Multiple endocrine neoplasia type 1 pathophysiology: Difference between revisions

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__NOTOC__
__NOTOC__
{{Multiple endocrine neoplasia type 1}}
{{Multiple endocrine neoplasia type 1}}
{{CMG}}; {{AE}} {{Ammu}}
{{CMG}};{{AE}}, {{Ammu}}, {{ARK}}
==Overview==
==Overview==
Multiple endocrine neoplasia type 1 is an autosomal dominant syndrome that is usually caused by mutations of the ''MEN1'' gene. The [[pathophysiology]] of multiple endocrine neoplasia type 1 depends on the [[histological]] subtype.
[[Multiple endocrine neoplasia type 1]] is an [[autosomal dominant]] syndrome that is usually caused by mutations of the [[MEN1]] gene. The [[pathophysiology]] of [[multiple endocrine neoplasia type 1]] depends on the [[histological]] subtype. [[Multiple endocrine neoplasia]] involves [[tumor]]s in at least two [[endocrine]] [[gland]]s, and [[tumor]]s can also develop in other organs and [[tissue]]s. These tumors may be either [[benign]] or [[malignant]]. A group of patients with MEN type 1 associated tumors may present with [[Adrenal gland|adrenal]], [[gonadal]], [[renal]], or [[thyroid]] tumors.  


==Pathogenesis==
==Pathophysiology==
* MEN type I is an autosomal dominant [[syndrome]] characterized by the development of the following tumors:<ref name=wikipedia>{{cite web | title = Wikipedia Multiple endocrine neoplasia (MEN) type I) | url = https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_1 }}</ref>
[[Multiple endocrine neoplasia]] is part of a group of disorders that affect the the [[endocrine]] system. [[Multiple endocrine neoplasia]] involves [[tumor]]s in at least two [[endocrine]] [[gland]]s, and [[tumor]]s can also develop in other organs and [[tissue]]s. These tumors may be either [[benign]] or [[malignant]]. MEN type I is an autosomal dominant [[syndrome]] characterized by the development of the following tumors:<ref name="wikipedia">{{cite web | title = Wikipedia Multiple endocrine neoplasia (MEN) type I) | url = https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_1 }}</ref>
:* [[Pituitary adenoma]]s
:* [[Pituitary adenoma]]s
:* [[Islet cell tumor]]s of the [[pancreas]] (commonly [[gastrinoma]] and glucogonoma)
:* [[Islet cell tumor]]s of the [[pancreas]] (commonly [[gastrinoma]] and [[glucagonoma]])
:* [[Parathyroid]] [[hyperplasia]] with resulting [[hyperparathyroidism]]
:* [[Parathyroid]] [[hyperplasia]] with resulting [[hyperparathyroidism]]
* Multiple endocrine neoplasia is part of a group of disorders that affect the the [[endocrine]] system. [[Multiple endocrine neoplasia]] involves [[tumor]]s in at least two [[endocrine]] [[gland]]s, and [[tumor]]s can also develop in other organs and [[tissue]]s. These tumors may be either benign or malignant.
===Parathyroid Tumors===
===Parathyroid Tumors===
* Overactivity of the [[parathyroid gland]] ([[hyperparathyroidism]]) disrupts the normal balance of [[calcium]] in the [[blood]], which can lead to [[kidney stones]], [[osteoporosis]], [[hypertension]], [[loss of appetite]], [[nausea]], [[weakness]], [[fatigue]], and [[depression]].  
* [[Multiple endocrine neoplasia type 1]] associated [[parathyroid]] [[tumor]]s are typically multiglandular and often [[hyperplastic]].
* Multiple endocrine neoplasia type 1-associated [[parathyroid]] [[tumor]]s are typically multiglandular and often [[hyperplastic]].
* Overactivity of the [[parathyroid gland]] ([[hyperparathyroidism]]) disrupts the normal balance of [[calcium]] in the [[blood]], which can lead to [[kidney stones]], [[osteoporosis]], [[hypertension]], [[loss of appetite]], [[nausea]], [[weakness]], [[fatigue]], and [[depression]].
 
===Pituitary Tumors===
===Pituitary Tumors===
* [[Neoplasia]] in the [[pituitary gland]] can manifest as [[prolactinoma]]s whereby too much [[prolactin]] is secreted, suppressing the release of [[gonadotropins]], causing a decrease in sex [[hormone]]s such as [[testosterone]]. [[Pituitary tumor]] in multiple endocrine neoplasia type 1 can be large and cause signs by compressing adjacent [[tissue]]s. Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are [[prolactin]]-secreting [[tumor]]s.
* [[Neoplasia]] in the [[pituitary gland]] can manifest as [[prolactinoma]]s whereby too much [[prolactin]] is secreted, suppressing the release of [[gonadotropins]], causing a decrease in sex [[hormone]]s such as [[testosterone]].
* [[Pituitary tumor]] in multiple endocrine neoplasia type 1 can be large and cause signs by compressing adjacent [[tissue]]s.
* Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are [[prolactin]]-secreting [[tumor]]s.
 
===Duodenopancreatic Neuroendocrine Tumors===
===Duodenopancreatic Neuroendocrine Tumors===
* Functioning [[pancreatic neuroendocrine tumor]]s seen in multiple endocrine neoplasia type 1 include the following:
* Functioning [[pancreatic neuroendocrine tumor]]s seen in [[multiple endocrine neoplasia type 1]] include the following:
:* [[Insulinoma]]s (10%–20% penetrance)
:* [[Insulinoma]]s (10%–20% penetrance)
:* [[Vasoactive intestinal peptide]] tumors (VIPomas) (~1% penetrance)
:* [[Vasoactive intestinal peptide]] tumors ([[VIPoma|VIPomas]]) (~1% penetrance)
:* [[Glucagonoma]]s (1%–5% penetrance)
:* [[Glucagonoma]]s (1%–5% penetrance)
:* [[Somatostatinoma]]s (~1% penetrance)
:* [[Somatostatinoma]]s (~1% penetrance)
* Pancreatic [[tumor]]s associated with multiple endocrine neoplasia type 1 usually form in the [[beta cells]] of the [[islets of Langerhans]], causing over-secretion of [[insulin]], resulting in low [[blood]] [[glucose]] levels ([[hypoglycemia]]). However, many other [[tumor]]s of the pancreatic Islets of Langerhans can occur in multiple endocrine neoplasia type 1. One of these, involving the [[alpha cells]], causes over-secretion of [[glucagon]], resulting in a classic triad of [[hyperglycemia]], a rash called [[necrolytic migratory erythema]], and [[weight loss]]. Another is a [[tumor]] of the non-beta [[islet cell]]s, known as a [[gastrinoma]], which causes the over-secretion of the [[hormone]] [[gastrin]], resulting in the over-production of [[acid]] by the [[acid]]-producing [[cell]]s of the [[stomach]] ([[parietal cells]]) and a constellation of sequelae known as [[Zollinger-Ellison syndrome]] which may include severe [[gastric ulcer]]s, [[abdominal pain]], [[loss of appetite]], chronic [[diarrhea]], [[malnutrition]], and subsequent [[weight loss]].
* Pancreatic [[tumor]]s associated with multiple endocrine neoplasia type 1 usually form in the [[beta cells]] of the [[islets of Langerhans]], causing over-secretion of [[insulin]], resulting in low [[blood]] [[glucose]] levels ([[hypoglycemia]]). However, many other [[tumor]]s of the [[Pancreas|pancreatic]] [[Islets of Langerhans]] can occur in multiple endocrine neoplasia type 1. One of these, involving the [[alpha cells]], causes over-secretion of [[glucagon]], resulting in a classic triad of [[hyperglycemia]], a rash called [[necrolytic migratory erythema]], and [[weight loss]]. Another is a [[tumor]] of the non-beta [[islet cell]]s, known as a [[gastrinoma]], which causes the over-secretion of the [[hormone]] [[gastrin]], resulting in the over-production of [[acid]] by the [[acid]]-producing [[cell]]s of the [[stomach]] ([[parietal cells]]) and a constellation of sequel known as [[Zollinger-Ellison syndrome]] which may include severe [[gastric ulcer]]s, [[abdominal pain]], [[loss of appetite]], chronic [[diarrhea]], [[malnutrition]], and subsequent [[weight loss]].
 
==MEN type 4==
*A group of patients with MEN type 1 associated tumors may present with [[Adrenal gland|adrenal]], [[gonadal]], [[renal]], or [[thyroid]] tumors. This rare group of patients carries a mutation in gene encoding a [[Cyclin-dependent kinase|cyclin dependent kinase inhibitor]] belonging to KIP/CIP family that regulates cell cycle progression through its inhibitory effect on transition from [[G1]] to [[S phase]] known as P27. P27 binds to cyclinE/CDK2 and cyclinA/CDK2 and inhibits them to arrest the cell cycle in G1. The mutant P27 thus cannot inhibit cyclin-CDK complexes which results in uninhibited cell growth in the affected tissues. The [[gene]] mainly responsible for this feature is CDKN1B. These group of patients with MEN type 1 associated tumors that carries this mutation are known as MEN type 4.<ref name="pmid20966355">{{cite journal |vauthors=Wander SA, Zhao D, Slingerland JM |title=p27: a barometer of signaling deregulation and potential predictor of response to targeted therapies |journal=Clin. Cancer Res. |volume=17 |issue=1 |pages=12–8 |year=2011 |pmid=20966355 |pmc=3017239 |doi=10.1158/1078-0432.CCR-10-0752 |url=}}</ref><ref name="Pellegata2012">{{cite journal|last1=Pellegata|first1=NS|title=MENX and MEN4|journal=Clinics|volume=67|issue=S1|year=2012|pages=13–18|issn=18075932|doi=10.6061/clinics/2012(Sup01)04}}</ref>


==Genetics==
==Genetics==
===MEN1 Gene===
===MEN1 Gene===
* The [[gene]] [[locus]] causing multiple endocrine neoplasia type 1 has been localised to [[chromosome]] 11q13 by studies of loss of heterozigosity (LOH) on multiple endocrine neoplasia type 1-associated [[tumor]]s and by linkage analysis in multiple endocrine neoplasia type 1 families.<ref name="pmid17014705">{{cite journal| author=Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Gozzini A, Luzi E et al.| title=Multiple endocrine neoplasia type 1. | journal=Orphanet J Rare Dis | year= 2006 | volume= 1 | issue=  | pages= 38 | pmid=17014705 | doi=10.1186/1750-1172-1-38 | pmc=PMC1594566 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17014705  }} </ref><ref name="pmid2894610">{{cite journal| author=Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld M| title=Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. | journal=Nature | year= 1988 | volume= 332 | issue= 6159 | pages= 85-7 | pmid=2894610 | doi=10.1038/332085a0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2894610  }} </ref><ref name="pmid2568587">{{cite journal| author=Thakker RV, Bouloux P, Wooding C, Chotai K, Broad PM, Spurr NK et al.| title=Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. | journal=N Engl J Med | year= 1989 | volume= 321 | issue= 4 | pages= 218-24 | pmid=2568587 | doi=10.1056/NEJM198907273210403 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2568587  }} </ref><ref name="pmid2568586">{{cite journal| author=Friedman E, Sakaguchi K, Bale AE, Falchetti A, Streeten E, Zimering MB et al.| title=Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. | journal=N Engl J Med | year= 1989 | volume= 321 | issue= 4 | pages= 213-8 | pmid=2568586 | doi=10.1056/NEJM198907273210402 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2568586  }} </ref><ref name="pmid1968641">{{cite journal| author=Byström C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B et al.| title=Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 5 | pages= 1968-72 | pmid=1968641 | doi= | pmc=PMC53606 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1968641  }} </ref>
* The [[gene]] [[locus]] causing multiple endocrine neoplasia type 1 has been localised to [[chromosome]] 11q13 by studies of loss of heterozigosity (LOH) on multiple endocrine neoplasia type 1 associated [[tumor]]s and by linkage analysis in multiple endocrine neoplasia type 1 families.<ref name="pmid17014705">{{cite journal| author=Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Gozzini A, Luzi E et al.| title=Multiple endocrine neoplasia type 1. | journal=Orphanet J Rare Dis | year= 2006 | volume= 1 | issue=  | pages= 38 | pmid=17014705 | doi=10.1186/1750-1172-1-38 | pmc=PMC1594566 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17014705  }} </ref><ref name="pmid2894610">{{cite journal| author=Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld M| title=Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma. | journal=Nature | year= 1988 | volume= 332 | issue= 6159 | pages= 85-7 | pmid=2894610 | doi=10.1038/332085a0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2894610  }} </ref><ref name="pmid2568587">{{cite journal| author=Thakker RV, Bouloux P, Wooding C, Chotai K, Broad PM, Spurr NK et al.| title=Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11. | journal=N Engl J Med | year= 1989 | volume= 321 | issue= 4 | pages= 218-24 | pmid=2568587 | doi=10.1056/NEJM198907273210403 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2568587  }} </ref><ref name="pmid2568586">{{cite journal| author=Friedman E, Sakaguchi K, Bale AE, Falchetti A, Streeten E, Zimering MB et al.| title=Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1. | journal=N Engl J Med | year= 1989 | volume= 321 | issue= 4 | pages= 213-8 | pmid=2568586 | doi=10.1056/NEJM198907273210402 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2568586  }} </ref><ref name="pmid1968641">{{cite journal| author=Byström C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B et al.| title=Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 5 | pages= 1968-72 | pmid=1968641 | doi= | pmc=PMC53606 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1968641  }} </ref>
* ''MEN1'', spans about 10 Kb and consists of ten exons encoding a 610 [[amino acid]] nuclear protein, named menin.<ref name="pmid17014705">{{cite journal| author=Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Gozzini A, Luzi E et al.| title=Multiple endocrine neoplasia type 1. | journal=Orphanet J Rare Dis | year= 2006 | volume= 1 | issue=  | pages= 38 | pmid=17014705 | doi=10.1186/1750-1172-1-38 | pmc=PMC1594566 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17014705  }} </ref>
* MEN1, spans about 10 Kb and consists of ten [[Exon|exons]] encoding a 610 [[amino acid]] nuclear [[protein]], named menin.<ref name="pmid17014705">{{cite journal| author=Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Gozzini A, Luzi E et al.| title=Multiple endocrine neoplasia type 1. | journal=Orphanet J Rare Dis | year= 2006 | volume= 1 | issue=  | pages= 38 | pmid=17014705 | doi=10.1186/1750-1172-1-38 | pmc=PMC1594566 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17014705  }} </ref>
* ''MEN1'' [[gene]] is a putative [[tumor suppressor gene]] and causes type 1 multiple endocrine neoplasia by Knudson's "two hits" model for [[tumor]] development.<ref name="pmid7902574">{{cite journal| author=Knudson AG| title=Antioncogenes and human cancer. | journal=Proc Natl Acad Sci U S A | year= 1993 | volume= 90 | issue= 23 | pages= 10914-21 | pmid=7902574 | doi= | pmc=PMC47892 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7902574  }} </ref>
* MEN1 [[gene]] is a putative [[tumor suppressor gene]] and causes [[multiple endocrine neoplasia type 1]] by Knudson's "two hits" model for [[tumor]] development.<ref name="pmid7902574">{{cite journal| author=Knudson AG| title=Antioncogenes and human cancer. | journal=Proc Natl Acad Sci U S A | year= 1993 | volume= 90 | issue= 23 | pages= 10914-21 | pmid=7902574 | doi= | pmc=PMC47892 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7902574  }} </ref>
* Knudson's "two hits" model for [[tumor]] development suggest that there is a [[germline mutation]] present in all [[cell]]s at birth and the second [[mutation]] is a somatic [[mutation]] that occurs in the predisposed [[endocrine]][[cell]] and leads to loss of the remaining wild type [[allele]]. This "two hits" model gives [[cell]]s the survival advantage needed for [[tumor]] development.
* Knudson's "two hits" model for [[tumor]] development suggest that there is a [[germline mutation]] present in all [[cell]]s at birth and the second [[mutation]] is a somatic [[mutation]] that occurs in the predisposed [[endocrine]][[cell]] and leads to loss of the remaining wild type [[allele]]. This "two hits" model gives [[cell]]s the survival advantage needed for [[tumor]] development.
* [[Mutation]]s are distributed over the entire coding region without showing any significant hot spot region.<ref name="pmid9215689">{{cite journal| author=Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC et al.| title=Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. | journal=Hum Mol Genet | year= 1997 | volume= 6 | issue= 7 | pages= 1169-75 | pmid=9215689 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9215689  }} </ref><ref name="pmid9683585">{{cite journal| author=Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N et al.| title=Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. | journal=Am J Hum Genet | year= 1998 | volume= 63 | issue= 2 | pages= 455-67 | pmid=9683585 | doi=10.1086/301953 | pmc=PMC1377295 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9683585  }} </ref><ref name="pmid9709921">{{cite journal| author=Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G et al.| title=Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. | journal=J Clin Endocrinol Metab | year= 1998 | volume= 83 | issue= 8 | pages= 2621-6 | pmid=9709921 | doi=10.1210/jcem.83.8.5059 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9709921  }} </ref><ref name="pmid9888389">{{cite journal| author=Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ et al.| title=Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases. | journal=Hum Mutat | year= 1999 | volume= 13 | issue= 1 | pages= 54-60 | pmid=9888389 | doi=10.1002/(SICI)1098-1004(1999)13:1<54::AID-HUMU6>3.0.CO;2-K | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9888389  }} </ref><ref name="pmid10576763">{{cite journal| author=Hai N, Aoki N, Matsuda A, Mori T, Kosugi S| title=Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1). | journal=Eur J Endocrinol | year= 1999 | volume= 141 | issue= 5 | pages= 475-80 | pmid=10576763 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10576763  }} </ref><ref name="pmid10664520">{{cite journal| author=Morelli A, Falchetti A, Martineti V, Becherini L, Mark M, Friedman E et al.| title=MEN1 gene mutation analysis in Italian patients with multiple endocrine neoplasia type 1. | journal=Eur J Endocrinol | year= 2000 | volume= 142 | issue= 2 | pages= 131-7 | pmid=10664520 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10664520  }} </ref>
* [[Mutation]]s are distributed over the entire coding region without showing any significant hot spot region.<ref name="pmid9215689">{{cite journal| author=Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC et al.| title=Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. | journal=Hum Mol Genet | year= 1997 | volume= 6 | issue= 7 | pages= 1169-75 | pmid=9215689 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9215689  }} </ref><ref name="pmid9683585">{{cite journal| author=Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N et al.| title=Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders. | journal=Am J Hum Genet | year= 1998 | volume= 63 | issue= 2 | pages= 455-67 | pmid=9683585 | doi=10.1086/301953 | pmc=PMC1377295 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9683585  }} </ref><ref name="pmid9709921">{{cite journal| author=Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G et al.| title=Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism. | journal=J Clin Endocrinol Metab | year= 1998 | volume= 83 | issue= 8 | pages= 2621-6 | pmid=9709921 | doi=10.1210/jcem.83.8.5059 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9709921  }} </ref><ref name="pmid9888389">{{cite journal| author=Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ et al.| title=Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases. | journal=Hum Mutat | year= 1999 | volume= 13 | issue= 1 | pages= 54-60 | pmid=9888389 | doi=10.1002/(SICI)1098-1004(1999)13:1<54::AID-HUMU6>3.0.CO;2-K | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9888389  }} </ref><ref name="pmid10576763">{{cite journal| author=Hai N, Aoki N, Matsuda A, Mori T, Kosugi S| title=Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1). | journal=Eur J Endocrinol | year= 1999 | volume= 141 | issue= 5 | pages= 475-80 | pmid=10576763 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10576763  }} </ref><ref name="pmid10664520">{{cite journal| author=Morelli A, Falchetti A, Martineti V, Becherini L, Mark M, Friedman E et al.| title=MEN1 gene mutation analysis in Italian patients with multiple endocrine neoplasia type 1. | journal=Eur J Endocrinol | year= 2000 | volume= 142 | issue= 2 | pages= 131-7 | pmid=10664520 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10664520  }} </ref>
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===MEN1 Protein (menin)===
===MEN1 Protein (menin)===
* ''MEN1'' [[gene]] encodes a 610 [[amino acid]] (67 Kda) [[nuclear protein]] called menin.<ref name="pmid10341092">{{cite journal| author=Guru SC, Crabtree JS, Brown KD, Dunn KJ, Manickam P, Prasad NB et al.| title=Isolation, genomic organization, and expression analysis of Men1, the murine homolog of the MEN1 gene. | journal=Mamm Genome | year= 1999 | volume= 10 | issue= 6 | pages= 592-6 | pmid=10341092 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10341092  }} </ref><ref name="pmid10524203">{{cite journal| author=Karges W, Maier S, Wissmann A, Dralle H, Dosch HM, Boehm BO| title=Primary structure, gene expression and chromosomal mapping of rodent homologs of the MEN1 tumor suppressor gene. | journal=Biochim Biophys Acta | year= 1999 | volume= 1446 | issue= 3 | pages= 286-94 | pmid=10524203 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10524203  }} </ref><ref name="pmid10529376">{{cite journal| author=Khodaei S, O'Brien KP, Dumanski J, Wong FK, Weber G| title=Characterization of the MEN1 ortholog in zebrafish. | journal=Biochem Biophys Res Commun | year= 1999 | volume= 264 | issue= 2 | pages= 404-8 | pmid=10529376 | doi=10.1006/bbrc.1999.1529 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10529376  }} </ref><ref name="pmid10818209">{{cite journal| author=Manickam P, Vogel AM, Agarwal SK, Oda T, Spiegel AM, Marx SJ et al.| title=Isolation, characterization, expression and functional analysis of the zebrafish ortholog of MEN1. | journal=Mamm Genome | year= 2000 | volume= 11 | issue= 6 | pages= 448-54 | pmid=10818209 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10818209  }} </ref><ref name="pmid11064160">{{cite journal| author=Maruyama K, Tsukada T, Honda M, Nara-Ashizawa N, Noguchi K, Cheng J et al.| title=Complementary DNA structure and genomic organization of Drosophila menin. | journal=Mol Cell Endocrinol | year= 2000 | volume= 168 | issue= 1-2 | pages= 135-40 | pmid=11064160 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11064160  }} </ref>
* [[MEN1]] [[gene]] encodes a 610 [[amino acid]] (67 Kda) [[nuclear protein]] called menin.<ref name="pmid10341092">{{cite journal| author=Guru SC, Crabtree JS, Brown KD, Dunn KJ, Manickam P, Prasad NB et al.| title=Isolation, genomic organization, and expression analysis of Men1, the murine homolog of the MEN1 gene. | journal=Mamm Genome | year= 1999 | volume= 10 | issue= 6 | pages= 592-6 | pmid=10341092 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10341092  }} </ref><ref name="pmid10524203">{{cite journal| author=Karges W, Maier S, Wissmann A, Dralle H, Dosch HM, Boehm BO| title=Primary structure, gene expression and chromosomal mapping of rodent homologs of the MEN1 tumor suppressor gene. | journal=Biochim Biophys Acta | year= 1999 | volume= 1446 | issue= 3 | pages= 286-94 | pmid=10524203 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10524203  }} </ref><ref name="pmid10529376">{{cite journal| author=Khodaei S, O'Brien KP, Dumanski J, Wong FK, Weber G| title=Characterization of the MEN1 ortholog in zebrafish. | journal=Biochem Biophys Res Commun | year= 1999 | volume= 264 | issue= 2 | pages= 404-8 | pmid=10529376 | doi=10.1006/bbrc.1999.1529 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10529376  }} </ref><ref name="pmid10818209">{{cite journal| author=Manickam P, Vogel AM, Agarwal SK, Oda T, Spiegel AM, Marx SJ et al.| title=Isolation, characterization, expression and functional analysis of the zebrafish ortholog of MEN1. | journal=Mamm Genome | year= 2000 | volume= 11 | issue= 6 | pages= 448-54 | pmid=10818209 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10818209  }} </ref><ref name="pmid11064160">{{cite journal| author=Maruyama K, Tsukada T, Honda M, Nara-Ashizawa N, Noguchi K, Cheng J et al.| title=Complementary DNA structure and genomic organization of Drosophila menin. | journal=Mol Cell Endocrinol | year= 2000 | volume= 168 | issue= 1-2 | pages= 135-40 | pmid=11064160 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11064160  }} </ref>
* The first identified partner of menin was JunD, a [[transcription]] factor belonging to the AP1 [[transcription]] complex family. Menin interacts with the N-terminus of [[JunD]] through its N-terminus and central domains. Wild type menin represses [[JunD]]-activated [[transcription]] maybe via a [[histone]] deacetylase-dependent mechanism.<ref name="pmid9989505">{{cite journal| author=Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY et al.| title=Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. | journal=Cell | year= 1999 | volume= 96 | issue= 1 | pages= 143-52 | pmid=9989505 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9989505  }} </ref><ref name="pmid10500243">{{cite journal| author=Gobl AE, Berg M, Lopez-Egido JR, Oberg K, Skogseid B, Westin G| title=Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism. | journal=Biochim Biophys Acta | year= 1999 | volume= 1447 | issue= 1 | pages= 51-6 | pmid=10500243 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10500243  }} </ref>
* The first identified partner of menin was [[JunD]], a [[transcription]] factor belonging to the AP1 [[transcription]] complex family. Menin interacts with the N-terminus of [[JunD]] through its [[N-terminus]] and central domains. Wild type menin represses [[JunD]]-activated [[transcription]] maybe via a [[histone]] deacetylase-dependent mechanism.<ref name="pmid9989505">{{cite journal| author=Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY et al.| title=Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. | journal=Cell | year= 1999 | volume= 96 | issue= 1 | pages= 143-52 | pmid=9989505 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9989505  }} </ref><ref name="pmid10500243">{{cite journal| author=Gobl AE, Berg M, Lopez-Egido JR, Oberg K, Skogseid B, Westin G| title=Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism. | journal=Biochim Biophys Acta | year= 1999 | volume= 1447 | issue= 1 | pages= 51-6 | pmid=10500243 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10500243  }} </ref>
* Menin interacts, directly, with three members of the nuclear factor [[NF-kB]] family of [[transcription]] regulators: NF-kB1 (''p50''), NF-kB2 (''p52'') and RelA (''p65'').<ref name="pmid11526476">{{cite journal| author=Heppner C, Bilimoria KY, Agarwal SK, Kester M, Whitty LJ, Guru SC et al.| title=The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation. | journal=Oncogene | year= 2001 | volume= 20 | issue= 36 | pages= 4917-25 | pmid=11526476 | doi=10.1038/sj.onc.1204529 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11526476  }} </ref> These [[protein]]s modulate the expression of various [[gene]]s and are involved in the [[oncogenesis]] of numerous organs. Menin interacts with [[NF-kB]] by its central domain and represses [[NF-kB]]-mediated [[transcription]].
* Menin interacts, directly, with three members of the nuclear factor [[NF-kB]] family of [[transcription]] regulators: [[NF-kB|NF-kB1]] (''[[p50]]''), [[NF-kB|NF-kB2]] (''p52'') and RelA (''p65'').<ref name="pmid11526476">{{cite journal| author=Heppner C, Bilimoria KY, Agarwal SK, Kester M, Whitty LJ, Guru SC et al.| title=The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation. | journal=Oncogene | year= 2001 | volume= 20 | issue= 36 | pages= 4917-25 | pmid=11526476 | doi=10.1038/sj.onc.1204529 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11526476  }} </ref> These [[protein]]s modulate the expression of various [[gene]]s and are involved in the [[oncogenesis]] of numerous organs. Menin interacts with [[NF-kB]] by its central domain and represses [[NF-kB]]-mediated [[transcription]].
* Moreover, menin interferes with the [[transforming growth factor beta]] ([[TGFβ]]) signalling pathway at the level of [[Smad3]]. Alteration of the [[TGFβ]] signalling pathways is important in pancreatic [[carcinogenesis]].
* Moreover, menin interferes with the [[transforming growth factor beta]] ([[TGFβ]]) signalling pathway at the level of [[Smad3]]. Alteration of the [[TGFβ]] signalling pathways is important in [[pancreatic]] [[carcinogenesis]].
* Although menin has been identified primarily as a [[nuclear protein]], recent studies have reported its interaction with the glial fibrillary acid [[protein]] (GFAP) and with [[vimentin]] (components of intermediate filaments (IFs), suggesting a putative role in [[glial cell]] [[oncogenesis]].
* Although menin has been identified primarily as a [[nuclear protein]], recent studies have reported its interaction with the [[Glial fibrillary acidic protein|glial fibrillary acid protein]] ([[GFAP]]) and with [[vimentin]] (components of [[intermediate filaments]] (IFs), suggesting a putative role in [[glial cell]] [[oncogenesis]].
* Finally, menin interacts with the [[metastasis]] suppressor Nm23H1.<ref name="pmid12145286">{{cite journal| author=Yaguchi H, Ohkura N, Tsukada T, Yamaguchi K| title=Menin, the multiple endocrine neoplasia type 1 gene product, exhibits GTP-hydrolyzing activity in the presence of the tumor metastasis suppressor nm23. | journal=J Biol Chem | year= 2002 | volume= 277 | issue= 41 | pages= 38197-204 | pmid=12145286 | doi=10.1074/jbc.M204132200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12145286  }} </ref> This interaction enables menin to act as an atypical GTPase and to hydrolyze GTP. The binding of menin to Nm23H1 may be relevant also to the control of genomic stability, as Nm23H1 is associated to the [[centrosome]] that is involved in the maintenance of chromosome integrity.<ref name="pmid1672620">{{cite journal| author=Scappaticci S, Maraschio P, del Ciotto N, Fossati GS, Zonta A, Fraccaro M| title=Chromosome abnormalities in lymphocytes and fibroblasts of subjects with multiple endocrine neoplasia type 1. | journal=Cancer Genet Cytogenet | year= 1991 | volume= 52 | issue= 1 | pages= 85-92 | pmid=1672620 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1672620  }} </ref><ref name="pmid1358429">{{cite journal| author=Scappaticci S, Brandi ML, Capra E, Cortinovis M, Maraschio P, Fraccaro M| title=Cytogenetics of multiple endocrine neoplasia syndrome. II. Chromosome abnormalities in an insulinoma and a glucagonoma from two subjects with MEN1. | journal=Cancer Genet Cytogenet | year= 1992 | volume= 63 | issue= 1 | pages= 17-21 | pmid=1358429 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1358429  }} </ref><ref name="pmid7889502">{{cite journal| author=Tomassetti P, Cometa G, Del Vecchio E, Baserga M, Faccioli P, Bosoni D et al.| title=Chromosomal instability in multiple endocrine neoplasia type 1. Cytogenetic evaluation with DEB test. | journal=Cancer Genet Cytogenet | year= 1995 | volume= 79 | issue= 2 | pages= 123-6 | pmid=7889502 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7889502  }} </ref><ref name="pmid10087948">{{cite journal| author=Sakurai A, Katai M, Itakura Y, Ikeo Y, Hashizume K| title=Premature centromere division in patients with multiple endocrine neoplasia type 1. | journal=Cancer Genet Cytogenet | year= 1999 | volume= 109 | issue= 2 | pages= 138-40 | pmid=10087948 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10087948  }} </ref>
* Finally, menin interacts with the [[metastasis]] suppressor Nm23H1.<ref name="pmid12145286">{{cite journal| author=Yaguchi H, Ohkura N, Tsukada T, Yamaguchi K| title=Menin, the multiple endocrine neoplasia type 1 gene product, exhibits GTP-hydrolyzing activity in the presence of the tumor metastasis suppressor nm23. | journal=J Biol Chem | year= 2002 | volume= 277 | issue= 41 | pages= 38197-204 | pmid=12145286 | doi=10.1074/jbc.M204132200 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12145286  }} </ref> This interaction enables menin to act as an atypical [[GTPase]] and to hydrolyze [[GTP-binding protein|GTP]]. The binding of menin to Nm23H1 may be relevant also to the control of genomic stability, as Nm23H1 is associated to the [[centrosome]] that is involved in the maintenance of [[chromosome]] integrity.<ref name="pmid1672620">{{cite journal| author=Scappaticci S, Maraschio P, del Ciotto N, Fossati GS, Zonta A, Fraccaro M| title=Chromosome abnormalities in lymphocytes and fibroblasts of subjects with multiple endocrine neoplasia type 1. | journal=Cancer Genet Cytogenet | year= 1991 | volume= 52 | issue= 1 | pages= 85-92 | pmid=1672620 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1672620  }} </ref><ref name="pmid1358429">{{cite journal| author=Scappaticci S, Brandi ML, Capra E, Cortinovis M, Maraschio P, Fraccaro M| title=Cytogenetics of multiple endocrine neoplasia syndrome. II. Chromosome abnormalities in an insulinoma and a glucagonoma from two subjects with MEN1. | journal=Cancer Genet Cytogenet | year= 1992 | volume= 63 | issue= 1 | pages= 17-21 | pmid=1358429 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1358429  }} </ref><ref name="pmid7889502">{{cite journal| author=Tomassetti P, Cometa G, Del Vecchio E, Baserga M, Faccioli P, Bosoni D et al.| title=Chromosomal instability in multiple endocrine neoplasia type 1. Cytogenetic evaluation with DEB test. | journal=Cancer Genet Cytogenet | year= 1995 | volume= 79 | issue= 2 | pages= 123-6 | pmid=7889502 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7889502  }} </ref><ref name="pmid10087948">{{cite journal| author=Sakurai A, Katai M, Itakura Y, Ikeo Y, Hashizume K| title=Premature centromere division in patients with multiple endocrine neoplasia type 1. | journal=Cancer Genet Cytogenet | year= 1999 | volume= 109 | issue= 2 | pages= 138-40 | pmid=10087948 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10087948  }} </ref>
 
===MEN Type 4===
MEN 4 is caused by loss of function mutation  in CDKN1B gene which is located on [[Chromosome 12 (human)|Chromosome 12]] in humans.
==Associated Conditions==
==Associated Conditions==
Multiple endocrine neoplasia type 1 is associated with the following conditions:<ref name=Radiopaedia2015>{{cite web | title = Multiple endocrine neoplasia (MEN) type I [Dr Matt A. Morgan and Dr Frank Gaillard]| url = http://radiopaedia.org/articles/multiple-endocrine-neoplasia-type-i-1 }}</ref>
[[Multiple endocrine neoplasia type 1]] is associated with the following conditions:<ref name="Radiopaedia2015">{{cite web | title = Multiple endocrine neoplasia (MEN) type I [Dr Matt A. Morgan and Dr Frank Gaillard]| url = http://radiopaedia.org/articles/multiple-endocrine-neoplasia-type-i-1 }}</ref>
* [[Lipomas]]
* [[Lipomas]]
* [[Angiofibroma]]s
* [[Angiofibroma]]s
* Adrenal cortical lesions
* [[Adrenocortical]] lesions
* [[Adrenal adenoma]]s
* [[Adrenal adenoma]]s
* [[Adrenocortical hyperplasia]]
* [[Adrenocortical hyperplasia]]
* [[Cortisol]]-secreting [[adenoma]]s
* [[Cortisol]]-secreting [[adenoma]]s
* [[Adrenal carcinoma]]s (rare)
* [[Adrenal carcinoma]]s (rare)
* Spinal ependymoma
* Spinal [[ependymoma]]
* [[Carcinoid tumor]]s
* [[Carcinoid tumor]]s
* [[Meningioma]]
* [[Meningioma]]
* [[Leiomyoma]]
* [[Leiomyoma]]
* [[Pheochromocytoma]]
* [[Pheochromocytoma]]
* Hepatic focal nodular [[hyperplasia]]<ref name="pmid10496602">{{cite journal| author=Vortmeyer AO, Lubensky IA, Skarulis M, Li G, Moon YW, Park WS et al.| title=Multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors. | journal=Mod Pathol | year= 1999 | volume= 12 | issue= 9 | pages= 919-24 | pmid=10496602 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10496602  }} </ref>
* [[Hepatic]] focal nodular [[hyperplasia]]<ref name="pmid10496602">{{cite journal| author=Vortmeyer AO, Lubensky IA, Skarulis M, Li G, Moon YW, Park WS et al.| title=Multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors. | journal=Mod Pathol | year= 1999 | volume= 12 | issue= 9 | pages= 919-24 | pmid=10496602 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10496602  }} </ref>
* [[Zollinger-Ellison syndrome]]<ref name="pmid14747767">{{cite journal| author=Gibril F, Schumann M, Pace A, Jensen RT| title=Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. | journal=Medicine (Baltimore) | year= 2004 | volume= 83 | issue= 1 | pages= 43-83 | pmid=14747767 | doi=10.1097/01.md.0000112297.72510.32 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14747767  }} </ref>
* [[Zollinger-Ellison syndrome]]<ref name="pmid14747767">{{cite journal| author=Gibril F, Schumann M, Pace A, Jensen RT| title=Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature. | journal=Medicine (Baltimore) | year= 2004 | volume= 83 | issue= 1 | pages= 43-83 | pmid=14747767 | doi=10.1097/01.md.0000112297.72510.32 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14747767  }} </ref>


Line 61: Line 68:
* Diffuse [[hyperplasia]] or multiple [[adenoma]]s of [[parathyroid]] are more common than solitary [[adenoma]]s.
* Diffuse [[hyperplasia]] or multiple [[adenoma]]s of [[parathyroid]] are more common than solitary [[adenoma]]s.
* [[Pancreatic tumor]]s are usually multicentric. Multiple [[adenoma]]s or diffuse islet cell [[hyperplasia]] commonly occurs; such [[tumor]]s may arise from the [[small bowel]] rather than the [[pancreas]].
* [[Pancreatic tumor]]s are usually multicentric. Multiple [[adenoma]]s or diffuse islet cell [[hyperplasia]] commonly occurs; such [[tumor]]s may arise from the [[small bowel]] rather than the [[pancreas]].
* [[Peptic ulcer]]s are multiple or atypical in location, and often [[bleed]], perforate, or become obstructed.
* [[Peptic ulcer]]s are multiple or atypical in location, and often [[bleed]], [[Perforated ulcer|perforate]], or become obstructed.


==Microscopic Pathology==
==Microscopic Pathology==
* Pancreatic involvement in multiple endocrine neoplasia is associated with following features.<ref>[http://www.nature.com/modpathol/journal/v24/n2s/full/modpathol2010127a.html] Pancreatic endocrine tumors</ref>
* Pancreatic involvement in [[multiple endocrine neoplasia]] is associated with following features:<ref>[http://www.nature.com/modpathol/journal/v24/n2s/full/modpathol2010127a.html] Pancreatic endocrine tumors</ref>
:* Nesidioblastosis also known as [[endocrine]] duct proliferation
 
:* [[Adenomas]]
:* [[Nesidioblastosis]] also known as [[endocrine]] duct proliferation,
:* Peliosis in islets
:* [[Adenomas]],
:* Cytologic atypia
:* [[Peliosis hepatis|Peliosis]] in islets,
:* Cytologic [[atypia]].


==References==
==References==
{{reflist|2}}
{{reflist|2}}
[[Category:Hereditary cancers]]
 
[[Category:Oncology]]
[[Category:Endocrinology]]
 
{{WS}}
{{WH}}
[[Category:Up-To-Date]]
[[Category:Oncology]]
[[Category:Medicine]]
[[Category:Endocrinology]]
[[Category:Surgery]]

Latest revision as of 12:03, 12 August 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2];Associate Editor(s)-in-Chief: , Ammu Susheela, M.D. [3], Aravind Reddy Kothagadi M.B.B.S[4]

Overview

Multiple endocrine neoplasia type 1 is an autosomal dominant syndrome that is usually caused by mutations of the MEN1 gene. The pathophysiology of multiple endocrine neoplasia type 1 depends on the histological subtype. Multiple endocrine neoplasia involves tumors in at least two endocrine glands, and tumors can also develop in other organs and tissues. These tumors may be either benign or malignant. A group of patients with MEN type 1 associated tumors may present with adrenal, gonadal, renal, or thyroid tumors.

Pathophysiology

Multiple endocrine neoplasia is part of a group of disorders that affect the the endocrine system. Multiple endocrine neoplasia involves tumors in at least two endocrine glands, and tumors can also develop in other organs and tissues. These tumors may be either benign or malignant. MEN type I is an autosomal dominant syndrome characterized by the development of the following tumors:[1]

Parathyroid Tumors

Pituitary Tumors

Duodenopancreatic Neuroendocrine Tumors

MEN type 4

  • A group of patients with MEN type 1 associated tumors may present with adrenal, gonadal, renal, or thyroid tumors. This rare group of patients carries a mutation in gene encoding a cyclin dependent kinase inhibitor belonging to KIP/CIP family that regulates cell cycle progression through its inhibitory effect on transition from G1 to S phase known as P27. P27 binds to cyclinE/CDK2 and cyclinA/CDK2 and inhibits them to arrest the cell cycle in G1. The mutant P27 thus cannot inhibit cyclin-CDK complexes which results in uninhibited cell growth in the affected tissues. The gene mainly responsible for this feature is CDKN1B. These group of patients with MEN type 1 associated tumors that carries this mutation are known as MEN type 4.[2][3]

Genetics

MEN1 Gene

MEN1 Protein (menin)

MEN Type 4

MEN 4 is caused by loss of function mutation in CDKN1B gene which is located on Chromosome 12 in humans.

Associated Conditions

Multiple endocrine neoplasia type 1 is associated with the following conditions:[29]

Gross Pathology

Microscopic Pathology

References

  1. ↑ "Wikipedia Multiple endocrine neoplasia (MEN) type I)".
  2. ↑ Wander SA, Zhao D, Slingerland JM (2011). "p27: a barometer of signaling deregulation and potential predictor of response to targeted therapies". Clin. Cancer Res. 17 (1): 12–8. doi:10.1158/1078-0432.CCR-10-0752. PMC 3017239. PMID 20966355.
  3. ↑ Pellegata, NS (2012). "MENX and MEN4". Clinics. 67 (S1): 13–18. doi:10.6061/clinics/2012(Sup01)04. ISSN 1807-5932.
  4. ↑ 4.0 4.1 Marini F, Falchetti A, Del Monte F, Carbonell Sala S, Gozzini A, Luzi E; et al. (2006). "Multiple endocrine neoplasia type 1". Orphanet J Rare Dis. 1: 38. doi:10.1186/1750-1172-1-38. PMC 1594566. PMID 17014705.
  5. ↑ Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjöld M (1988). "Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma". Nature. 332 (6159): 85–7. doi:10.1038/332085a0. PMID 2894610.
  6. ↑ Thakker RV, Bouloux P, Wooding C, Chotai K, Broad PM, Spurr NK; et al. (1989). "Association of parathyroid tumors in multiple endocrine neoplasia type 1 with loss of alleles on chromosome 11". N Engl J Med. 321 (4): 218–24. doi:10.1056/NEJM198907273210403. PMID 2568587.
  7. ↑ Friedman E, Sakaguchi K, Bale AE, Falchetti A, Streeten E, Zimering MB; et al. (1989). "Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1". N Engl J Med. 321 (4): 213–8. doi:10.1056/NEJM198907273210402. PMID 2568586.
  8. ↑ Byström C, Larsson C, Blomberg C, Sandelin K, Falkmer U, Skogseid B; et al. (1990). "Localization of the MEN1 gene to a small region within chromosome 11q13 by deletion mapping in tumors". Proc Natl Acad Sci U S A. 87 (5): 1968–72. PMC 53606. PMID 1968641.
  9. ↑ Knudson AG (1993). "Antioncogenes and human cancer". Proc Natl Acad Sci U S A. 90 (23): 10914–21. PMC 47892. PMID 7902574.
  10. ↑ Agarwal SK, Kester MB, Debelenko LV, Heppner C, Emmert-Buck MR, Skarulis MC; et al. (1997). "Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states". Hum Mol Genet. 6 (7): 1169–75. PMID 9215689.
  11. ↑ Giraud S, Zhang CX, Serova-Sinilnikova O, Wautot V, Salandre J, Buisson N; et al. (1998). "Germ-line mutation analysis in patients with multiple endocrine neoplasia type 1 and related disorders". Am J Hum Genet. 63 (2): 455–67. doi:10.1086/301953. PMC 1377295. PMID 9683585.
  12. ↑ Teh BT, Kytölä S, Farnebo F, Bergman L, Wong FK, Weber G; et al. (1998). "Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism". J Clin Endocrinol Metab. 83 (8): 2621–6. doi:10.1210/jcem.83.8.5059. PMID 9709921.
  13. ↑ Poncin J, Abs R, Velkeniers B, Bonduelle M, Abramowicz M, Legros JJ; et al. (1999). "Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases". Hum Mutat. 13 (1): 54–60. doi:10.1002/(SICI)1098-1004(1999)13:1<54::AID-HUMU6>3.0.CO;2-K. PMID 9888389.
  14. ↑ Hai N, Aoki N, Matsuda A, Mori T, Kosugi S (1999). "Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1)". Eur J Endocrinol. 141 (5): 475–80. PMID 10576763.
  15. ↑ Morelli A, Falchetti A, Martineti V, Becherini L, Mark M, Friedman E; et al. (2000). "MEN1 gene mutation analysis in Italian patients with multiple endocrine neoplasia type 1". Eur J Endocrinol. 142 (2): 131–7. PMID 10664520.
  16. ↑ Guru SC, Crabtree JS, Brown KD, Dunn KJ, Manickam P, Prasad NB; et al. (1999). "Isolation, genomic organization, and expression analysis of Men1, the murine homolog of the MEN1 gene". Mamm Genome. 10 (6): 592–6. PMID 10341092.
  17. ↑ Karges W, Maier S, Wissmann A, Dralle H, Dosch HM, Boehm BO (1999). "Primary structure, gene expression and chromosomal mapping of rodent homologs of the MEN1 tumor suppressor gene". Biochim Biophys Acta. 1446 (3): 286–94. PMID 10524203.
  18. ↑ Khodaei S, O'Brien KP, Dumanski J, Wong FK, Weber G (1999). "Characterization of the MEN1 ortholog in zebrafish". Biochem Biophys Res Commun. 264 (2): 404–8. doi:10.1006/bbrc.1999.1529. PMID 10529376.
  19. ↑ Manickam P, Vogel AM, Agarwal SK, Oda T, Spiegel AM, Marx SJ; et al. (2000). "Isolation, characterization, expression and functional analysis of the zebrafish ortholog of MEN1". Mamm Genome. 11 (6): 448–54. PMID 10818209.
  20. ↑ Maruyama K, Tsukada T, Honda M, Nara-Ashizawa N, Noguchi K, Cheng J; et al. (2000). "Complementary DNA structure and genomic organization of Drosophila menin". Mol Cell Endocrinol. 168 (1–2): 135–40. PMID 11064160.
  21. ↑ Agarwal SK, Guru SC, Heppner C, Erdos MR, Collins RM, Park SY; et al. (1999). "Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription". Cell. 96 (1): 143–52. PMID 9989505.
  22. ↑ Gobl AE, Berg M, Lopez-Egido JR, Oberg K, Skogseid B, Westin G (1999). "Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism". Biochim Biophys Acta. 1447 (1): 51–6. PMID 10500243.
  23. ↑ Heppner C, Bilimoria KY, Agarwal SK, Kester M, Whitty LJ, Guru SC; et al. (2001). "The tumor suppressor protein menin interacts with NF-kappaB proteins and inhibits NF-kappaB-mediated transactivation". Oncogene. 20 (36): 4917–25. doi:10.1038/sj.onc.1204529. PMID 11526476.
  24. ↑ Yaguchi H, Ohkura N, Tsukada T, Yamaguchi K (2002). "Menin, the multiple endocrine neoplasia type 1 gene product, exhibits GTP-hydrolyzing activity in the presence of the tumor metastasis suppressor nm23". J Biol Chem. 277 (41): 38197–204. doi:10.1074/jbc.M204132200. PMID 12145286.
  25. ↑ Scappaticci S, Maraschio P, del Ciotto N, Fossati GS, Zonta A, Fraccaro M (1991). "Chromosome abnormalities in lymphocytes and fibroblasts of subjects with multiple endocrine neoplasia type 1". Cancer Genet Cytogenet. 52 (1): 85–92. PMID 1672620.
  26. ↑ Scappaticci S, Brandi ML, Capra E, Cortinovis M, Maraschio P, Fraccaro M (1992). "Cytogenetics of multiple endocrine neoplasia syndrome. II. Chromosome abnormalities in an insulinoma and a glucagonoma from two subjects with MEN1". Cancer Genet Cytogenet. 63 (1): 17–21. PMID 1358429.
  27. ↑ Tomassetti P, Cometa G, Del Vecchio E, Baserga M, Faccioli P, Bosoni D; et al. (1995). "Chromosomal instability in multiple endocrine neoplasia type 1. Cytogenetic evaluation with DEB test". Cancer Genet Cytogenet. 79 (2): 123–6. PMID 7889502.
  28. ↑ Sakurai A, Katai M, Itakura Y, Ikeo Y, Hashizume K (1999). "Premature centromere division in patients with multiple endocrine neoplasia type 1". Cancer Genet Cytogenet. 109 (2): 138–40. PMID 10087948.
  29. ↑ "Multiple endocrine neoplasia (MEN) type I [Dr Matt A. Morgan and Dr Frank Gaillard]".
  30. ↑ Vortmeyer AO, Lubensky IA, Skarulis M, Li G, Moon YW, Park WS; et al. (1999). "Multiple endocrine neoplasia type 1: atypical presentation, clinical course, and genetic analysis of multiple tumors". Mod Pathol. 12 (9): 919–24. PMID 10496602.
  31. ↑ Gibril F, Schumann M, Pace A, Jensen RT (2004). "Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: a prospective study of 107 cases and comparison with 1009 cases from the literature". Medicine (Baltimore). 83 (1): 43–83. doi:10.1097/01.md.0000112297.72510.32. PMID 14747767.
  32. ↑ [1] Pancreatic endocrine tumors

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