Multiple endocrine neoplasia type 2

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 2 is part of a group of disorders that affect the endocrine system through development of neoplastic lesions in the thyroid, the parathyroid gland, and the adrenal gland. Multiple endocrine neoplasia type 2 was first described by Dr. John H. Sipple, an American physician, in 1961 by reporting a case of a patient with pheochromocytoma, medullary thyroid carcinoma and parathyroid adenoma. Development of multiple endocrine neoplasia type 2 is the result of genetic mutations. RET gene is involved in the pathogenesis of multiple endocrine neoplasia type 2. Multiple endocrine neoplasia type 2A is associated with medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Multiple endocrine neoplasia type 2B is associated with medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus, and mucosal and digestive neurofibromatosis. Surgery is the mainstay of treatment for multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 was first described by Dr. John H. Sipple, an American physician, in 1961 by reporting a case of a patient with pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma.

Multiple endocrine neoplasia type 2 may be classified according to the types of tumor involved into 2 subtypes: multiple endocrine neoplasia type 2A and multiple endocrine neoplasia type 2B.

Development of multiple endocrine neoplasia type 2 is the result of genetic mutations. The RET gene is involved in the pathogenesis of multiple endocrine neoplasia. Multiple endocrine neoplasia type 2A is associated with medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism. Multiple endocrine neoplasia type 2B is associated with medullary thyroid carcinoma, pheochromocytoma, marfanoid habitus, and mucosal and digestive neurofibromatosis.

Multiple endocrine neoplasia type 2 is caused by a mutation in the RET gene.

Multiple endocrine neoplasia type 2 must be differentiated from other hereditary tumors such as medullary thyroid carcinoma, C-cell hyperplasia pheochromocytoma, von Hippel Lindau syndrome, hereditary paraganglioma–pheochromocytoma, polycythemia and paraganglioma/pheochromocytoma syndrome, neurofibromatosis type 1, and multiple endocrine neoplasia type 1 (MEN 1).

The prevalence of multiple endocrine neoplasia type 2 is approximately 2.5 per 100,000 individuals worldwide. Multiple endocrine neoplasia type 2B manifest in early infancy while multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma manifest in adulthood.

Family history is the most common risk factor in the development of multiple endocrine neoplasia type 2.

According to the American Society of Clinical Oncology, screening for multiple endocrine neoplasia type 2 by RET gene testing is recommended for children with increased risk of multiple endocrine neoplasia type 2.

Multiple endocrine neoplasia type 2 has a variable natural history. Life threatening complications of multiple endocrine neoplasia type 2 include malignant hypertension, megacolon, and metastasis. Prognosis of multiple endocrine neoplasia type 2 is mainly related to the stage-dependant prognosis of medullary thyroid cancer.

According to the American Society of Clinical Oncology, diagnosis of multiple endocrine neoplasia type 2 requires existence of two or more specific endocrine tumors (medullary thyroid carcinoma, pheochromocytoma, or parathyroid hyperplasia). Multiple endocrine neoplasia type 2 is also diagnosed with four or more cases of medullary thyroid carcinoma without pheochromocytoma and parathyroid adenoma or if there is early onset of medullary thyroid carcinoma, mucosal neuromas of lips and tongue, disctinctive facial features with enlarged lips and marfanoid body habitus.

Symptoms of multiple endocrine neoplasia type 2 include headache, hoarseness of voice, palpitations, anxiety, pallor and weight loss.

Patients with multiple endocrine neoplasia type 2 usually appear tall, thin and have disproportionately elongated extremities. Physical examination of patients with multiple endocrine neoplasia type 2 is usually remarkable for episodic hypertension, thyromegaly, and anxiety.

Laboratory findings consistent with the diagnosis of multiple endocrine neoplasia type 2 include hypercalcemia, hypophosphatemia, elevated parathyroid hormone, and elevated norepinephrine.

There are no specific electrocardiogram findings associated with multiple endocrine neoplasia type 2. Electrocardiogram findings in multiple endocrine neoplasia type 2 may vary depending on the underlying disease.

Neck CT scan may be helpful in the diagnosis of multiple endocrine neoplasia type 2. Findings on CT scan suggestive of multiple endocrine neoplasia type 2 include irregular dense calcific foci within thyroid.

MRI scan may be helpful in the diagnosis of multiple endocrine neoplasia type 2. Findings on MRI scan suggestive of multiple endocrine neoplasia type 2 include intermediate to low signal at T1 and hyperintense signal at T2 suggesting parathyroid hyperplasia.

Ultrasound scan may be helpful in the diagnosis of multiple endocrine neoplasia type 2. Findings on ultrasound scan suggestive of multiple endocrine neoplasia type 2 include punctate high echogenic foci resembling calcification within the thyroid gland, solid to mixed cystic masses on adrenal gland, and homogeneously hypoechoic parathyroid gland.

Other imaging studies for multiple endocrine neoplasia type 2 include fluoro-di-glucose-PET, [18F]-fluorodopamine ([18F]DA) PET, and 99mTc-sestamibi scintigraphy.

Other diagnostic studies for multiple endocrine neoplasia type 2 include molecular genetic testing which include sequence analysis of select exons of mainly 10,11, 13-16 and sequence analysis of RET gene.

The mainstay of multiple endocrine neoplasia type 2 is surgery. Medical therapies for multiple endocrine neoplasia type 2 include vandetanib, external beam radiation therapy analogues, and intensity modulated radiation therapy.

Surgery is the mainstay of treatment for multiple endocrine neoplasia type 2.

There are no primary preventive measures for multiple endocrine neoplasia type 2.

According to the American Society of Clinical Oncology, surveillance for multiple endocrine neoplasia type 2 by annual measurement of serum calcitonin, serum calcium, serum parathyroid hormone, and catecholamines is recommended post-surgically to monitor for recurrence and complications for multiple endocrine neoplasia type 2.

Cost-effectiveness of therapy of multiple endocrine neoplasia type 2 include targeted therapy, prophylactic thyroidectomy and restricted molecular screening.

Future or investigational therapies of multiple endocrine neoplasia type 2 include treatment with axitinib, gefitinib, imatinib, motesanib, sorafenib, sunitinib, vandetanib and XL184.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sogand Goudarzi, MD [2] , Ammu Susheela, M.D. [3]

Multiple endocrine neoplasia type 2 was first described by Dr. John H. Sipple, an American physician, in 1961 by reporting a case of a patient with pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma.

The historical background of multiple endocrine neoplasia type 2 is given in the table below:^{[1][2][3][4][5]}

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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] Sogand Goudarzi, MD [3]

Multiple endocrine neoplasia type 2 may be classified according to the types of tumor involved into 2 subtypes: multiple endocrine neoplasia type 2A and multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2 (MEN2) can be further divided into three subtypes: type 2A, type 2B, and familial medullary thyroid carcinoma (FMTC).^[1][2]

• These subtypes differ in their characteristic signs and symptoms and risk of specific tumors, but are relatively consistent within any one family.
• Multiple endocrine neoplasia type 2A is characterized by the presence of medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia or tumor.
• Multiple endocrine neoplasia type 2B is characterized by the presence of pheochromocytoma, mucocutaneous neuroma, and medullary thyroid cancer.
• The following flowchart depicts the classification of multiple endocrine neoplasia type 2.

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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 progression to multiple endocrine neoplasia type 2 usually involves the genetic mutations. The pathogenesis of multiple endocrine neoplasia type 2 involves a mutation of the RET gene.

The common feature among the three subtypes of multiple endocrine neoplasia type 2 is a high propensity to develop medullary thyroid carcinoma.

• Multiple endocrine neoplasia type 2 (MEN2) generally occur in endocrine organs (e.g. thyroid, parathyroid, and adrenals), but may also occur in endocrine tissues of organs not classically thought of as endocrine.^[1]
• Although many different types of hormone-producing tumors are associated with multiple endocrine neoplasia type 2, the most common manifestation is a form of thyroid cancer called medullary thyroid carcinoma. This tumor secretes an inactive hormone called calcitonin. ^[2]
• Many people with this disorder also develop pheochromocytoma, which is a tumor of the adrenal glands (located above each kidney) that can cause dangerously high blood pressure. In addition, overactivity of the parathyroid gland (hyperparathyroidism) occurs in some cases of multiple endocrine neoplasia type 2. Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of bones, weakness, and fatigue.^[3]
• In multiple endocrine neoplasia type 2, primary hyperparathyroidism occurs in only 10–30% and is usually diagnosed after the third decade of life. It can occur in children but this is rare. It may be the sole clinical manifestation of this syndrome but this is unusual.^[4]
• Multiple endocrine neoplasia type 2 associates medullary thyroid carcinoma with pheochromocytoma in about 20–50% of cases and with primary hyperparathyroidism in 5–20% of cases.^[5]
• Other components of the disease are absent in familial isolated medullary thyroid carcinoma.^[6]

• Multiple endocrine neoplasia type 2B is associated with medullary thyroid carcinoma and pheochromocytoma as well as with marfanoid habitus and with mucosal and digestive neurofibromatosis.

• Most cases of multiple endocrine neoplasia type 2 are inherited in an autosomal dominant pattern, which means affected people may have affected siblings and relatives in successive generations (such as parents and children). An affected person usually has one parent with the condition. Some cases, however, result from new mutations in the RET proto-oncogene. These cases occur in people with no history of the disorder in their family.

• Germline mutations are responsible for sporadic multiple endocrine neoplasia type 2, while mutations in the cysteine residues in the exons of the RET protein product are common in familial multiple endocrine neoplasia type 2.^[7]
• The majority of multiple endocrine neoplasia type 2 patients, derive from a variation in the RET proto-oncogene, and are specific for cells of neural crest origin.^[8]
• The RET protooncogene is a 21-exon gene and encodes for a tyrosine kinase transmembrane receptor located on chromosome 10q11.2.^[9]
• Four different ligands have so far been recognized: The glial cell line-derived neutrophilic factor (GDNF), neurturin (NTN), persepin (PNS) and artemin (ART). The interaction is mediated by a ligand-specific coreceptor (e.g., the GFRα-1 is the co-receptor for the GDNF).^[10]
• The receptor is composed of an extracellular domain (EC), with a distal cadherin-like region and a juxtamembrane cysteine-rich region, a transmembrane domain (TM) and an intracellular domain with tyrosine-kinase activity (TK).^[11]

The table below summarizes specific RET codons and their functions.^[12][13]

• Multiple endocrine neoplasia type 2 generally results from a gain-of-function variant of a RET gene. Other diseases, such as Hirschsprung disease, result from loss-of-function variants.^[14]
• Multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant. Nevertheless, it can result from spontaneous new mutations in the RET gene with no family history of the disorder, as reported in some cases. For instance, among multiple endocrine neoplasia type 2B, spontaneous new mutations were observed in about 50% of the total number of cases.
• Activating germline point mutations of the RET proto-oncogene are causative events in multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma (FMTC). RET mutations have been found to be widely distributed not only among the 5 cysteine codons 609, 611, 618, 620, and 634 but also in other noncysteine codons, such as codon 804 in exon 14, codon 883 in exon 15, and others.^[15]
• The following figure depicts the structure and mutation of RET receptor.^[12]

• Dimerization of RET proto-oncogene mediated through formation of multicomponent complex. RET proto-oncogene is activated by binding both a soluble ligand and a non signaling extracellular co-receptor. RET activation leads to phosphorylation of multiple intracellular tyrosine kinase.

• Some of the diseases specific to the genes of multiple endocrine neoplasia type 2 are as follows.^[12]

• 
  ADRENAL GLAND: BILATERAL PHEOCHROMOCYTOMA Cross section of bilateral pheochromocytomas from a 30-year-old man with MEN syndrome type IIa. The right adrenal tumor weighed 168 g and the left 220 g. Note the distinct multinodular, multicentric pattern of growth on both sides Source: Wikimedia Commons
• 
  Pheochromocytoma, Image courtesy of Dr Frank Gaillard^[16]
• 
  Pheochromocytoma, Image courtesy of Dr Frank Gaillard^[16]

• Nests of C cells invading the basement membrane and infiltrating thyroid follicles

• 
  Pheochromocytoma, Case courtesy of Dr Andrew Ryan, Radiopaedia.org From the case <a href=”http://radiopaedia.org/cases/22683″>rID: 22683

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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]

Multiple endocrine neoplasia type 2 is caused by a mutation in the RET gene.

• Mutations in the RET proto-oncogene cause multiple endocrine neoplasia type 2.^[1]
  • The protein produced by the RET proto-oncogene gene normally plays an important role in signaling cells to respond to their environment, for example by dividing or maturing. Mutations in this gene cause an overactivation of the protein‘s signaling function, which can lead to an overgrowth of cells and the formation of tumors characteristic of multiple endocrine neoplasia type 2.
  • MEN2A patients with cutaneous lichen amyloidosis have mutation in codon 634.^[2]
  • Patients with MEN2A and Hirschsprung disease observed mutations involving RET exon 10.^[3]

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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]

Multiple endocrine neoplasia type 2 must be differentiated from other hereditary tumors such as medullary thyroid carcinoma, C-cell hyperplasia, pheochromocytoma, von Hippel Lindau syndrome, hereditary paraganglioma–pheochromocytoma, polycythemia and paraganglioma/pheochromocytoma syndrome, neurofibromatosis type 1, and multiple endocrine neoplasia type 1 (MEN 1).

Multiple endocrine neoplasia type 2 must be differentiated from the following diseases.^[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]

The prevalence of multiple endocrine neoplasia type 2 is approximately 2.5 per 100,000 individuals worldwide. Multiple endocrine neoplasia type 2B manifests in early infancy while multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma manifest in adulthood.

• Worldwide, the prevalence of multiple endocrine neoplasia type 2 is 2.5 per 100,000 individuals in 2010.^[1]
• Multiple endocrine neoplasia type 2 has been reported in approximately 500 to 1000 families worldwide.^[2]
• 70-80% of all multiple endocrine neoplasia type 2 cases are multiple endocrine neoplasia type 2A.

• In the United States, an estimated 468 cases of multiple endocrine neoplasia type 2-related medullary thyroid cancer are diagnosed per year.^[3]

• Multiple endocrine neoplasia type 2 can be found in any age group.
• Multiple endocrine neoplasia type 2B manifests in early infancy while multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma manifest in adulthood.^[4]

• The prevalence and incidence of multiple endocrine neoplasia type 2 do not vary by gender.^[5]

• The prevalence of multiple endocrine neoplasia type 2 does not vary by race.^[6]

• In United States the prevalence of multiple endocrine neoplasia type 2 is 2 – 4 per 100,000 individuals.^[7]

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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]

Family history is the most common risk factor in the development of multiple endocrine neoplasia type 2.

• Family history is the most common risk factor in the development of multiple endocrine neoplasia type 2.^[1][2][3][4]
• In 1999, during the Seventh International Multiple Endocrine Neoplasia Meeting in Gubbio , the risk of medullary thyroid cancer has been stratified in three categories according to the mutations of c-RET as following.^[5][3]

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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 American Society of Clinical Oncology, screening for multiple endocrine neoplasia type 2 by RET gene testing is recommended for children with increased risk of multiple endocrine neoplasia type 2.

• The DNA-based testing of the c-RET gene is recommended for children with increased risk of multiple endocrine neoplasia type 2.^[1][2][3][4]
• The DNA-based testing of the c-RET gene can be easily performed on a blood sample at any age.
• The DNA-based testing of the c-RET gene offers the opportunity for early identification of the c-RET germline mutations, thus contributing to the reduction of morbidity and mortality of multiple endocrine neoplasia type 2 syndrome. In fact, the early recognition of the mutant gene carriers makes possible the prevention and cure of medullary thyroid cancer, by performing a prophylactic thyroidectomy before the clinical expression of the tumor.
• The DNA-based testing of the c-RET gene test is also of importance to detect and thus, to reduce the risk of an unsuspected pheochromocytoma.
• Screening for multiple endocrine neoplasia type 2 include the following tests:

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 2 has a variable natural history. Life threatening complications of multiple endocrine neoplasia type 2 include malignant hypertension, megacolon, and metastasis. Prognosis of multiple endocrine neoplasia type 2 is mainly related to the stage-dependent prognosis of medullary thyroid cancer.

Multiple endocrine neoplasia type 2 has a variable natural history. Specific c-RET mutations, are associated to peculiar clinical phenotypes and thus to different courses of the disease. Multiple endocrine neoplasia type 2 can vary from a dormant type after the surgical removal of medullary thyroid carcinoma to a rapidly progressive one with metastatic complications resulting in death.^[1]

• Common complications of multiple endocrine neoplasia type 2 include the following:^[2]

• Malignant hypertension
• Metastasis

• Osteoporosis
• Fractures
• Hypoparathyroidism from parathyroidectomy
• Hyperglycemia

• Kidney stones

• Obstruction
• Infection
• Stricture
• Fistula
• Constipation
• Fecal incontinence
• Diverticulum
• Gastrointestinal ganglioneuromatosis
• Megacolon
• Colitis

• Prognosis of multiple endocrine neoplasia type 2 is mainly related to the stage-dependent prognosis of medullary thyroid cancer indicating the necessity of a complete thyroid surgery for index cases with medullary thyroid cancer and the early thyroidectomy for screened at risk subjects.^[3]
• The 10 year survival of medullary thyroid cancer of multiple endocrine neoplasia type 2 is 61-76%.^[4]
• Multiple endocrine neoplasia type 2A has a better prognosis among the tumors of multiple endocrine neoplasia. Specific c-RET mutations, in fact, are associated to peculiar clinical phenotypes and thus to different course and prognosis of the disease. The following factors influencing survival rate of medullary thyroid carcinoma.

• Stage of disease at diagnosis
• Size of the tumor
• Age of the patient
• Sex of the patient
• Calcitonin doubling time

• The following table depicts the stage dependent prognosis of medullary thyroid cancer.^[5][6]

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