  4. ↑ [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
  5. ↑ 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.
  6. ↑ Marx, Stephen J (2011). "Chapter 41: Multiple endocrine neoplasia". In Melmed, Shlomo. Williams Textbook of Endocrinology, 12th ed. pp. 1728–1767.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.


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