Multiple endocrine neoplasia type 2 pathophysiology

Multiple endocrine neoplasia type 2 Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Multiple endocrine neoplasia type 2 from other Diseases
Epidemiology & Demographics
Risk Factors
Screening
Natural History, Complications & Prognosis
Diagnosis
Diagnostic Criteria
History & Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
X Ray
CT
MRI
Echocardiography or Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Multiple endocrine neoplasia type 2 pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Multiple endocrine neoplasia type 2 pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Multiple endocrine neoplasia type 2 pathophysiology
CDC on Multiple endocrine neoplasia type 2 pathophysiology
Multiple endocrine neoplasia type 2 pathophysiology in the news
Blogs on Multiple endocrine neoplasia type 2 pathophysiology
Directions to Hospitals Treating Multiple endocrine neoplasia type 2
Risk calculators and risk factors for Multiple endocrine neoplasia type 2 pathophysiology

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

Overview

Development of multiple endocrine neoplasia type 2 is the result of genetic mutations. Mutation of theRET gene is responsible for the pathogenesis of multiple endocrine neoplasia type 2.

Pathogenesis

• 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 2A

• Multiple endocrine neoplasia type 2A (MEN2) (also known as "pheochromocytoma and amyloid producing medullary thyroid carcinoma", "PTC syndrome," and "Sipple syndrome") is a group of medical disorders associated with tumors of the endocrine system.
• 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.
• Although many different types of hormone-producing tumors are associated with multiple endocrine neoplasia, the most common manifestation is a form of thyroid cancer called medullary thyroid carcinoma. This tumor secretes an inactive hormone called calcitonin. 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.
• 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.
• 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.
• In familial isolated medullary thyroid carcinoma the other components of the disease are absent.

Multiple Endocrine Neoplasia type 2B

• Multiple endocrine neoplasia type 2B (also known as MEN2B, mucosal neuromata with endocrine tumors, multiple endocrine neoplasia type 3, and Wagenmann–Froboese syndrome) is a genetic disease that causes multiple tumors on the mouth, eyes, and endocrine glands. It is the most severe type of multiple endocrine neoplasia, differentiated by the presence of benign oral and submucosal tumors in addition to endocrine malignancies.
• 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.

Clinical features of multiple endocrine neoplasia syndrome

Subtype	Medullary Thyroid Carcinoma	Pheochromocytoma	Parathyroid Disease
Multiple endocrine neoplasia type 2A	95%	50%	20% to 30%
Multiple endocrine neoplasia type 2B	100%	50%	Uncommon
Familial medullary thyroid carcinoma	100%	0%	0%

Genetics

Autosomal dominent pattern of inheritance

• 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.

RET kinase domain

• 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.
• Most cases of multiple endocrine neoplasia type 2, derive from a variation in the RET proto-oncogene, and are specific for cells of neural crest origin.
• The protein produced by the RET proto-oncogene gene plays an important role in the TGF-beta (transforming growth factor beta) signaling system. Because the TGF-beta system operates in nervous tissues throughout the body, variations in the RET proto-oncogene can have effects in nervous tissues throughout the body.
• The RET protooncogene is a 21-exon gene and encodes for a tyrosine kinase transmembrane receptor located on chromosome 10q11.2.
• 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).
• 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).

The table below summarizes specific RET codons and their functions.

Molecular effects of RET mutations in multiple endocrine neoplasia type2

Mutation location	RET codons	Function of wild type codon	Mutated effects	Phenotype
Extracellular cysteine rich location	c609 c611 c618 c620 c630	Helps to form teritiary structure with the help of disulfide bonds	Alteration in protein folding and maturation	Multiple endocrine neoplasia type 2A and familial medullaty thryoid carcinoma (FMTC)
	c634	Formation of intramolecular disulfide bonds	Ligand independant dimerization of receptor molecules	Multiple endocrine neoplasia type 2A
Intracellular tyrosine kinase domain	L790 Y791	Terminal lobe of RET kinase	Affects ATP binding and interlobe flexibility	Multiple endocrine neoplasia type 2A and familial medullaty thryoid carcinoma (FMTC)
	E768	Close proximity with ATP binding site	Alters interactions within the region	Familial medullaty thryoid carcinoma (FMTC)
	V804	Gatekeeper residue that regulates access to ATP binding site	Alters interactions within the region	Familial medullaty thryoid carcinoma (FMTC)
	S891	C terminal lobe of kinase	Alters activation of loop conformation	Multiple endocrine neoplasia type 2A and familial medullaty thryoid carcinoma (FMTC)
	A883	Situated next to activated loop	Local conformational change	Multiple endocrine neoplasia type 2B
	M918	Substrate binding pocket of the kinase	Alters protein conformation	Multiple endocrine neoplasia type 2B

• 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.
• When inherited, multiple endocrine neoplasia type 2 is transmitted in an autosomal dominant pattern, which means affected people have one affected parent, and possibly-affected siblings and children. Some cases, however, result from spontaneous new mutations in the RET gene. These cases occur in people with no family history of the disorder. In multiple endocrine neoplasia type 2B, for example, about half of all cases arise as spontaneous new mutations.
• 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 medullaty thryoid 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.
• The following figure depicts the structure and mutation of RET receptor.

Structure, activation and oncogenic mutation of RET receptor. Figure A depicts location of oncogenic mutations of RET recpetor. RET protein has cystine rich extracellular domain, cadherin homology domain, transmembrane domain and an intracellular tyrosine kinase domain. FIgure B depicts RET activation

RET Activation

• 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.

MEN type 2 mutations

Associated Conditions

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

Associated tumors

Subtype	Associated diseases
Multiple endocrine neoplasia type 2A	Cutaneous lichen amyloidosis, hirschsprung disease
Multiple endocrine neoplasia type 2B	Ganglioneuromatosis, marfanoid habitus
Familial medullaty thryoid carcinoma (FMTC)	Rare diseases

Gross Pathology

• 

  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

• 

  Pheochromocytoma, Image courtesy of Dr Frank Gaillard

• 

  Pheochromocytoma, Image courtesy of Dr Frank Gaillard

Microscopic Pathology

Medullary Carcinoma of Thyroid

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

• 

  High magnification micrograph of medullary thyroid carcinoma, abbreviated MTC. H&E stain. MTC can be remembered by the 3 Ms:aMyloid. Median node dissection. MEN 2A & MEN 2B. It typically stains with: Calcitonin. CEA. Chromogranin A. Multiple endocrine neoplasia 2A: Medullary thyroid carcinoma

• 

  Micrograph of a pheochromocytoma (at high magnification) showing the characteristic stippled (finely granular) chromatin. The chromatin pattern is sometimes referred to as "salt-and-pepper" chromatin

• 

  Pheochromocytoma, Case courtesy of Dr Andrew Ryan,

Histopathological Video

Video

{{#ev:youtube|P2uPUbDPbuI}}

{{#ev:youtube|7yjxG3KmX98}}

{{#ev:youtube|crwGfnWKEZ8}}