Multiple endocrine neoplasia type 1

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Multiple endocrine neoplasia type 1
Other namesMEN-1 syndrome, Wermer's syndrome
Autosomal dominant - en.svg
Multiple endocrine neoplasia type 1 is inherited in an autosomal dominant manner.
Specialty Oncology, endocrine surgery   OOjs UI icon edit-ltr-progressive.svg

Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas. [1] Individuals suffering from this disorder are prone to developing multiple endocrine and nonendocrine tumors. [2] [3] It was first described by Paul Wermer in 1954. [4]

Contents

Signs and symptoms

Parathyroid

Hyperparathyroidism is present in ≥ 90% of patients. Asymptomatic hypercalcemia is the most common manifestation: about 25% of patients have evidence of nephrolithiasis or nephrocalcinosis. In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia or multiple adenomas are more common than solitary adenomas.

Pancreas

Pancreatic islet cell tumors are today the major cause of death in persons with MEN-1. Tumors occur in 60-80% of persons with MEN-1 and they are usually multicentric. Multiple adenomas or diffuse islet cell hyperplasia commonly occurs. About 30% of tumors are malignant and have local or distant metastases. [5] About 10-15% of islet cell tumors originate from a β-cell, secrete insulin (insulinoma), and can cause fasting hypoglycemia. β-cell tumors are more common in patients < 40 years of age.

Most islet cell tumors secrete pancreatic polypeptide, the clinical significance of which is unknown. Gastrin is secreted by many non–β-cell tumors (increased gastrin secretion in MEN 1 also often originates from the duodenum). Increased gastrin secretion increases gastric acid, which may inactivate pancreatic lipase, leading to diarrhea and steatorrhea. Increased gastrin secretion also leads to peptic ulcers in > 50% of MEN 1 patients. Usually the ulcers are multiple or atypical in location, and often bleed, perforate, or become obstructed. Peptic ulcer disease may be intractable and complicated. Among patients presenting with Zollinger-Ellison syndrome, 20 to 60% have MEN 1.

A severe secretory diarrhea can develop and cause fluid and electrolyte depletion with non–β-cell tumors. This complex, referred to as the watery diarrhea, hypokalemia and achlorhydria syndrome (VIPoma) has been ascribed to vasoactive intestinal polypeptide, although other intestinal hormones or secretagogues (including prostaglandins) may contribute. Hypersecretion of glucagon, somatostatin, chromogranin, or calcitonin, ectopic secretion of ACTH resulting in Cushing's syndrome, and hypersecretion of somatotropin–releasing hormone (causing acromegaly) sometimes occur in non–β-cell tumors. All of these are rare in MEN 1.[ citation needed ]Nonfunctioning pancreatic tumors also occur in patients with MEN 1 and may be the most common type of pancreatoduodenal tumor in MEN 1. The size of the nonfunctioning tumor correlates with risk of metastasis and death.

Pituitary

Pituitary tumors occur in 15 to 42% of MEN 1 patients. From 25 to 90% are prolactinomas. About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Excess prolactin may cause galactorrhea, and excess growth hormone causes acromegaly clinically indistinguishable from sporadically occurring acromegaly. About 3% of tumors secrete ACTH, producing Cushing's disease. Most of the remainder are nonfunctional. Local tumor expansion may cause visual disturbance, headache, and hypopituitarism. Pituitary tumors in MEN 1 patients appear to be larger and behave more aggressively than sporadic pituitary tumors.

Other manifestations

Adenomas of adrenal glands occurs occasionally in MEN 1 patients. Hormone secretion is rarely altered as a result, and the significance of these abnormalities is uncertain. Carcinoid tumors, particularly those derived from the embryologic foregut (lungs, thymus), occur in isolated cases. Multiple subcutaneous and visceral lipomas, angiofibromas, and collagenomas may also occur.

Genetic

People with multiple endocrine neoplasia type 1 are born with one mutated copy of the MEN1 gene in each cell. [6] [3] Then, during their lifetime, the other copy of the gene is mutated in a small number of cells. These genetic changes result in no functional copies of the MEN1 gene in selected cells, allowing the cells to divide with little control and form tumors. This is known as Knudson's two-hit hypothesis [7] and is a common feature seen with inherited defects in tumor suppressor genes. Oncogenes can become neoplastic with only one activating mutation, but tumor suppressors inherited from both mother and father must be damaged before they lose their effectiveness. The exception to the "two-hit hypothesis" occurs when suppressor genes exhibit dose-response, such as ATR. [8] The exact function of MEN1 and the protein, menin, produced by this gene is not known, [9] but following the inheritance rules of the "two-hit hypothesis" indicates that it acts as a tumor suppressor.

Diagnosis

In a diagnostic workup individuals with a combination of endocrine neoplasias suggestive of the MEN1 syndrome are recommended to have a mutational analysis of the MEN1 gene if additional diagnostic criteria are sufficiently met, mainly including: [1] [10]

Types

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.

Comparison of main types of multiple endocrine neoplasia. Multiple endocrine neoplasia.png
Comparison of main types of multiple endocrine neoplasia.

The two major forms of multiple endocrine neoplasia are called type 1 and type 2. These two types are often confused because of their similar names. However, type 1 and type 2 are distinguished by the genes involved, [1] the types of hormones made, and the characteristic signs and symptoms.

These disorders greatly increase the risk of developing multiple cancerous and noncancerous tumors in glands such as the parathyroid, pituitary, and pancreas. Multiple endocrine neoplasia occurs when tumors are found in at least two of the three main endocrine glands (parathyroid, pituitary, and pancreatico-duodenum). Tumors can also develop in organs and tissues other than endocrine glands. If the tumors become cancerous, some cases can be life-threatening. The disorder affects 1 in 30,000 people.

Although many different types of hormone-producing tumors are associated with multiple endocrine neoplasia, tumors of the parathyroid gland, pituitary gland, and pancreas are most frequent in multiple endocrine neoplasia type 1. MEN1-associated overactivity of these three endocrine organs are briefly described here:

Treatment

The treatment of choice of parathyroid tumors is open bilateral exploration with subtotal (3/4) or total parathyroidectomy. Autoimplantation may be considered in case of a total parathyroidectomy. Optimal timing for this operation has not yet been established but it should be performed by an experienced endocrine surgeon. The treatment discovered by Joseph Shepherd in 1997-2001 does not provide a cure, rather extends life expectancy. The treatment requires frequent monitoring to the 1 in 30,000 that suffer from MEN-1. [3]

Endocrine pancreatic tumor are treated with surgery and cytotoxic drugs in case of malignant disease.

Pituitary tumors are treated with surgery (acromegaly and Mb. Cushing) or medicine (prolactinomas). [3]

See also

Related Research Articles

<span class="mw-page-title-main">Endocrine system</span> Hormone-producing glands of a body

The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems.

<span class="mw-page-title-main">Gigantism</span> Human growth disorder

Gigantism, also known as giantism, is a condition characterized by excessive growth and height significantly above average. In humans, this condition is caused by over-production of growth hormone in childhood.

<span class="mw-page-title-main">Multiple endocrine neoplasia</span> Group of genetic conditions

Multiple endocrine neoplasia is a condition which encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.

<span class="mw-page-title-main">Anterior pituitary</span> Anterior lobe of the pituitary gland

A major organ of the endocrine system, the anterior pituitary is the glandular, anterior lobe that together with the posterior lobe makes up the pituitary gland (hypophysis) which, in humans, is located at the base of the brain, protruding off the bottom of the hypothalamus.

<span class="mw-page-title-main">Zollinger–Ellison syndrome</span> Condition in which tumours stimulate excessive gastric acid production

Zollinger–Ellison syndrome is rare disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea.

<span class="mw-page-title-main">Parathyroid chief cell</span>

Parathyroid chief cells are one of the two cell types of the parathyroid glands, along with oxyphil cells. The chief cells are much more prevalent in the parathyroid gland than the oxyphil cells. It is perceived that oxyphil cells may be derived from chief cells at puberty, as they are not present at birth like chief cells.

<span class="mw-page-title-main">Insulinoma</span> Tumor of the pancreas which secretes insulin

An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a minority metastasize. Insulinomas are one of the functional pancreatic neuroendocrine tumour (PNET) group. In the Medical Subject Headings classification, insulinoma is the only subtype of "islet cell adenoma".

<span class="mw-page-title-main">Pituitary adenoma</span> Tumor of the pituitary gland

Pituitary adenomas are tumors that occur in the pituitary gland. Most pituitary tumors are benign, approximately 35% are invasive and just 0.1% to 0.2% are carcinomas. Pituitary adenomas represent from 10% to 25% of all intracranial neoplasms, with an estimated prevalence rate in the general population of approximately 17%.

<span class="mw-page-title-main">Prolactinoma</span> Pituitary gland tumor which secretes the hormone prolactin

A prolactinoma is a tumor (adenoma) of the pituitary gland that produces the hormone prolactin. It is the most common type of functioning pituitary tumor. Symptoms of prolactinoma are due to abnormally high levels of prolactin in the blood (hyperprolactinemia), or due to pressure of the tumor on surrounding brain tissue and/or the optic nerves. Based on its size, a prolactinoma may be classified as a microprolactinoma or a macroprolactinoma.

<span class="mw-page-title-main">Endocrine gland</span> Glands of the endocrine system that secrete hormones to blood

The endocrine system is a network of glands and organs located throughout the body. It’s similar to the nervous system in that it plays a vital role in controlling and regulating many of the body’s functions. Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testicles, thyroid gland, parathyroid gland, hypothalamus and adrenal glands. The hypothalamus and pituitary glands are neuroendocrine organs.

<span class="mw-page-title-main">Multiple endocrine neoplasia type 2</span> Medical condition

Multiple endocrine neoplasia type 2 is a group of medical disorders associated with tumors of the endocrine system. The tumors may be benign or malignant (cancer). They generally occur in endocrine organs, but may also occur in endocrine tissues of organs not classically thought of as endocrine. MEN2 is a sub-type of MEN and itself has sub-types, as discussed below. Variants in MEN2A have been associated with Hirschsprung disease. Screening for this condition can begin as young as eight years old for Pheochromocytoma.

<span class="mw-page-title-main">Gastrinoma</span> Medical condition

Gastrinomas are neuroendocrine tumors (NETs), usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger–Ellison syndrome (ZES). A large number of gastrinomas develop in the pancreas or duodenum, with near-equal frequency, and approximately 10% arise as primary neoplasms in lymph nodes of the pancreaticoduodenal region.

<span class="mw-page-title-main">Hyperpituitarism</span> Medical condition

Hyperpituitarism is a condition due to the primary hypersecretion of pituitary hormones; it typically results from a pituitary adenoma. In children with hyperpituitarism, disruption of growth regulation is rare, either because of hormone hypersecretion or because of manifestations caused by local compression of the adenoma.

<span class="mw-page-title-main">Neuroendocrine tumor</span> Tumors of the endocrine and nervous systems

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body.

<span class="mw-page-title-main">Enteroendocrine cell</span> Cell that produces gastrointestinal hormones

Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic effect, diffuse them as local messengers, or transmit them to the enteric nervous system to activate nervous responses. Enteroendocrine cells of the intestine are the most numerous endocrine cells of the body. They constitute an enteric endocrine system as a subset of the endocrine system just as the enteric nervous system is a subset of the nervous system. In a sense they are known to act as chemoreceptors, initiating digestive actions and detecting harmful substances and initiating protective responses. Enteroendocrine cells are located in the stomach, in the intestine and in the pancreas. Microbiota play key roles in the intestinal immune and metabolic responses in these enteroendocrine cells via their fermentation product, acetate.

<span class="mw-page-title-main">Endocrine disease</span> Disorders of the endocrine system

Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology.

<span class="mw-page-title-main">MEN1</span> Protein

Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 and has autosomal dominant inheritance. Variations in the MEN1 gene can cause pituitary adenomas, hyperparathyroidism, pancreatic neuroendocrine tumors, gastrinoma, and adrenocortical cancers.

<span class="mw-page-title-main">Adrenal gland disorder</span> Medical condition

Adrenal gland disorders are conditions that interfere with the normal functioning of the adrenal glands. Your body produces too much or too little of one or more hormones when you have an adrenal gland dysfunction. The type of issue you have and the degree to which it affects your body's hormone levels determine the symptoms.

<span class="mw-page-title-main">Pancreatic neuroendocrine tumor</span> Tumors of the nervous or endocrine system within the pancreas

Pancreatic neuroendocrine tumours, often referred to as "islet cell tumours", or "pancreatic endocrine tumours" are neuroendocrine neoplasms that arise from cells of the endocrine (hormonal) and nervous system within the pancreas.

References

  1. 1 2 3 Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, et al. (July 1997). "Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1". Human Molecular Genetics. 6 (7): 1177–1183. doi: 10.1093/hmg/6.7.1177 . PMID   9215690.
  2. ↑ Duro T, Gonzales KL (2023-01-01). "Adrenal Liposarcoma: A Novel Presentation of Multiple Endocrine Neoplasia Type 1". AACE Clinical Case Reports. 9 (1): 10–12. doi:10.1016/j.aace.2022.11.003. PMC   9837086 . PMID   36654999.
  3. 1 2 3 4 Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, et al. (September 2012). "Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1)". The Journal of Clinical Endocrinology and Metabolism. 97 (9): 2990–3011. doi: 10.1210/jc.2012-1230 . PMID   22723327. S2CID   40362497.
  4. ↑ Wermer P (March 1954). "Genetic aspects of adenomatosis of endocrine glands". The American Journal of Medicine. 16 (3): 363–371. doi:10.1016/0002-9343(54)90353-8. PMID   13138607.
  5. ↑ Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV (March 2021). "Multiple Endocrine Neoplasia Type 1: Latest Insights". Endocrine Reviews. 42 (2): 133–170. doi: 10.1210/endrev/bnaa031 . PMC   7958143 . PMID   33249439.
  6. ↑ Duro T, Gonzales KL (2023-01-01). "Adrenal Liposarcoma: A Novel Presentation of Multiple Endocrine Neoplasia Type 1". AACE Clinical Case Reports. 9 (1): 10–12. doi:10.1016/j.aace.2022.11.003. PMC   9837086 . PMID   36654999.
  7. ↑ Knudson AG (April 1971). "Mutation and cancer: statistical study of retinoblastoma". Proceedings of the National Academy of Sciences of the United States of America. 68 (4): 820–823. Bibcode:1971PNAS...68..820K. doi: 10.1073/pnas.68.4.820 . PMC   389051 . PMID   5279523.
  8. ↑ Fang Y, Tsao CC, Goodman BK, Furumai R, Tirado CA, Abraham RT, Wang XF (August 2004). "ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background". The EMBO Journal. 23 (15): 3164–3174. doi:10.1038/sj.emboj.7600315. PMC   514932 . PMID   15282542.
  9. ↑ Kumar V, Abbas AK, Aster JC (2014-09-05). Robbins & Cotran Pathologic Basis of Disease. Elsevier Health Sciences. p. 291. ISBN   9780323296359.
  10. ↑ Karges W, Schaaf L, Dralle H, Boehm BO (2000). "Concepts for screening and diagnostic follow-up in multiple endocrine neoplasia type 1 (MEN1)". Experimental and Clinical Endocrinology & Diabetes. 108 (5): 334–340. doi:10.1055/s-2000-8146. PMID   10989951. S2CID   260137587.
  11. ↑ Duro T, Gonzales KL (2023-01-01). "Adrenal Liposarcoma: A Novel Presentation of Multiple Endocrine Neoplasia Type 1". AACE Clinical Case Reports. 9 (1): 10–12. doi:10.1016/j.aace.2022.11.003. PMC   9837086 . PMID   36654999.

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