Multiple endocrine neoplasia: Difference between revisions
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==Overview== | ==Overview== | ||
Multiple endocrine neoplasia (MEN) encompasses several distinct [[syndrome]]s featuring [[Endocrine gland neoplasm|tumors of endocrine gland]]s, 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 (MEN) encompasses several distinct [[syndrome]]s featuring [[Endocrine gland neoplasm|tumors of endocrine gland]]s, 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== | ==Multiple Endocrine Neoplasia== | ||
* The term multiple endocrine neoplasia (MEN) encompasses several distinct [[syndrome]]s featuring [[Endocrine gland neoplasm|tumors of endocrine gland]]s, each with its own characteristic pattern. In some cases, the [[tumor]]s are [[malignant]], in others, [[benign]]. [[Benign]] or [[malignant]] [[tumor]]s of nonendocrine [[tissue]]s occur as components of some of these [[tumor]] [[syndrome]]s. | * The term multiple endocrine neoplasia (MEN) encompasses several distinct [[syndrome]]s featuring [[Endocrine gland neoplasm|tumors of endocrine gland]]s, each with its own characteristic pattern. In some cases, the [[tumor]]s are [[malignant]], in others, [[benign]]. [[Benign]] or [[malignant]] [[tumor]]s of nonendocrine [[tissue]]s occur as components of some of these [[tumor]] [[syndrome]]s. | ||
| Line 9: | Line 9: | ||
* [[Multiple endocrine neoplasia type 1]] | * [[Multiple endocrine neoplasia type 1]] | ||
* [[Multiple endocrine neoplasia type 2a]] | * [[Multiple endocrine neoplasia type 2a]] | ||
* | * Multiple endocrine neoplasia type 2b | ||
==Terminology== | ==Terminology== | ||
| Line 21: | Line 21: | ||
== History == | == History == | ||
* In 1903 Erdheim described the case of an acromegalic patient with a [[pituitary adenoma]] and three enlarged [[parathyroid gland]]s. | * 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 | * 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 1954 Wermer noted that this [[syndrome]] was transmitted as a dominant trait. | ||
* In 1959 Hazard ''et al.'' described medullary (solid) [[thyroid carcinoma]]. | * 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 1961 Sipple described a combination of a [[pheochromocytoma]], [[medullary thyroid carcinoma]] and [[parathyroid adenoma]]. | ||
* In 1966 Williams ''et al.'' described the combination of | * 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 | * 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 | * 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 1988 the [[MEN1]] [[locus]] was assigned to [[Chromosome]] 11 (11q13). | ||
* In 1993 [[mutation]]s in the | * 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> | 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> | * 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> | ||
| Line 43: | Line 43: | ||
|- | |- | ||
! [[Multiple endocrine neoplasia type 2|MEN 2A]] | ! [[Multiple endocrine neoplasia type 2|MEN 2A]] | ||
! | ! Multiple endocrine neoplasia type 2b|MEN 2B | ||
! [[Medullary thyroid cancer|FMTC]] | ! [[Medullary thyroid cancer|FMTC]] | ||
|- | |- | ||
| | | Eponym | ||
| Wermer syndrome | | Wermer syndrome | ||
| Sipple syndrome | | Sipple syndrome | ||
| Line 132: | Line 132: | ||
<nowiki>*</nowiki>- of patients with MEN1 and gastrinoma | <nowiki>*</nowiki>- of patients with MEN1 and gastrinoma | ||
FMTC = [[ | 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 | * 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 | * [[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) == | == Multiple Endocrine Neoplasia Type 1 (MEN1) == | ||
=== The MEN1 gene === | === The MEN1 gene === | ||
* The [[MEN1]] [[gene]] consists of ten [[exon]]s, spanning about 10 kb, and encodes a 610 [[amino acid]] [[protein]] named | * 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 === | === 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 === | === 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. | * 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 === | === Mnemonic === | ||
* A useful mnemonic to remember the associated neoplasias is below: | * A useful mnemonic to remember the associated neoplasias is below: | ||
:* MEN I '''(3 Ps)''' - [[Pituitary]], [[Parathyroid]], [[Pancreatic]]<br> | :* MEN I '''(3 Ps)''' - [[Pituitary]], [[Parathyroid]], [[Pancreatic]]<br> | ||
:* MEN IIa '''(1M,2Ps)''' - [[ | :* MEN IIa '''(1M,2Ps)''' - Medullary [[Thyroid]] [[Carcinoma]], [[Pheochromocytoma]], [[Parathyroid]]<br> | ||
:* MEN IIb '''(2Ms,1P)''' - [[ | :* MEN IIb '''(2Ms,1P)''' - Medullary [[Thyroid]] [[Carcinoma]], Marfanoid habitus/mucosal [[neuroma]], [[Pheochromocytoma]] | ||
=== ''MEN1'' mutations in multiple endocrine neoplasia patients and clinical genetics === | === ''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. | * 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 | * 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 === | === 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. | * [[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. | * 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 === | === Recommended cancer surveillance === | ||
Revision as of 10:53, 26 August 2015
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [4]
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
- 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.[1]
See also
- Multiple endocrine neoplasia type 1
- Multiple endocrine neoplasia type 2a
- Multiple endocrine neoplasia type 2b
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
- Although not officially categorized as multiple endocrine neoplasia syndromes, Von Hippel-Lindau disease[3] and Carney complex[4] are two other autosomal dominant endocrine tumor syndromes with features that overlap the clinical features of the MEN syndromes. Although not transmitted in the germline, McCune-Albright syndrome is a genetic disorder characterized by endocrine neoplastic features involving endocrine glands that overlap with those involved in MEN1 or MEN2.
History
- 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.[5]
- In 1998 the MEN1 gene was cloned[6]
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%[7]), insulinoma (20%[7]), vipoma, glucagonoma, PPoma |
- | - | - |
| Pituitary adenoma | 66%[7] | - | - | - |
| Angiofibroma | 64%*[8] | - | - | - |
| Lipoma | 17%*[8] | - | - | - |
| Parathyroid hyperplasia | 90%[7] | 50%[7] | - | - |
| Medullary thyroid carcinoma | - | 100%[7] | 85%[7] | 100% |
| Pheochromocytoma | - | >33%[7] | 50% | - |
| Marfanoid body habitus | - | - | 80% | - |
| Mucosal neuroma | - | - | 100%[7] | - |
| 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)[9] |
1 in 40,000[10] | 1 in 1,000,000 (1 in 600,000[11] to 1 in 4,000,000[12])[13] |
|
| Initial description (year) | 1954[14] | 1961[15] | 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.[16]
- OMIM also includes a fourth form of multiple endocrine neoplasia ("MEN4"), associated with CDKN1B.[17] The presentation is believed to overlap that of MEN1 and MEN2.[18]
Multiple Endocrine Neoplasia Type 1 (MEN1)
The MEN1 gene
- The MEN1 gene consists of ten exons, 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 tissues (pancreas, thymus, adrenal glands, thyroid, testis, leukocytes, 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 cells 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 cells 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
- MEN IIa (1M,2Ps) - Medullary Thyroid Carcinoma, Pheochromocytoma, Parathyroid
- MEN IIb (2Ms,1P) - Medullary Thyroid Carcinoma, Marfanoid habitus/mucosal neuroma, Pheochromocytoma
- MEN I (3 Ps) - Pituitary, Parathyroid, Pancreatic
MEN1 mutations in multiple endocrine neoplasia patients and clinical genetics
- MEN1 gene mutations can be identified in 70-95% of MEN1 patients and in about 20% of familial isolated hyperparathyroidism cases. Almost all patients are heterozygous for mutations. One affected family has been identified with individuals both homozygous and heterozygous for MEN1 mutations. In this family, there was no difference in disease history between the homozygous and heterozygous mutation carriers.
- Fifty percent of patients develop signs and symptoms 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.[19]
Manifestations
- Multiple Endocrine Neoplasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterized primarily by tumors of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic (GEP) tract (30-80% of cases), and anterior pituitary (15-90% of cases).[20] Other endocrine and non-endocrine neoplasms including adrenocortical and thyroid tumors, visceral and cutaneous lipomas, meningiomas, facial angiofibromas and collagenomas, and thymic, gastric, and bronchial carcinoids 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 mutations can be identified in 70-95% of MEN1 patients.
- Many endocrine tumors in MEN1 are benign and cause symptoms by overproduction of hormones or local mass effects, while other MEN1 tumors 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 gastrinomas and thymic and bronchial carcinoids 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. [21]
References
- ↑ Template:DorlandsDict
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 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.
- ↑ 8.0 8.1 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.
- ↑ "Multiple Endocrine Neoplasia Type 1: In Familial Cancer Syndromes. DL Riegert-Johnson and others. NCBI 2009". Retrieved 2009-09-01.
- ↑ "Multiple Endocrine Neoplasia Type 1 : In Familial Cancer Syndromes. DL Riegert-Johnson and others. NCBI 2009". Retrieved 2009-09-11.
- ↑ "Multiple Endocrine Neoplasia Type 1: In Familial Cancer Syndromes. DL Riegert-Johnson and others. NCBI 2009". Retrieved 2009-09-01.