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* Diffuse hyperplasia or multiple adenomas of parathyroid are more common than solitary adenomas.
* Diffuse hyperplasia or multiple adenomas of parathyroid are more common than solitary adenomas.
* Pancreatic tumors are usually multicentric. Multiple adenomas or diffuse islet cell hyperplasia commonly occurs; such tumors may arise from the small bowel rather than the pancreas.


==Microscopic Pathology==
==Microscopic Pathology==

Revision as of 21:04, 2 September 2015

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]

Overview

Pathogenesis

  • MEN type I is an autosomal dominant syndrome characterized by:
  • Pituitary adenomas
  • Islet cell tumours of the pancreas: most often gastrinomas followed by glucogonomas
  • Parathyroid hyperplasia: with resulting hyperparathyroidism
  • Multiple endocrine neoplasia or MEN is part of a group of disorders that affect the body's network of hormone-producing glands (the endocrine system). Hormones are chemical messengers that travel through the bloodstream and regulate the function of cells and tissues throughout the body. Multiple endocrine neoplasia involves tumors in at least two endocrine glands; tumors can also develop in other organs and tissues. These growths can be noncancerous (benign) or cancerous (malignant). If the tumors become cancerous, some cases can be life-threatening.
  • Overactivity of the parathyroid gland (hyperparathyroidism) disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of the bones (osteoporosis), high blood pressure (hypertension), loss of appetite, nausea, weakness, fatigue, and depression.
  • Neoplasia in the pituitary gland can manifest as prolactinomas whereby too much prolactin is secreted, suppressing the release of gonadotropins, causing a decrease in sex hormones such as testosterone. Pituitary tumor in MEN1 can be large and cause signs by compressing adjacent tissues.
  • Pancreatic tumors associated with MEN-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 tumors of the pancreatic Islets of Langerhans can occur in MEN-1. One of these, involving the alpha cells, causes over-secretion of glucagon, resulting in a classic triad of high blood glucose levels (hyperglycemia), a rash called necrolytic migratory erythema, and weight loss. Another is a tumor of the non-beta islet cells, known as a gastrinoma, which causes the over-secretion of the hormone gastrin, resulting in the over-production of acid by the acid-producing cells of the stomach (parietal cells) and a constellation of sequelae known as Zollinger-Ellison syndrome. Zollinger-Ellison syndrome may include severe gastric ulcers, abdominal pain, loss of appetite, chronic diarrhea, malnutrition, and subsequent weight loss. Other non-beta islet cell tumors associated with MEN1 are discussed below.

Genetics

MEN1 gene

  • The gene locus causing MEN1 has been localised to chromosome 11q13 by studies of loss of heterozigosity (LOH) on MEN1-associated tumours and by linkage analysis in MEN1 families[1][2][3][4]
  • The results of these studies agree with Knudson's "two hits" model for tumour development[5] and indicated that the MEN1 gene is a putative tumour suppressor gene.
  • The mutated MEN1allele is a germline mutation present in all cells at birth. The second mutation is a somatic mutation that occurs in the predisposed endocrine cell and leads to loss of the remaining wild type allele; it gives cells the survival advantage needed for tumour development.
  • The responsible gene, MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.
  • Mutation analysis revealed that the MEN1 gene was frequently, but not always, mutated in MEN1 families[6]. To date, more than 400 different germline or somatic mutations have been reported in MEN1 families and sporadic cases from several international studies.
  • Mutations are distributed over the entire coding region without showing any significant hot spot region[7][8][9][10][11][12].
  • Approximately 20% of mutations are nonsense mutations, about 50% are frameshift insertions and deletions, 20% are missense mutations and about 7% are splice site defects.
  • The nonsense mutations and many of the frameshift insertions and deletions and donor-splice site mutations are truncating mutations predicting a loss-of-function of menin, and therefore supporting the hypothesis that MEN1 is a tumour suppressor gene.
  • About 68% of identified missense mutations occur on an amino acid that is conserved among humans, mice, zebrafish and Drosophila.
  • More than 10% of the MEN1mutations arise de novo and may be transmitted to subsequent generations. Nevertheless, about 10–20% of MEN1 patients may not harbour mutations within the coding region of the MEN1 gene[9][13][14]; these individuals may have mutations in the promoter or untranslated regions (UTRs), which remain to be investigated. Moreover, because all MEN1 families investigated to date have tight linkage to 11q13, the presence of another tumour suppressor gene in this region is also a possibility[15].

MEN1 protein (menin)

  • MEN1 gene encodes a 610 amino acid (67 Kda) nuclear protein that is highly conserved among humans, mice (98%) and rats (97%), and more distantly among zebrafish (75%) and Drosophila(47%)[16][17][18][19][20]. Analysis of the menin amino acid sequence did not reveal homology to any other known protein, sequence motif or signal peptide, thus the putative function of menin could not be deduced. Since the amino acid sequence and mutation profile of menin provide a few clues to the functions of menin, most of what is known about its role is derived from in vitro studies. These studies revealed that menin is located primarily in the nucleus[21] and identified at least two independent nuclear localisation signals (NLSs) in the C-terminus of the protein. None of the MEN1missense mutations or in-frame deletions[22][23][24][25] alter either of these NLSs. However, all truncating mutations induce a lack of at least one of these NLSs. The nuclear localisation of menin suggests that this protein may have an important role in the regulation of DNA transcription and replication, in cell cycle, or in the maintenance of genome integrity. Recent studies have demonstrated that over-expression of menin in a Ras-transformed NIH3T3 cell model reversed the transformed phenotype[26], inducing decreased proliferation, suppression of growth in soft agar and inhibition of tumour growth in nude mice. There is increasing evidence that menin may act in DNA repair or synthesis, but the exact mechanism by which menin regulates DNA synthesis or DNA repair in response to DNA damage, is currently unknown. In the last years menin has been shown to interact with several proteins of known functions.
  • The first identified partner of menin was JunD, a transcriptional factor belonging to the AP1 transcription complex family. Menin interacts with the N-terminus of JunD through its N-terminus and central domains (which are critical for this interaction). Wild type menin represses JunD-activated transcription maybe via a histone deacetylase-dependent mechanism[27][28].
  • 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)[29]. These proteins modulate the expression of various genes 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.
  • Even the rodent protein Pem has been shown to bind menin directly[30]. Pem is a homeobox-containing protein which plays a role in the regulation of transcription. However, since Pem sequence has no known homolog in the human genome, its direct relevance to MEN1 in humans is still controversial. Mouse and human menin are very similar and this could suggest the existence of a human protein, with a function similar to that of Pem, which binds menin and thus plays a role in the pathogenicity of MEN1 mutations.
  • 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.
  • Finally, menin interacts with the metastasis suppressor Nm23H1[31]. 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. This may be supported by the fact that normal cells from MEN1 patients present an elevated level of chromosome alterations[32][33][34][35] and that MEN1 tumors have more genome aberrations than equivalent tumors from non-MEN1 patients.

Associated Conditions

Gross Pathology

  • Diffuse hyperplasia or multiple adenomas of parathyroid are more common than solitary adenomas.
  • Pancreatic tumors are usually multicentric. Multiple adenomas or diffuse islet cell hyperplasia commonly occurs; such tumors may arise from the small bowel rather than the pancreas.

Microscopic Pathology

References

  1. ↑ 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.
  2. ↑ 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.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ Knudson AG (1993). "Antioncogenes and human cancer". Proc Natl Acad Sci U S A. 90 (23): 10914–21. PMC 47892. PMID 7902574.
  6. ↑ Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR; et al. (1997). "Positional cloning of the gene for multiple endocrine neoplasia-type 1". Science. 276 (5311): 404–7. PMID 9103196.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 9.0 9.1 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V; et al. (1997). "Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1". Hum Mol Genet. 6 (7): 1177–83. PMID 9215690.
  14. ↑ Bassett JH, Forbes SA, Pannett AA, Lloyd SE, Christie PT, Wooding C; et al. (1998). "Characterization of mutations in patients with multiple endocrine neoplasia type 1". Am J Hum Genet. 62 (2): 232–44. doi:10.1086/301729. PMC 1376903. PMID 9463336.
  15. ↑ Chakrabarti R, Srivatsan ES, Wood TF, Eubanks PJ, Ebrahimi SA, Gatti RA; et al. (1998). "Deletion mapping of endocrine tumors localizes a second tumor suppressor gene on chromosome band 11q13". Genes Chromosomes Cancer. 22 (2): 130–7. PMID 9598800.
  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. ↑ Guru SC, Goldsmith PK, Burns AL, Marx SJ, Spiegel AM, Collins FS; et al. (1998). "Menin, the product of the MEN1 gene, is a nuclear protein". Proc Natl Acad Sci U S A. 95 (4): 1630–4. PMC 19125. PMID 9465067.
  22. ↑ Mayr B, Apenberg S, Rothämel T, von zur Mühlen A, Brabant G (1997). "Menin mutations in patients with multiple endocrine neoplasia type 1". Eur J Endocrinol. 137 (6): 684–7. PMID 9437237.
  23. ↑ Shimizu S, Tsukada T, Futami H, Ui K, Kameya T, Kawanaka M; et al. (1997). "Germline mutations of the MEN1 gene in Japanese kindred with multiple endocrine neoplasia type 1". Jpn J Cancer Res. 88 (11): 1029–32. PMID 9439676.
  24. ↑ Toliat MR, Berger W, Ropers HH, Neuhaus P, Wiedenmann B (1997). "Mutations in the MEN I gene in sporadic neuroendocrine tumours of gastroenteropancreatic system". Lancet. 350 (9086): 1223. doi:10.1016/S0140-6736(05)63453-8. PMID 9652567.
  25. ↑ Sato M, Matsubara S, Miyauchi A, Ohye H, Imachi H, Murao K; et al. (1998). "Identification of five novel germline mutations of the MEN1 gene in Japanese multiple endocrine neoplasia type 1 (MEN1) families". J Med Genet. 35 (11): 915–9. PMC 1051484. PMID 9832038.
  26. ↑ Kim YS, Burns AL, Goldsmith PK, Heppner C, Park SY, Chandrasekharappa SC; et al. (1999). "Stable overexpression of MEN1 suppresses tumorigenicity of RAS". Oncogene. 18 (43): 5936–42. doi:10.1038/sj.onc.1203005. PMID 10557080.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ Lemmens IH, Forsberg L, Pannett AA, Meyen E, Piehl F, Turner JJ; et al. (2001). "Menin interacts directly with the homeobox-containing protein Pem". Biochem Biophys Res Commun. 286 (2): 426–31. doi:10.1006/bbrc.2001.5405. PMID 11500056.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ 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.
  36. ↑ "Multiple endocrine neoplasia (MEN) type I [Dr Matt A. Morgan and Dr Frank Gaillard]".
  37. ↑ 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.
  38. ↑ 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.
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