Multiple endocrine neoplasia type 1 pathophysiology
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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:
- 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:
- 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.
- 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.
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-  Pancreatic endocrine tumors