Multiple Endocrine Neoplasia

Multiple endocrine neoplasia syndromes are autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance inherited conditions characterized by 2 or more hormone-producing tumors involving the endocrine organs. There are different types of MEN, namely MEN1–4. The MEN1 syndrome is associated with MEN1 gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations and has a predilection for primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism, pituitary adenomas Pituitary adenomas Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas, and pancreatic tumors (the 3 P’s). Due to the RET proto-oncogene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations, MEN2 syndrome can be further categorized as MEN2A and MEN2B. Medullary thyroid carcinoma and pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma are common features. The MEN2A variant is associated with primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism, whereas MEN2B (also considered MEN3) is associated with neuromas and Marfanoid habitus. The newer and rare entity, MEN4, has features of MEN1 but results from CDKN1B mutations. The diagnosis is clinical, and tumors are detected based on imaging and correlating hormone levels. Genetic testing plays a crucial role in MEN2 syndromes in determining further management. Treatment is dependent on the tumors that are present and genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Multiple endocrine neoplasia (MEN) syndromes are genetic disorders characterized by the presence of ≥ 2 endocrine tumors.

Types

  • MEN1: 
    • Characterized by either clinical setting:
      • Predilection for hyperplasia/tumors commonly involving the parathyroid glands Parathyroid glands The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Parathyroid Glands, anterior pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland, and pancreatic islet cells
      • Presence of a tumor associated with MEN1 in a family with clinically confirmed MEN1
  • MEN2:
    • Characterized by a predisposition to develop medullary thyroid carcinoma (MTC), parathyroid tumors, and pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
    • General subtypes:
      • MEN2A: MTC, pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma, primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism/parathyroid adenoma
      • MEN2B or MEN3: MTC, pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma, neuromas
  • MEN4:
    • Fairly new entity
    • Similar to MEN1
    • Tumors of parathyroid glands Parathyroid glands The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Parathyroid Glands, anterior pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland, and pancreatic islet cells, in association with gonadal, adrenal, renal, or thyroid tumors

General descriptions

Table: Multiple endocrine neoplasia (MEN) syndromes
MEN1 MEN2A and MEN2B MEN4
Pattern Autosomal dominant Autosomal dominant Autosomal dominant
Genetic mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations MEN1 gene on chromosome 11 (11q13) RET proto-oncogene on chromosome 10 (10q11.2) CDKN1B on chromosome 12 (12p13)
Clinical features
  • Primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism
  • Pancreatic tumors
  • Pituitary tumors
  • Thymic or bronchial carcinoid tumors Carcinoid tumors Carcinoid tumors are small, well-differentiated, slow-growing neuroendocrine tumors (NET). Carcinoid syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by neuroendocrine tumors. Carcinoid tumors are most commonly found in the GI and bronchopulmonary tracts. Carcinoid Tumors and Syndrome
  • Gastrinomas
  • Enterochromaffin cell-like gastric tumors
  • Adrenocortical adenomas
  • Other tumors
MEN2A
  • MTC
  • Pheochromocytoma
  • Primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism

MEN2B
  • MTC
  • Pheochromocytoma
  • Mucosal neuromas
  • Ganglioneuromatosis
  • Marfanoid habitus
  • Primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism
  • Pituitary tumors
  • Pancreatic tumors
  • Thyroid tumors
  • Gonadal tumors
  • Adrenal tumors
  • Renal tumors
Treatment
  • Parathyroidectomy
  • Excision of pancreatic tumors
  • Transsphenoidal surgery
  • Thyroidectomy
  • Adrenalectomy
  • Parathyroidectomy
  • Parathyroidectomy
  • Transsphenoidal surgery
  • Excision of pancreatic tumors
Main types of multiple endocrine neoplasia syndromes

Image summary of the main types of multiple endocrine neoplasia syndromes

Image: “Multiple endocrine neoplasia” by Mikael Häggström. License: CC0 1.0, edited by Lecturio.

MEN1

MEN1 syndrome

  • Formerly known as Wermer syndrome
  • Commonly involves the 3 P’s: Parathyroid glands, anterior Pituitary gland, and Pancreatic islet cells

Etiology and epidemiology

  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
    • Autosomal dominant inheritance
    • Mutation of MEN1 gene (protein product is menin)
    • Gene is located on the long arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm of chromosome 11 (11q13).
  • Prevalence: 2 per 100,000 individuals
  • In 90% of cases, the condition MEN1 syndrome is inherited from an affected parent.
  • Pancreatic neuroendocrine tumors Pancreatic Neuroendocrine Tumors Pancreatic neuroendocrine tumors (PanNETs) arise from the endocrine pancreas (islet cells) and represent 2%-5% of primary pancreatic neoplasms; the other 95%-98% of pancreatic neoplasms are from the exocrine pancreas. The majority of PanNETs are nonfunctional (50%-75%), while others that are functional may be benign or malignant. Pancreatic Neuroendocrine Tumors (PanNETs) (NETs) occur at an earlier age when associated with MEN1.

Pathophysiology

  • Menin (coded by MEN1) regulates genome stability, proliferation, and apoptosis.
  • Mutation of the gene increases the risk of the development of neoplasia.
  • In approximately 10% of individuals, de novo mutations of MEN1 occur, which are associated with nonfamilial/sporadic MEN1 syndrome.

Clinical presentation

  • Endocrine:
    • Primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism (95% of cases):
      • ↑ Parathyroid hormone (PTH), ↑ calcium
      • “Stones ( nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis), bones (osteopenia), abdominal groans (obstipation), and psychic moans (neuropsychiatric symptoms)”
    • Entero-pancreatic NETs (50%–80%):
      • Gastrinoma Gastrinoma A gastrinoma is a tumor that secretes excessive levels of the hormone gastrin and is responsible for Zollinger-Ellison syndrome (ZES). Gastrinomas are frequently associated with multiple endocrine neoplasia 1 (MEN 1) and can arise from the pancreas, stomach, duodenum, jejunum, and/or even from the lymph nodes. Gastrinoma (most common entero-pancreatic tumor): Zollinger-Ellison syndrome (ZES) characterized by peptic ulcers, reflux, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
      • Insulinoma: hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia
      • Glucagonoma Glucagonoma A glucagonoma is a glucagon-secreting neuroendocrine tumor that originates from the β-cells in the pancreatic islets. Most glucagonomas are malignant, and many of them are part of the autosomal dominant condition known as multiple endocrine neoplasia syndrome type 1 (MEN 1). Elevated levels of glucagon lead to increased gluconeogenesis and glycogenolysis. Glucagonoma: diabetes, necrolytic migratory erythema (NME), anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis, and neuropsychiatric symptoms
      • VIPoma VIPoma A VIPoma is a rare neuroendocrine tumor arising primarily in the pancreas that releases large amounts of vasoactive intestinal polypeptide (VIP). This process leads to chronic watery diarrhea with concomitant hypokalemia and dehydration, as well as wheezing and flushing (known as Verner-Morrison or WDHA syndrome). VIPoma: chronic watery diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing, flushing
      • Somatostatinoma: diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, steatorrhea, and cholelithiasis Cholelithiasis Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). Cholelithiasis
    • Pituitary adenomas (30%–40%):
      • Prolactinoma (20%): hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia
      • Growth hormone-secreting: acromegaly Acromegaly Acromegaly and gigantism are caused by an excessive production of growth hormone (GH) by the pituitary gland. Acromegaly is usually produced by pituitary tumors secreting GH or, less commonly, by extrapituitary disorders. Acromegaly and Gigantism, gigantism Gigantism Acromegaly and gigantism are caused by an excessive production of growth hormone (GH) by the pituitary gland. Gigantism typically results in children from excess GH before growth-plate closure; acromegaly typically results from excess GH after growth-plate closure. Acromegaly and Gigantism
      • Adrenocorticotropic hormone-secreting: Cushing’s disease
    • Carcinoid tumors:
      • Thymic
      • Bronchial
      • Gastric enterochromaffin-like tumor
    • Adrenal cortical tumor (40%): nonfunctioning
  • Non-endocrine origin:
    • Lipoma Lipoma A lipoma is a benign neoplasm of fat cells (adipocytes) and the most common soft tissue tumor in adults. The etiology is unknown, but obesity is a predisposing factor; genetics also play a role, with multiple lipomas occurring in various inherited disorders. Lipoma
    • Angiofibroma
    • Collagenoma

Diagnosis

  • Clinical findings may be either:
    • Occurrence of ≥ 2 MEN1 primary tumors
    • Family history of clinical diagnosis of MEN1 + 1 primary MEN1-associated tumor
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure testing:
    • Benefit of routine testing in MEN1 is unclear in relation to management.
    • Diagnosis made on a case-by-case basis:
      • The index patient with MEN1
      • 1st-degree relatives of known carriers of MEN1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
      • Atypical or suspicious MEN1
  • Screening other family members:
    • Primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism is the most common feature of MEN1 syndrome.
    • Asymptomatic family members can undergo these less-expensive optional tests: 
      • Serum calcium
      • PTH
      • Vitamin D levels
Mri insulinoma

Insulinoma:
Magnetic resonance imaging of the abdomen of a 34-year-old man presenting with hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia and hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia. Multiple pancreatic lesions are seen with the arrows highlighting the largest lesion. The mass is a 2.8 cm x 1.3 cm area of variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables enhancement and diffusion restriction within the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, consistent with insulinoma.
Further tests revealed elevated intact parathyroid hormone. With primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism and insulinoma, genetic testing was performed, which showed MEN1 gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations that confirmed the presence of MEN1 syndrome.

Image: “Abdominal MRI” by Nance, M. E., et al. License: CC BY 4.0

Management

  •  Treatment:
    • Removal of tumors:
      • Parathyroidectomy
      • Excision of pancreatic and gastric/enteric tumors
      • Transsphenoidal surgery for pituitary tumors
    • Proton pump inhibitors given for patients with ZES
  • Additional surveillance for asymptomatic family members with confirmed MEN1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (MEN1 carriers):
    • Observe for signs and symptoms of MEN1-associated tumors
    • Annual monitoring of serum calcium, PTH, and prolactin levels
    • Baseline imaging (entero-pancreatic neoplasia and pituitary tumors) + follow-up
  • Prognosis:
    • Approximately 30% of patients succumb to causes associated with MEN1.
    • Pancreatic endocrine tumors and carcinoids have malignant potential and contribute to a higher risk of mortality in affected patients.

Mnemonic

To recall the locations of tumor development in MEN1, remember the 3 Ps:

  • Pituitary
  • Parathyroid
  • Pancreas 

MEN2

MEN2 syndrome

  • MEN2A: 
    • Formerly known as Sipple’s syndrome
    • Variants:
      • Classical MEN2A (most common): MTC, pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma, primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism
      • MEN2A with cutaneous lichen amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis (CLA)
      • MEN2A with Hirschsprung’s disease (HD)
      • Familial MTC only
  • MEN2B: 
    • MTC, pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma
    • Associated with Marfanoid habitus, mucosal neuromas (lip, tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue), and intestinal ganglioneuromas

Etiology and epidemiology

  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
    • Autosomal dominant inheritance pattern
    • Mutation of RET (REarranged during Transfection) proto-oncogene (coding for a transmembrane tyrosine kinase)
    • Gene is located in chromosome 10 (10q11.2).
  • Prevalence of 1 in 30,000 individuals
  • MEN2B is less common, comprising only 5%–6% of MEN2 cases.

Pathophysiology

  • Activation of RET leads to stimulation of multiple downstream pathways (involving kinases) → cell growth and proliferation
  • MEN2 is associated with gain-of-function mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the RET gene.
  • Risk of MTC is dependent on the codon involved in germline mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations:
    • Most MEN2A: RET codon Cys634Arg
    • Most MEN2B: RET codon Met918Thr (highest risk of early metastasis and aggressive MTC)

Clinical presentation

  • MEN2A (classical):
    • MTC (95%–100%): 
      • Neck mass or lymph node
      • Peak incidence by 3rd decade of life
    • Pheochromocytoma (50%): 
      • Hypertension, tachycardia, headache, and sweating
      • Average age on presentation: 25–32 years
      • Can be bilateral
    • Primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism (25%)
  • MEN2 with CLA: 
    • Interscapular or extensor lesions described as papular, scaly, and pruritic
    • Pathology: contains amyloid deposits
  • MEN2 with HD: aganglionic megacolon Megacolon Megacolon is a severe, abnormal dilatation of the colon, and is classified as acute or chronic. There are many etiologies of megacolon, including neuropathic and dysmotility conditions, severe infections, ischemia, and inflammatory bowel disease. Megacolon (absent autonomic ganglion cells in the colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix)
  • MEN2B:
    • MTC (95%–100%): presents at a slightly earlier age than MEN2A
    • Pheochromocytoma (50%): similar to MEN2A
    • Mucosal neuromas
    • Intestinal ganglioneuromas
    • Marfanoid habitus

Diagnosis

  • Suspect MEN2 in patients presenting with MTC, pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma, or related tumors:
    • < 35 years of age
    • Multicentric and/or bilateral lesions
    • In addition to family history
  • Tests for specific tumors:
    • Pheochromocytoma: plasma-fractionated metanephrines, then CT of the adrenal gland
    • Hyperparathyroidism: serum calcium, PTH
    • MTC: obtain serum calcitonin, neck ultrasound, and thyroid biopsy if a mass is present
  • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure testing (RET mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations analysis):
    • Compared to MEN1, genetic testing offers a clear benefit for diagnosing family members (especially individuals at risk for aggressive MTC).
    • Indications:
      • Clinically confirmed MEN2
      • Presence of MTC or pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma + a family member with either condition
      • Presence of MTC or pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma or related tumors with suspicious features (young age, multicentric lesions, 2 different organs affected)
      • Sporadic MTC
      • 1st and 2nd-degree relatives of patients with MEN2
  • If there is no RET mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations or no autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance pattern:
    • ≥ 2 classic clinical features of MEN2A required for diagnosis
    • Majority of classic clinical features of MEN2B required for diagnosis

Management

  •  General principles:
    • Surgical treatment based on tumor(s) that are present: 
      • Thyroidectomy
      • Adrenalectomy
      • Parathyroidectomy
    • In MTC:
      • Pheochromocytoma must be ruled out before any surgery is performed.
      • If pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma is present, adrenalectomy is performed before thyroidectomy to avoid fatal complications.
    • In pheochromocytoma Pheochromocytoma Pheochromocytoma is a catecholamine-secreting tumor derived from chromaffin cells. The majority of tumors originate in the adrenal medulla, but they may also arise from sympathetic ganglia (also referred to as paraganglioma). Symptoms are associated with excessive catecholamine production and commonly include hypertension, tachycardia, headache, and sweating. Pheochromocytoma:
      • Prior to adrenalectomy, preoperative alpha blockade is recommended to prevent a hypertensive crisis.
      • If bilateral adrenalectomy is needed, glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids are administered to avoid adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease.
    • In hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism, monitoring after surgery is necessary:
      • For hypoparathyroidism Hypoparathyroidism Hypoparathyroidism is defined as reduced parathyroid hormone (PTH) levels due to poor function of the parathyroid glands. The cause of hypoparathyroidism is most commonly iatrogenic following neck surgery, but it can also be associated with genetic or autoimmune disorders as well as infiltrative diseases causing destruction of the normal parathyroid tissue. Hypoparathyroidism
      • For recurrent or superior laryngeal nerve injury
  • Further recommendations for carriers of RET mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations:
    • Risk of MTC depends on the codon mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.
    • Prophylactic thyroidectomy depends on the risk: 
      • High-risk mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations (codon Met918Thr): surgery within the 1st year of life
      • Annual screening for other patients; age-dependent timing of surgery
    • Annual determination of fractionated metanephrines (proceed with imaging if positive)
    • Serum calcium (proceed with PTH if elevated)

Mnemonic

To recall the location of tumor development in MEN2, remember the 3 Ps:

  • MEN2A: 2 Ps
    • Parathyroid
    • Pheochromocytoma
  • MEN2B: 1 P
    • Pheochromocytoma

MEN4

MEN4 syndrome

  • Limited data given; findings emerged over the past decade
  • Initially named MENX in rats
  • Characterized by:
    • MEN1-associated tumors (parathyroid adenomas, pituitary adenomas Pituitary adenomas Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas, and pancreatic NETs)
    • With gonadal, renal, thyroid, and adrenal tumors

Etiology and epidemiology

  • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
    • Autosomal dominant inheritance pattern
    • Mutation of the cyclin-dependent kinase inhibitor (CDKN) gene CDKN1B
    • Found in chromosome 12p13
  • Patients exhibiting MEN1 tumors:
    • Approximately 10% do not have the MEN1 gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations.
    • In about 3% of cases, the gene involved is CDKN1B.

Pathophysiology

  • Loss-of-function CDKN1B mutations identified in patients with MEN1-like tumors.
  • Results in reduced cell-cycle checkpoint protein, p27 (regulates transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription, inhibiting cell-cycle progression)
  • Decreased function of p27 → genomic instability, unchecked cell growth and proliferation

Clinical presentation

  • Parathyroid adenoma (in approximately 80% of patients)
  • Pituitary adenoma Pituitary adenoma Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas (in approximately 37% of patients) can vary from:
    • Nonfunctional
    • Somatotropinoma
    • Prolactinoma
    • Corticotropinoma
  • Pancreatic NETs: less penetrance than MEN1
  • Renal tumors
  • Some reports indicate reproductive and adrenal tumors.

Diagnosis

  • Definitive guidelines are lacking, given the rarity of the condition and the few reported cases.
  • Offer genetic testing for patients with CDKN1B mutations who exhibit features of MEN1 tumors but are MEN1 mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations-negative
  • Genetic testing can be offered to 1st-degree relatives too.

Management

  • Primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism (adenoma): parathyroidectomy
  • Pituitary adenoma Pituitary adenoma Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas: transsphenoidal surgery per indications
  • Excision of pancreatic NETs
  • Surveillance for other tumors

Clinical Relevance

  • Hyperparathyroidism: a condition associated with elevated blood PTH levels. Hyperparathyroidism can be classified as primary, secondary, or tertiary, based on the pathogenesis. Primary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism is a disease of the parathyroid gland associated with abnormal PTH secretion. Secondary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism results from abnormal calcium metabolism, which, when untreated, can progress to the tertiary type, which is associated with parathyroid gland hypertrophy and PTH oversecretion. Diagnosis is based on serum PTH, calcium, phosphate, and urinary calcium levels. Surgical parathyroidectomy is performed in patients with primary and tertiary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism. Secondary hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism requires treatment of the underlying disease.
  • Gastrinoma Gastrinoma A gastrinoma is a tumor that secretes excessive levels of the hormone gastrin and is responsible for Zollinger-Ellison syndrome (ZES). Gastrinomas are frequently associated with multiple endocrine neoplasia 1 (MEN 1) and can arise from the pancreas, stomach, duodenum, jejunum, and/or even from the lymph nodes. Gastrinoma: tumors that secrete gastrin and are responsible for ZES. Gastrinomas are associated with MEN1. The tumor, which is often malignant, can arise from the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas, stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach, small bowel, and/or lymph nodes. Zollinger-Ellison syndrome is associated with elevated gastrin levels and gastric acid production, and manifests with peptic ulcers, gastroesophageal reflux, and diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea. Diagnosis is based on fasting serum gastrin levels. Management involves the surgical resection of gastrinomas and/or symptomatic management for unresectable disease.
  • Insulinoma: a NET that manifests with hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia caused by inappropriately high secretion of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin. Insulinomas Insulinomas An insulinoma is a type of functional neuroendocrine tumor that manifests with hypoglycemia due to autologous secretion of insulin. It more commonly presents as a solitary benign tumor but can sometimes be associated with MEN type 1 (MEN1). Patients present with fasting hypoglycemia, which may manifest as episodes of diaphoresis, palpitations, tremor, and confusion. Insulinomas more commonly present as a solitary benign tumor, but can sometimes be associated with MEN1. Symptoms of hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia and adrenergic stimulation include palpitations, weakness, diaphoresis, abnormal behavior, tremors, and blurring of vision. Diagnosis is based on biochemical testing. Surgical resection is the treatment of choice.
  • Glucagonoma Glucagonoma A glucagonoma is a glucagon-secreting neuroendocrine tumor that originates from the β-cells in the pancreatic islets. Most glucagonomas are malignant, and many of them are part of the autosomal dominant condition known as multiple endocrine neoplasia syndrome type 1 (MEN 1). Elevated levels of glucagon lead to increased gluconeogenesis and glycogenolysis. Glucagonoma: a glucagon-secreting tumor, originating from the α cells of the pancreatic islets. Most glucagonomas are malignant, and many are part of MEN1. Elevated glucagon levels lead to increased gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis and glycogenolysis. Patients present with diabetes, NME, weight loss, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview, deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis, and neuropsychiatric symptoms. Diagnosis is based on lab tests showing elevated glucagon levels and a pancreatic mass on imaging studies. Management is usually supportive and involves octreotide therapy (a somatostatin analog). Surgical resection is attempted in localized disease. Chemotherapy and targeted molecular agents are used in advanced cases.
  • VIPoma VIPoma A VIPoma is a rare neuroendocrine tumor arising primarily in the pancreas that releases large amounts of vasoactive intestinal polypeptide (VIP). This process leads to chronic watery diarrhea with concomitant hypokalemia and dehydration, as well as wheezing and flushing (known as Verner-Morrison or WDHA syndrome). VIPoma: a rare tumor characterized by the hypersecretion of vasoactive intestinal polypeptide (VIP). The tumor arises from the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas and manifests with chronic watery diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea with concomitant hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia and dehydration Dehydration Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Dehydration is primarily caused by decreased water intake and presents with increased thirst and can progress to altered mental status and low blood pressure if severe. Volume Depletion and Dehydration, as well as wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing and flushing (known as Verner-Morrison or WDHA syndrome). Most tumors arise sporadically, but some are associated with MEN1. Diagnosis is based on determining serum VIP levels. Treatment consists of the medical management of symptoms and complete surgical removal of the tumor.
  • Pituitary adenoma Pituitary adenoma Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas: a tumor that develops within the anterior lobe of the pituitary gland Pituitary gland The pituitary gland, also known as the hypophysis, is considered the "master endocrine gland" because it releases hormones that regulate the activity of multiple major endocrine organs in the body. The gland sits on the sella turcica, just below the hypothalamus, which is the primary regulator of the pituitary gland. Pituitary Gland. Pituitary adenomas are classified based on size as either micro- or macroadenomas and their ability to secrete hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview. Non-functioning or non-secretory adenomas do not secrete hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview but compress the surrounding pituitary tissue and lead to hypopituitarism Hypopituitarism Hypopituitarism is a condition characterized by pituitary hormone deficiency. This condition primarily results from a disease of the pituitary gland, but it may arise from hypothalamic dysfunction. Pituitary tumors are one of the most common causes. The majority of cases affect the anterior pituitary lobe (adenohypophysis), which accounts for 80% of the gland. Hypopituitarism. Secretory adenomas secrete various hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview depending on the cell type they evolved from and can lead to hyperpituitarism.
  • Carcinoid tumor: a small, well-differentiated, slow-growing NET commonly found in the GI and bronchopulmonary tracts. Carcinoid syndrome Carcinoid syndrome Carcinoid tumors are small, well-differentiated, slow-growing neuroendocrine tumors (NET). Carcinoid syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by neuroendocrine tumors. Carcinoid tumors are most commonly found in the GI and bronchopulmonary tracts. Carcinoid Tumors and Syndrome describes the signs and symptoms associated with unregulated vasoactive hormone production by the tumors. Vasoactive substances produced by the GI NET do not cause carcinoid syndrome until the tumors metastasize to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver. Symptoms of carcinoid syndrome include flushing, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, and wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing. Treatment primarily involves surgical tumor resection and the use of somatostatin analogs.
  • Thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer: a malignancy arising from the cells of the thyroid gland Thyroid gland The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland and calcitonin-producing C cells (medullary carcinomas). Driver mutations involving the receptor tyrosine kinase pathway, family history of cancer or related syndromes, and ionizing radiations increase the risk. Thyroid cancer Thyroid cancer Thyroid cancer is a malignancy arising from the thyroid gland cells: thyroid follicular cells (papillary, follicular, and anaplastic carcinomas) and calcitonin-producing C cells (medullary carcinomas). Rare cancers are derived from the lymphocytes (lymphoma) and/or stromal and vascular elements (sarcoma). Thyroid Cancer may present as a thyroid nodule Thyroid nodule A thyroid nodule is a disordered growth of thyroid cells that produces a mass in the thyroid gland. Most thyroid nodules are benign and detected either by the patient or by the clinician on examination. In other cases, a thyroid nodule is found in radiologic imaging incidentally. Ruling out of malignancy is important. Thyroid Nodules or enlarged cervical lymph nodes. Diagnosis is by determining thyroid stimulating hormone levels, as well as ultrasound and biopsy. Treatment is via thyroidectomy, with radioactive iodine therapy and systemic therapy depending on the type and extent of the thyroid malignancy.
  • Pheochromocytoma: a catecholamine-secreting tumor derived from chromaffin cells, with the majority originating in the adrenal medulla. Pheochromocytomas can also arise from the sympathetic ganglia (paragangliomas). Excessive catecholamine production can cause hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, tachycardia, headache, and sweating. Diagnosis is based on plasma-fractionated metanephrines. Surgical resection is the only curative treatment.

Reference

  1. Alrezk, R., Hannah-Shmouni, F., Stratakis, C. (2017). MEN4 and CDKN1B mutations: The latest of the MEN syndromes. Endocrine-Related Cancer. 24(10), T195–T208. Retrieved March 13, 2021, from https://erc.bioscientifica.com/view/journals/erc/24/10/ERC-17-0243.xml
  2. Anastasopoulou, C., Sajja, P. (2017). Multiple endocrine neoplasia type 1 (MEN1). Medscape. Retrieved March 12, 2021, from https://emedicine.medscape.com/article/126438-overview#a5
  3. Arnold, A. (2019). Multiple endocrine neoplasia type 1: Definition and genetics. UpToDate. Retrieved March 7, 2021, from https://www.uptodate.com/contents/multiple-endocrine-neoplasia-type-1-definition-and-genetics
  4. Frederiksen, A., et al. (2019). Clinical Features of Multiple Endocrine Neoplasia Type 4: Novel Pathogenic Variant and Review of Published Cases. The Journal of Clinical Endocrinology & Metabolism. 104(9),3637–3646. https://doi.org/10.1210/jc.2019-00082
  5. Richards, M., Carter, S. (2018). Multiple endocrine neoplasia type 2 (MEN2). Medscape. Retrieved March 12, 2021, from https://emedicine.medscape.com/article/123447-overview
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  7. Thakker, R. (2014). Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and cellular endocrinology. 386(1–2), 2–15. https://doi.org/10.1016/j.mce.2013.08.002

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