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* 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>
* 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>
* [[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>
== Multiple Endocrine Neoplasia Type 1 (MEN1) ==
=== The MEN1 gene ===
* The [[MEN1]] [[gene]] consists of ten [[exon]]s, spanning about 10 kb, and encodes a 610 [[amino acid]] [[protein]] named menin. The first [[exon]] and the last part of [[exon]] 10 are not translated. A main transcript of 2.8 kb has been described in a large variety of human [[tissue]]s ([[pancreas]], [[thymus]], [[adrenal gland]]s, [[thyroid]], [[testis]], [[leukocyte]]s, [[heart]], [[brain]], [[lung]], [[muscle]], [[small intestine]], [[liver]], and [[kidney]]); an additional transcript of approximately 4 kb has been detected in [[pancreas]] and [[thymus]], suggesting a [[tissue]]-specific alternative splicing.
=== The Menin Protein ===
* Menin is a 610 [[amino acid]] (67Kda) nuclear [[protein]], highly conserved from mouse (98%), rat (97%) and, more distantly, zebrafish (75%) and [[Drosophila]] (47%) (47-51). Human and mouse MEN1 [[amino acid]] sequences share 95.8% identity and 98.4% similarity. Analysis of menin [[amino acid]] sequence did not reveal homologies to any other known human or mammalian [[protein]], sequence motif, or signal [[peptide]]. The absence of significant homology to any other [[protein]] complicates efforts to elucidate the functions of menin.
=== Pathophysiology ===
* MEN1 follows Knudson’s “two-hit” model for [[tumor suppressor]] [[gene]] [[carcinogenesis]]. The first hit is a [[heterozygous]] [[MEN1]] [[germline mutation]], inherited from one parent (familial cases) or developed in an early embryonic stage (sporadic cases) and present in all [[cell]]s at birth. The second hit is a [[MEN1]] [[somatic mutation]], usually a large [[deletion]], that occurs in the predisposed [[endocrine]] [[cell]] as loss of the remaining wild-type [[allele]] and gives [[cell]]s the survival advantage needed for [[tumor]] development.
=== Mnemonic ===
* A useful mnemonic to remember the associated neoplasias is below:
:* MEN I '''(3 Ps)''' - [[Pituitary]], [[Parathyroid]], [[Pancreatic]]<br>
:* MEN IIa '''(1M,2Ps)''' - Medullary [[Thyroid]] [[Carcinoma]], [[Pheochromocytoma]], [[Parathyroid]]<br>
:* MEN IIb '''(2Ms,1P)''' - Medullary [[Thyroid]] [[Carcinoma]], Marfanoid habitus/mucosal [[neuroma]], [[Pheochromocytoma]]
=== ''MEN1'' mutations in multiple endocrine neoplasia patients and clinical genetics ===
* MEN1 [[gene]] [[mutation]]s can be identified in 70-95% of MEN1 patients and in about 20% of familial isolated [[hyperparathyroidism]] cases. Almost all patients are [[heterozygous]] for [[mutation]]s. One affected family has been identified with individuals both [[homozygous]] and [[heterozygous]] for [[MEN1]] [[mutation]]s. In this family, there was no difference in disease history between the [[homozygous]] and [[heterozygous]] [[mutation]] carriers.
* Fifty percent of patients develop signs and [[symptom]]s by 20 years of age and more than 95% have symptoms by 40 years of age. There is significant intra- and inter-familial variability in the age of onset, severity of [[disease]], and [[tumor]] types. Despite numerous studies, no [[genotype]]-[[phenotype]] correlations have been established, suggesting that unknown genetic and environmental modifiers are involved in the expression of the [[MEN1]] [[phenotype]].<ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=famcan&part=ch1famcan |title= Multiple Endocrine Neoplasia Type 1: In Familial Cancer Syndromes. DL Riegert-Johnson and others. NCBI 2009|accessdate=2009-09-01 |format= |work=}}</ref>
=== Manifestations ===
* Multiple Endocrine Neoplasia type 1 (MEN1) is a rare hereditary [[endocrine]] [[cancer]] [[syndrome]] characterized primarily by [[tumor]]s of the [[parathyroid gland]]s (95% of cases), [[endocrine]] gastroenteropancreatic (GEP) tract (30-80% of cases), and anterior [[pituitary]] (15-90% of cases).<ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=famcan&part=ch1famcan |title= Multiple Endocrine Neoplasia Type 1 : In Familial Cancer Syndromes. DL Riegert-Johnson and others. NCBI 2009|accessdate=2009-09-11 |format= |work=}}</ref> Other [[endocrine]] and non-[[endocrine]] [[neoplasm]]s including adrenocortical and [[thyroid]] [[tumor]]s, visceral and cutaneous [[lipoma]]s, [[meningioma]]s, facial [[angiofibroma]]s and collagenomas, and thymic, gastric, and bronchial [[carcinoid]]s also occur. The [[phenotype]] of [[MEN1]] is broad, and over 20 different combinations of [[endocrine]] and non-[[endocrine]] manifestations have been described. [[MEN1]] should be suspected in patients with an [[endocrinopathy]] of two of the three characteristic affected organs, or with an [[endocrinopathy]] of one of these organs plus a first-degree relative affected by [[MEN1]] syndrome.
* [[MEN1]] patients usually have a family history of [[MEN1]]. Inheritance is [[autosomal dominant]]; any affected parent has a 50% chance to transmit the [[disease]] to his or her progeny. [[MEN1]] [[gene]] [[mutation]]s can be identified in 70-95% of [[MEN1]] patients.
* Many [[endocrine]] [[tumor]]s in [[MEN1]] are [[benign]] and cause symptoms by overproduction of [[hormone]]s or local mass effects, while other [[MEN1]] [[tumor]]s are associated with an elevated risk for [[malignancy]]. About one third of patients affected with [[MEN1]] will die early from an [[MEN1]]-related [[cancer]] or associated [[malignancy]]. Entero-pancreatic [[gastrinoma]]s and thymic and bronchial [[carcinoid]]s are the leading cause of morbidity and mortality. Consequently, the average age of death in individuals with [[MEN1]] is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.
=== Recommended cancer surveillance ===
* A recommend surveillance program for Multiple Endocrine Neoplasia Type 1 has been suggested by the International Guidelines for Diagnosis and Therapy of MEN syndromes group. <ref>{{cite web |url=http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=famcan&part=ch3famcan&rendertype=table&id=ch3famcan.T6|title= Multiple Endocrine Neoplasia Type 1: In Familial Cancer Syndromes. DL Riegert-Johnson and others. NCBI 2009|accessdate=2009-09-01 |format= |work=}}</ref>
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Revision as of 01:46, 21 September 2015

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [4]

Synonyms and keywords: MEN syndromes

Overview

Multiple endocrine neoplasia (MEN) encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. Multiple endocrine neoplasia may be classified according to tumor characteristics into 3 subtypes: Multiple endocrine neoplasia type 1, Multiple endocrine neoplasia type 2a, and Multiple endocrine neoplasia type 2b.

Multiple Endocrine Neoplasia

See also

Terminology

  • The older names, "multiple endocrine adenomas" and "multiple endocrine adenomatosis" (MEA), have been replaced by the current terminology.
  • The term multiple endocrine neoplasia is used when two or more endocrine tumor types, known to occur as a part of one of the defined MEN syndromes, occurs in a single patient and there is evidence for either a causative mutation or hereditary transmission. The presence of two or more tumor types in a single patient does not automatically designate that individual as having MEN because there is a small statistical chance that development of two "sporadic" tumors that occur in one of the MEN syndromes could occur by chance.
  • The term "multiple endocrine neoplasia" was introduced in 1968, but descriptions of the condition date back to 1903.[2]

Related Conditions

History

Classification

MEN type 1

Main article: Multiple endocrine neoplasia type 1

Type 1 is also known as Wermer's syndrome after Dr Paul Wermer, who described it in 1954:[7]

  1. Parathyroid hyperplasia/tumour causing hyperparathyroidism.
  2. Pancreatic islet cell tumours causing hypoglycaemia (insulinoma) and Zollinger-Ellison syndrome (gastrinoma).
  3. 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 article: 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.

Type 2 is also known as Sipple syndrome (after the American Dr John H. Sipple, who described it in 1961)[8] and used to be called type 2A:

  1. 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.
  2. Pheochromocytoma
  3. Parathyroid hyperplasia/tumour causing hyperparathyroidism.

MEN type 3/type 2b

This syndrome has no eponym; it was described by Schimke et al in 1968.[9] 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.

  1. Pheochromocytoma
  2. 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.
  3. Mucosal neuromas which are usually situated in the gastrointestinal tract.
  4. 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%[10]),
insulinoma (20%[10]),
vipoma,
glucagonoma,
PPoma 		- - -
Pituitary adenoma 66%[10] - - -
Angiofibroma 64%*[11] - - -
Lipoma 17%*[11] - - -
Parathyroid hyperplasia 90%[10] 50%[10] - -
Medullary thyroid carcinoma - 100%[10] 85%[10] 100%
Pheochromocytoma - >33%[10] 50% -
Marfanoid body habitus - - 80% -
Mucosal neuroma - - 100%[10] -
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)[12] 		1 in 40,000[13] 1 in 1,000,000
(1 in 600,000[14] to
1 in 4,000,000[15])[16]
Initial description (year) 1954[17] 1961[18] 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.[19]
  • OMIM also includes a fourth form of multiple endocrine neoplasia ("MEN4"), associated with CDKN1B.[20] The presentation is believed to overlap that of MEN1 and MEN2.[21]

References

  1. ↑ Template:DorlandsDict
  2. ↑ Carney JA (Feb 2005). "Familial multiple endocrine neoplasia: the first 100 years". Am. J. Surg. Pathol. 29 (2): 254–74. doi:10.1097/01.pas.0000147402.95391.41. PMID 15644784.
  3. ↑ Carney JA (Jun 1998). "Familial multiple endocrine neoplasia syndromes: components, classification, and nomenclature". J. Intern. Med. 243 (6): 425–32. doi:10.1046/j.1365-2796.1998.00345.x. PMID 9681839.
  4. ↑ Callender GG, Rich TA, Perrier ND (Aug 2008). "Multiple endocrine neoplasia syndromes". Surg. Clin. North Am. 88 (4): 863–95. doi:10.1016/j.suc.2008.05.001. PMID 18672144.
  5. ↑ 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
  6. ↑ 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
  7. ↑ Wermer P. Genetic aspect of adenomatosis of endocrine glands. Am J Med 1954;16:363-371. PMID 13138607.
  8. ↑ Sipple JH. The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 1961;31:163-166.
  9. ↑ 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
  10. ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8 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.
  11. ↑ 11.0 11.1 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.
  12. ↑ [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
  13. ↑ 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.
  14. ↑ Marx, Stephen J (2011). "Chapter 41: Multiple endocrine neoplasia". In Melmed, Shlomo. Williams Textbook of Endocrinology, 12th ed. pp. 1728–1767.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ Online Mendelian Inheritance in Man (OMIM) MULTIPLE ENDOCRINE NEOPLASIA, TYPE IV; MEN4 -610755
  21. ↑ 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.

External links

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