Multiple endocrine neoplasia type 1

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

Multiple endocrine neoplasia type 1 (MEN-1 syndrome) or Wermer’s syndrome is part of a group of disorders that affect the endocrine system through development of neoplastic lesions in the pituitary, the parathyroid gland and the pancreas. Multiple endocrine neoplasia type 1 was first described by Dr.Erdheim, a German physician, in 1903 by reporting a case of an acromegalic patient with pituitary adenoma and three enlarged parathyroid glands. Development of multiple endocrine neoplasia type 1 is the result of multiple genetic mutations of mainly MEN1 gene. The pathophysiology of multiple endocrine neoplasia type 1 depends on the histological subtype. Common risk factors in the development of multiple endocrine neoplasia type 1 are family history, history of Zollinger-Ellison syndrome and pituitary dysfunction. Symptoms of multiple endocrine neoplasia type 1 include lethargy, depression, oligomenorrhea, constipation, headache and diarrhea. Biochemical tests and imaging techniques are used to screen for multiple endocrine neoplasia type 1. Symptoms of multiple endocrine neoplasia type 1 include lethargy, depression, oligomenorrhea, constipation, headache and diarrhea. MRI may be helpful in the diagnosis of multiple endocrine neoplasia type 1. Surgery is the mainstay of treatment for multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 was first described by Dr.Erdheim, a German physician, in 1903 by reporting a case of an acromegalic patient with pituitary adenoma and three enlarged parathyroid glands.

Development of multiple endocrine neoplasia type 1 is the result of multiple genetic mutations. Gene involved in the pathogenesis of multiple endocrine neoplasia type 1 is MEN1 gene. The pathophysiology of multiple endocrine neoplasia type 1 depends on the histological subtype.

Multiple endocrine neoplasia type-1 occurs due to the mutations in gene MEN-1. This gene encodes for menin protein. Menin prevents the cells from growing and dividing aggressively. Menin is likely involved in cell functions such as copying and repairing DNA and regulating the activity of other genes. Inactivating mutations of both the copies of the MEN1 gene leads to lack of availability of menin to control cell growth and division. This leads to the formation of tumors characteristic of the MEN-1 syndrome. Why these tumors preferentially affect endocrine tissues is unclear.

Multiple endocrine neoplasia type 1 must be differentiated from other hereditary diseases such as von Hippel-Lindau syndrome, tuberous sclerosis, carney complex, neurofibromatosis type 1, Li-Fraumeni syndrome, multiple endocrine neoplasia type 2, familial hyperparathyroidism, pheochromocytoma and acromegaly.

The prevalence of multiple endocrine neoplasia type 1 is approximately 2-3 per 100,000 individuals worldwide. Patients of all age groups may develop multiple endocrine neoplasia type 1, but it is commonly diagnosed among patients between 18-50 years of age. Multiple endocrine neoplasia type 1 affects men and women equally. There is no racial predilection to multiple endocrine neoplasia type 1.

Common risk factors in the development of multiple endocrine neoplasia type 1 are family history, history of Zollinger-Ellison syndrome and pituitary dysfunction.

According to the National Caner Institute, screening for multiple endocrine neoplasia type 1 by imaging studies such as brain MRI, abdominal CT and abdominal MRI is recommended every 3-5 year among patients with pituitary tumors and pancreatic neuroendocrine tumors respectively. Biochemical tests such as serum prolactin, insulin-like growth factor 1, fasting total serum calcium, ionized calcium, parathyroid hormone, fasting serum gastrin, chromogranin A, pancreatic polypeptide, glucagon and vasointestinal polypeptide are recommended every year among patients with pituitary tumors, pancreatic neuroendocrine tumors and primary hyperparathyroidism.

The natural history largely depends on the manifestation and virulence of the manifestations. The manifestations of multiple endocrine neoplasia type 1 usually develop in the first, second, or third decade of life. If left untreated, manifestations of multiple endocrine neoplasia type 1 may gradually worsen, and patients may die of complications of the disease. Life-threatening complications of multiple endocrine neoplasia type 1 include gastrointestinal bleeding, convulsions, hypokalemia, hypoglycemia, and venous thrombosis. Although many tumors associated with multiple endocrine neoplasia type 1 are benign, approximately half of people with multiple endocrine neoplasia type 1 eventually develop a cancerous tumor. The prognosis of multiple endocrine neoplasia type 1 is generally good with treatment. Development of pancreatic cancer is associated with poor prognosis.

There are no established criteria for the diagnosis of MEN 1.

Symptoms of multiple endocrine neoplasia type 1 include lethargy, depression, oligomenorrhea, constipation, headache and diarrhea.

Common physical examination findings of multiple endocrine neoplasia type 1 include rash, lymphadenopathy, fever and abdominal mass.

Laboratory findings consistent with the diagnosis of multiple endocrine neoplasia type 1 include increased parathyroid hormone, increased gastrin, and increased cortisol.

Abdominal ultrasound may be helpful in monitoring tumor growth and metastases in multiple endocrine neoplasia type 1.

Abdominal CT scan may be helpful in the diagnosis of multiple endocrine neoplasia type 1. Findings on CT scan suggestive of multiple endocrine neoplasia type 1 include thickened stomach rugal folds, multiple gastric nodules and calcified or cystic pancreatic tumors.

MRI may be helpful in the diagnosis of multiple endocrine neoplasia type 1. Findings on MRI suggestive of multiple endocrine neoplasia type 1 include diffuse heterogenous enhancement of T1 C+ (Gd), low T1 signal and high T2 signal.

Other imaging studies for multiple endocrine neoplasia type 1 include fluoro-di-glucose-PET/CT, venous sampling, angiography and endovascular procedures, such as trans-arterial chemo-embolization (TACE).

Other diagnostic studies for multiple endocrine neoplasia type 1 include genetic testing, which demonstrates gene mutation in proband of MEN1 gene.

Pharmacologic medical therapies for multiple endocrine neoplasia type 1 include cabergoline, somatostatin analogues, and H2-receptor blockers.

Surgery is the mainstay of treatment for multiple endocrine neoplasia type 1.

There is no established method for prevention of Multiple endocrine neoplasia 1.

According to the National Cancer Institute, surveillance for multiple endocrine neoplasia type 1 by imaging studies such as brain MRI, abdominal CT and abdominal MRI is recommended every 3-5 year among patients with pituitary tumors and pancreatic neuroendocrine tumors respectively. Biochemical tests such as serum prolactin, insulin-like growth factor 1, fasting total serum calcium, ionized calcium, parathyroid hormone, fasting serum gastrin, chromogranin A, pancreatic polypeptide, glucagon and vasointestinal polypeptide are recommended every year among patients with pituitary tumors, pancreatic neuroendocrine tumors and primary hyperparathyroidism.

Future or investigational therapies of multiple endocrine neoplasia type 1 include TRK-inhibitors (tropomyosin receptor kinase inhibitors), mTOR inhibitors, thienopyrimidine analogs and molecular phenotyping.

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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]

Multiple endocrine neoplasia type 1 was first described by Dr.Erdheim, a German physician, in 1903 by reporting a case of an acromegalic patient with pituitary adenoma and three enlarged parathyroid glands.

The following table describes the major historically significant events about multiple endocrine neoplasia type 1.

MEN I Historical Background

Years	Scientist	Contribution
1903	Erdheim	Reported case of an acromegalic patient with pituitary adenoma and three enlarged parathyroid glands.
1953	Underdahl	Reported case series of patients with syndrome of pituitary, parathyroid, and pancreatic islet adenomas.
1954	Wermer	Identified that multiple endocrine neoplasia was transmitted as a dominant trait.
1962	Williams and Celestin	First described bronchial carcinoid as a feature of multiple endocrine neoplasia type 1.
1963	Jacobs and Underwood	Reported case of hypoglycemia and islet cell adenomas in 3 members of the family, with father having hyperparathyroidism and broncial carcinoma and son and daughter with idiopathic epilepsy [1].
1966	Guida	Identified pituitary adenoma and duodenal carcinoid in patients with multiple endocrine neoplasia type 1 syndrome [2].
1967	Johnson	Presented a multiple endocrine neoplasia type 1 case devoid of peptic ulcer [3].
1968	Steiner	Introduced the term “multiple endocrine neoplasia” (MEN) to describe disorders featuring combinations of endocrine tumors and proposed the terms ‘Wermer syndrome’ for multiple endocrine neoplasia type 1 and ‘Sipple syndrome’ for multiple endocrine neoplasia type 2.
1972	Vance	Suggested the importance of primary genetic lesion in endocrine adenomatosis in developing neoplasia and hyperfunctioning of islet of langerhans [4].
1982	McCarthy	Identified 2 different causes of Zollinger-Ellison syndrome, malignant type and the one linked with multiple endocrine neoplasia type 1 [5].
1983	Hershon	Identified family members from Pacific Northwest with prolactinomas but with no pancreatic tumors.
1985	Bear	Referred the disorders reported from Burin as multiple endocrine neoplasia type 1 Burin.
1986	Brandi	Suggested the humoral cause of primary hyperparathyroidism in familial multiple endocrine neoplasia type 1.
1986	Schimke	Suggested a 2 step model of pathogenesis which include germline mutation followed by somatic mutation later.
1986	Bahn	Identified 25 year old monozygotic twins with one having primary hyperparathyroidism, Zollinger-Ellison syndrome, cushing’s disease, and hyperprolactinemia and the other have primary hyperparathyroidism and hyperprolactinemia [6].
1986	Maton	Identified that cushing’s syndrome is more common with Zollinger-Ellison syndrome [7].
1988		The multiple endocrine neoplasia type 1 locus was assigned to chromosome 11 (11q13).
1993	Gaitan	Described mother and daughter with cushing’s disease due to ACTH secreting tumor [8].
1994	Petty	Identified that gene involved in Pacific Northwest studies and Burin studies linked to 11q chromosome.
1997	Darling	Suggested that one of the diagnostic findings of multiple endocrine neoplasia type 1 is cutaneous manifestations.
1998		The multiple endocrine neoplasia type 1 gene was cloned [9].
1999	Yu	Identified that gastrinoma growth is the single most important factor in deciding the long term survival of patients with Zollinger-Ellison syndrome [10].
2001	Bordi	Identified patients with multiple endocrine neoplasia syndrome to have carcinoid tumors [11].

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Reddy Kothagadi M.B.B.S[2] Ajay Gade MD[3]]

MEN-1 syndrome encompasses entero-pancreatic tumors, pituitary adenoma, parathyroid adenoma and other associated tumors such as adrenal cortical tumor, pheochromocytoma, bronchopulmonary (neuroendocrine tumor) NET, thymic NET, gastric NET, lipomas, angiofibromas, collagenomas and meningiomas.

MEN-1 syndrome encompasses entero-pancreatic tumors, pituitary adenoma, parathyroid adenoma and other associated tumors.^{[1][2][3][4][5][6][7][8]}

Multiple Endocrine Neoplasia-1 (MEN-1) Syndrome Tumors
Enteropancreatic tumor	Gastrinoma Insulinoma Glucagonoma Nonfunctioning and PPoma VIPoma
Pituitary adenoma	Prolactinoma Somatotrophinoma Corticotropinoma Nonfunctioning
Associated tumors	Adrenocortical tumor Pheochromocytoma Bronchopulmonary NET Thymic NET Gastric NET Lipomas Angiofibromas Collagenomas Meningiomas
Parathyroid adenoma	–

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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]

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:^[1]

• 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.

• 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.

• 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]

• 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.^{[4][5][6][7][8]}
• MEN1, spans about 10 Kb and consists of ten exons encoding a 610 amino acid nuclear protein, named menin.^[4]
• MEN1 gene is a putative tumor suppressor gene and causes multiple endocrine neoplasia type 1 by Knudson’s “two hits” model for tumor development.^[9]
• 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.^{[10][11][12][13][14][15]}
• 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 gene encodes a 610 amino acid (67 Kda) nuclear protein called menin.^{[16][17][18][19][20]}
• 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.^[21][22]
• 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).^[23] 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.^[24] 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.^{[25][26][27][28]}

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:^[29]

• Lipomas
• Angiofibromas
• Adrenocortical lesions
• Adrenal adenomas
• Adrenocortical hyperplasia
• Cortisol-secreting adenomas
• Adrenal carcinomas (rare)
• Spinal ependymoma
• Carcinoid tumors
• Meningioma
• Leiomyoma
• Pheochromocytoma
• Hepatic focal nodular hyperplasia^[30]
• Zollinger-Ellison syndrome^[31]

• 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:^[32]

• Nesidioblastosis also known as endocrine duct proliferation,
• Adenomas,
• Peliosis in islets,
• Cytologic atypia.

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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] Aravind Reddy Kothagadi M.B.B.S[3] Ajay Gade MD[4]]

Multiple endocrine neoplasia type 1 is caused by a mutation in the MEN-1 gene.This gene encodes for menin protein. Menin prevents the cells from growing and dividing aggressively. Menin is likely involved in cell functions such as copying and repairing DNA and regulating the activity of other genes. Inactivating mutations of both the copies of the MEN-1 gene leads to lack of availability of menin to control cell growth and division.

The causes of MEN-1 are as follows:^[1][2][3][4]

• Genetic mutation is suspected to be the main cause of type 1 multiple endocrine neoplasia. It is caused by mutation in the MEN-1 gene.
• This gene encodes for menin protein. Menin prevents the cells from growing and dividing aggressively.

• Menin is likely involved in cell functions such as copying and repairing DNA and regulating the activity of other genes.
• Inactivating mutations of both the copies of the MEN1 gene leads to lack of availability of menin to control cell growth and division.
• This leads to the formation of tumors characteristic of the MEN-1 syndrome. Why these tumors preferentially affect endocrine tissues is unclear.
• MEN-1 syndrome is inherited in an autosomal dominant fashion. The altered gene is usually inherited from an affected parent. People with this condition are born with one mutated MEN1 gene copy in each cell.
• New mutations in MEN-1 without a family history can also occur in some patients.
• In most autosomal dominant conditions, in order to cause the disorder one altered copy of a gene in each cell is usually enough, two copies of the MEN1 gene must be altered to trigger tumor formation in multiple endocrine neoplasia type 1.
• In an individuals lifetime, in a small number of cells, a mutation in the second copy of the MEN1 gene occurs. Individuals with one MEN1 mutation acquire a second mutation in few cells leading to form tumors as a result of the unregulated division of cells.

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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] Aditya Ganti M.B.B.S. [3]

Multiple endocrine neoplasia type 1 must be differentiated from other diseases with similar presentation such as von Hippel-Lindau syndrome, tuberous sclerosis, carney complex, neurofibromatosis type 1, Li-Fraumeni syndrome, multiple endocrine neoplasia type 2, familial hyperparathyroidism, pheochromocytoma, and acromegaly.

The table below summarizes the findings that differentiate multiple endocrine neoplasia type 1 from other conditions with similar presentations: ^[1][2][3]

Disease	Gene	Chromosome	Differentiating Features	Components of MEN			Diagnosis
				Parathyroid	Pitutary	Pancreas
von Hippel-Lindau syndrome	Von Hippel–Lindau tumor suppressor	3p25.3	Angiomatosis,  Hemangioblastomas Pheochromocytoma Renal cell carcinoma Pancreatic cysts (pancreatic serous cystadenoma) Endolymphatic sac tumor Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)	–	–	+	Clinical diagnosis In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.
Carney complex	PRKAR1A	17q23-q24	Myxomas of the heart Hyperpigmentation of the skin (lentiginosis) Endocrine (ACTH-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease)	–	–	–	Clinical diagnosis
Neurofibromatosis type 1	RAS	17	Scoliosis Learning disabilities Vision disorders Cutaneous lesions Epilepsy.	–	–	–	Prenatal Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus. Postnatal Cardinal Clinical Features” are required for positive diagnosis. Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals. Two or more neurofibromas of any type or 1 plexiform neurofibroma Freckling in the axillary (Crowe sign) or inguinal regions Optic glioma Two or more Lisch nodules (pigmented iris hamartomas) A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
Li-Fraumeni syndrome	TP53	17	Early onset of diverse amount of cancers such as Sarcoma Cancers of Breast Brain Adrenal glands	–	–	–	Criteria Sarcoma at a young age (below 45) A first-degree relative diagnosed with any cancer at a young age (below 45) A first or second degree relative with any cancer diagnosed before age 60.
Gardner’s syndrome	APC	5q21	Multiple polyps in the colon  Osteomas of the skull Thyroid cancer Epidermoid cysts Fibromas Desmoid tumors	–	–	–	Clinical diagnosis Colonoscopy
Multiple endocrine neoplasia type 2	RET	–	Medullary thyroid carcinoma (MTC) Pheochromocytoma Primary hyperparathyroidism	+	–	–	Hypercalcemia Hypophosphatemia, Elevated parathyroid hormone, Elevated norepinephrine Criteria Two or more specific endocrine tumors Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia
Cowden syndrome	PTEN	–	Hamartomas	–	–	–	PTEN mutation probability risk calculator
Acromegaly/gigantism	–	–	Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin Hypertrichosis Hyperpigmentation Hyperhidrosis Carpal tunnel syndrome.	–	+	–	An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.
Pituitary adenoma	–	–	Visual field defects classically bitemporal hemianopsia Increased intracranial pressure Migraine Lateral rectus palsy	–	+	–	Elevated serum level of prolactin Elevated or decreased serum level of adrenocorticotropic hormone (ACTH) Elevated or decreased serum level of growth hormone (GH) Elevated or decreased serum level of thyroid-stimulating hormone (TSH) Elevated or decreased serum level of follicle-stimulating hormone (FSH) Elevated or decreased serum level of luteinizing hormone (LH)
Hyperparathyroidism	–	–	Kidney stones Hypercalcemia Constipation Peptic ulcers Depression	+	–	–	An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism. Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium. An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.
Pheochromocytoma/paraganglioma	VHL RET NF1   SDHB  SDHD	–	Characterized by Episodic hypertension Palpitations Anxiety Diaphoresis Weight loss	–	–	–	Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.
Adrenocortical carcinoma	p53 Retinoblastoma h19 Insulin-like growth factor II (IGF-II) p57kip2	17p, 13q	Cushing syndrome (cortisol hypersecretion) Conn syndrome (aldosterone hypersecretion) virilization (testosterone hypersecretion)	–	–	–	Increased serum glucose Increased urine cortisol Serum androstenedione and dehydroepiandrosterone Low serum potassium Low plasma renin activity High serum aldosterone Excess serum estrogen
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013[4]

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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]

The prevalence of multiple endocrine neoplasia type-1 (MEN-1) is approximately 2-3 per 100,000 individuals worldwide. Patients of all age groups may develop MEN-1, but it is commonly diagnosed among patients between 18-50 years of age. MEN-1 affects men and women equally. There is no racial predilection to MEN-1.

• Worldwide, the prevalence of MEN-1 is estimated to be 2-3 per 100,000.^[1]

• Endocrine and non-endocrine manifestations of the disease in MEN-1 patients most often begin in the fourth or fifth decade.
• The onset of the disease is rare before 10 years of age.^[2][3]

• Men and women are affected equally by MEN-1.^[2][4]
• Men have a higher incidence of pancreatic tumors, whereas women have a higher incidence of pituitary tumors.
• Thymic tumors are common among men.

• There is no racial predilection to MEN-1.

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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]

Common risk factors in the development of multiple endocrine neoplasia type-1 are family history, history of Zollinger-Ellison syndrome and pituitary dysfunction.

Common risk factors in the development of multiple endocrine neoplasia type-1 include: ^[1]

• Positive family history ^[2]
• History of Zollinger-Ellison syndrome ^[3][4]
• Pituitary dysfunction ^[5][6]

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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]

According to the National Caner Institute, screening for multiple endocrine neoplasia type 1 by imaging studies such as brain MRI, abdominal CT and abdominal MRI is recommended every 3-5 year among patients with pituitary tumors and pancreatic neuroendocrine tumors respectively. Biochemical tests such as serum prolactin, insulin-like growth factor 1, fasting total serum calcium, ionized calcium, parathyroid hormone, fasting serum gastrin, chromogranin A, pancreatic polypeptide, glucagon and vaso-intestinal polypeptide are recommended every year among patients with pituitary tumors, pancreatic neuroendocrine tumors and primary hyperparathyroidism.

Screening and surveillance for multiple endocrine neoplasia type 1 may employ a combination of biochemical tests and imaging. Available recommendations are summarized in the following table. ^{[1][2][3][4][5]}

Biochemical Test or Procedure	Condition Screened For	Age Screening Initiated (y)	Frequency
Serum prolactin and/or insulin-like growth factor 1	Pituitary tumors	5	Every 1 year
Fasting total serum calcium and/or ionized calcium and parathyroid hormone	Parathyroidtumors and primary hyperparathyroidism	8	Every 1 year
Fasting serum gastrin	Duodenopancreatic gastrinoma	20	Every 1 year
Chromogranin A, pancreatic polypeptide, glucagon, and vasointestinal polypeptide	Pancreatic neuroendocrine tumors	<10years	Every 1 year
Fasting glucose and insulin	Insulinoma	5	Every 1 year
Brain MRI	Pituitary tumors	5	Every 3–5 years based on biochemical results
Abdominal CT or MRI	Pancreatic neuroendocrine tumors	20	Every 3–5 years based on biochemical results
Abdominal CT, MRI, or endoscopic US	Pancreatic neuroendocrine tumors	<10	Every 1 year

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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]

The natural history largely depends on the manifestation and virulence of the manifestations. The manifestations of multiple endocrine neoplasia type-1 (MEN-1) usually develop in the first, second, or third decade of life. If left untreated, manifestations of MEN-1 may gradually worsen, and patients may die of complications of the disease. Life-threatening complications of MEN-1 include gastrointestinal bleeding, convulsions, hypokalemia, hypoglycemia, and venous thrombosis. Although many tumors associated with MEN-1 are benign, approximately half of people with MEN-1 eventually develop a cancerous tumor. The prognosis of MEN-1 is generally good with treatment. Development of pancreatic cancer is associated with poor prognosis.

• The natural history of MEN-1 is difficult to delineate given the rarity of the disease. ^[1]
• The manifestations of MEN-1 usually develop in the first, second, or third decade of life.
• The age at which MEN-1 develops may vary significantly, even among members of the same family.
• If left untreated, manifestations of MEN-1 may gradually worsen, and patients may die of complications of the disease.

• Complications that can develop as a result of MEN-1 are as follows. ^{[2][3][4][5][6][7][8]}

• Necrolytic migratory erythema
• Hypoglycemia
• Hypokalemia
• Achlorhydria
• Hypercalcemia
• Diabetes mellitus
• Cushing’s syndrome
• Gynecomastia
• Gigantism
• Acromegaly
• Paresis
• Ataxia
• Convulsions
• Infertility
• Impotence
• Kidney stones
• Venous thrombosis
• Glossitis
• Anemia
• GI bleeding

• The prognosis of MEN-1 is generally good with treatment.
• Early death can occur due to the effect of hormones produced by these tumors. ^[9]
• Although many tumors associated with MEN-1 are benign, approximately half of people with MEN-1 will eventually develop a cancerous tumor. ^[10]
• The presence of pancreatic tumors is associated with a particularly poor prognosis among patients with MEN-1.

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