Multiple endocrine neoplasia type 1 pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. ;Associate Editor(s)-in-Chief: , Ammu Susheela, M.D. , Aravind Reddy Kothagadi M.B.B.S
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.
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:
- Pituitary adenomas
- Islet cell tumors of the pancreas (commonly gastrinoma and glucagonoma)
- Parathyroid hyperplasia with resulting hyperparathyroidism
- Multiple endocrine neoplasia type 1 associated parathyroid tumors 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.
- 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 multiple endocrine neoplasia type 1 can be large and cause signs by compressing adjacent tissues.
- Two-thirds are microadenomas (<1.0 cm in diameter), and the majority are prolactin-secreting tumors.
Duodenopancreatic Neuroendocrine Tumors
- Functioning pancreatic neuroendocrine tumors seen in multiple endocrine neoplasia type 1 include the following:
- Insulinomas (10%–20% penetrance)
- Vasoactive intestinal peptide tumors (VIPomas) (~1% penetrance)
- Glucagonomas (1%–5% penetrance)
- Somatostatinomas (~1% penetrance)
- Pancreatic tumors 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 tumors 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 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 sequel known as Zollinger-Ellison syndrome which may include severe gastric ulcers, 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, 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.
- 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 tumors and by linkage analysis in multiple endocrine neoplasia type 1 families.
- MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.
- MEN1 gene is a putative tumor suppressor gene and causes multiple endocrine neoplasia type 1 by Knudson's "two hits" model for tumor development.
- Knudson's "two hits" model for tumor development suggest that there is a germline mutation present in all cells at birth and the second mutation is a somatic mutation that occurs in the predisposed endocrinecell and leads to loss of the remaining wild type allele. This "two hits" model gives cells the survival advantage needed for tumor development.
- Mutations are distributed over the entire coding region without showing any significant hot spot region.
- 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.
MEN1 Protein (menin)
- MEN1 gene encodes a 610 amino acid (67 Kda) nuclear protein called menin.
- 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.
- 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). 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.
- 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. 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.
MEN Type 4
MEN 4 is caused by loss of function mutation in CDKN1B gene which is located on Chromosome 12 in humans.
Multiple endocrine neoplasia type 1 is associated with the following conditions:
- Adrenocortical lesions
- Adrenal adenomas
- Adrenocortical hyperplasia
- Cortisol-secreting adenomas
- Adrenal carcinomas (rare)
- Spinal ependymoma
- Carcinoid tumors
- Hepatic focal nodular hyperplasia
- Zollinger-Ellison syndrome
- 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.
- Peptic ulcers are multiple or atypical in location, and often bleed, perforate, or become obstructed.
- Pancreatic involvement in multiple endocrine neoplasia is associated with following features:
- Nesidioblastosis also known as endocrine duct proliferation,
- Peliosis in islets,
- Cytologic atypia.
- ↑ "Wikipedia Multiple endocrine neoplasia (MEN) type I)".
- ↑ 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.
- ↑ Pellegata, NS (2012). "MENX and MEN4". Clinics. 67 (S1): 13–18. doi:10.6061/clinics/2012(Sup01)04. ISSN 1807-5932.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Knudson AG (1993). "Antioncogenes and human cancer". Proc Natl Acad Sci U S A. 90 (23): 10914–21. PMC 47892. PMID 7902574.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ "Multiple endocrine neoplasia (MEN) type I [Dr Matt A. Morgan and Dr Frank Gaillard]".
- ↑ 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.
- ↑ 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.
- ↑  Pancreatic endocrine tumors