Multiple Endocrine Neoplasia Type 2 (MEN2)

Updated: May 31, 2018
  • Author: Melanie L Richards, MD, MPHE; Chief Editor: George T Griffing, MD  more...
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Overview

Practice Essentials

Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumors, and pheochromocytoma.  MEN2 results from germline mutations in the RET proto-oncogene and is transmitted in an autosomal dominant fashion. There are two MEN2 syndromes: MEN2A and MEN2B. 

The MEN2A syndrome is further classified on the basis of the presence of associated conditions. Classical MEN2A is characterized by MTC, pheochromocytoma, and primary hyperparathyroidism. Three additional variants are MEN2A with cutaneous lichen amyloidosis (CLA), MEN2A with Hirschsprung disease (HSCR), and familial medullary thyroid cancer (FMTC), which is diagnosed when the patient has a RET germline pathogenic variant and MTC but no family history of pheochromocytoma or hyperparathyroidism. [1]  

MEN2B is less common than MEN2A, accounting for 5% of MEN2 cases. It is characterized by more aggressive MTC (occurring in 100% of cases), pheochromocytoma (50%), mucosal neuromas (95%-98%) and intestinal ganglion neuromas (40%). Hyperparathyroidism is absent. In addition, nearly all patients have have a distinct marfanoid habitus. [2]

Substantiation of the genotype-phenotype correlation of inherited MTC may lead to the development of an individual approach to risk management in childhood genotype carriers, and research into potential modifying factors should take place. Early total thyroidectomy remains effective in preventing the development of MTC in the long term. [3, 4, 5]

 

 

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Pathophysiology

Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2. Although its function is still unknown, the protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain. [6, 7]

The extracellular domain interacts with one of four ligands identified to date. These ligands—glial cell line–derived neurotrophic factor (GDNF), neurturin, persephin, and artemin—also interact with one of four coreceptors in the GDNF-family receptor–alpha family. GDNF appears to play a critical role in the normal function of pathways involved in enteric nervous system neurogenesis and renal organogenesis. The tyrosine kinase catalytic core is located in the intracellular domain and causes downstream signaling events through a variety of second-messenger molecules. [8]

Medullary thyroid carcinoma

MTC is a calcitonin-secreting tumor of the parafollicular or C cells of the thyroid. MTC develops in virtually all patients with MEN2A; it is is often the first expressed abnormality, with onset usually in the first to third decade of life. In patients with MEN2A, MTC is typically bilateral and multicentric and preceded by C-cell hyperplasia, in contrast to sporadic MTC, which is unilateral. [9]

Pheochromocytoma

Pheochromocytomas are present in approximately half of MEN2A patients. They are bilateral in 60-80% of cases, compared with 10% of sporadic pheochromocytomas. Pheochromocytomas tend to be diagnosed at the same time as MTC or several years later (with both occurring primarily in the second or third decade). The pheochromocytomas of MEN2A patients are nearly all benign. Even so, these lesions can cause life-threatening episodes of hypertension or arrhythmia.

Parathyroid hyperplasia

Parathyroid hyperplasias are present in nearly half of patients with MEN2A but are less common than pheochromocytomas. In many patients, such hyperplasias can be clinically silent. However, as in other cases of hyperparathyroidism, comprehensive questioning will often elicit a history of symptoms.

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Etiology

Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Classical MEN2A is associated with germline missense mutations in RET codons 609, 611, 618, or 620 of exon 10 or codon 634 of exon 11, which map to the receptor’s extracellular cysteine-rich domain. MEN2A with cutaneous lichen amyloidosis is nearly always associated with mutation of codon 634, while patients with MEN2A and Hirschsprung disease typically harbor mutations involving RET exon 10. [10]  

Approximately 75% of MEN2B cases are sporadic and affected patients have de novo RET mutations, while 25% of cases occur in families with previous or current manifestations of MEN2B. Approximately 95% of patients with MEN2B have RET germline mutations in exon 16 (codon M918T) and fewer than 5% have RET germline mutations in exon 15 (codon A883F). [1]  

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Epidemiology

The overall frequency of MEN2 in the United States is 1 case per 30,000-50,000 population. In decreasing order of frequency, MEN occurs as follows: MEN2A, MEN2A with FMTC only, and MEN 2B.

In MEN2A patients, 50% of those with RET gene mutations develop disease by age 50 years, and 70% develop the disease by age 70 years. MTC has been detected shortly after birth in MEN2B. (See Workup and Treatment.)

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Prognosis

Early treatment of medullary thyroid carcinoma (MTC) can prevent death, and careful monitoring for pheochromocytomas can decrease the chance of hypertensive episodes.

MTC, the characteristic tumor of MEN2, is present in all subtypes. Pheochromocytomas appear in MEN2A and MEN2B patients. Primary hyperparathyroidism frequently develops in patients with MEN2A but rarely in those with MEN2B. Gastrointestinal, skeletal, and dermatologic abnormalities occur only in patients with MEN2B.

Almost all published reports on MEN2B concern patients with the RET codon M918T mutation. Little is known about the clinical behavior of patients with the RET codon A883F mutation. Recent reports, however, suggest that patients with the A883F codon mutation have a more indolent natural course compared with that of M918T carriers and that pheochromocytomas manifests later in A883F carriers than in M918T carriers. [11]

Medullary thyroid carcinoma

The prognosis in patients with MTC varies in part with the disease stage at the time of diagnosis. In addition, MTC associated with MEN2B is the most aggressive, whereas FMTC in the absence of other endocrine malignancies is the least aggressive. [9]   

Because the penetrance of MTC is nearly 100%, prophylactic thyroidectomy in infancy is indicated for patients with high-risk RET mutations or by age 5 years in children with an identifiable RET mutation. [12, 13] Patients who are at risk but who have not had genetic screening should undergo annual biochemical screening.

The 5- and 10-year survival rates in patients with MTC and MEN 2A are approximately 90% and 75%, respectively.

Pheochromocytoma

These benign tumors of the adrenal medulla occur in 50% of patients with MEN2 by the time they are in their late 30s; however, prevalence varies in different families. Pheochromocytomas develop in more than 50% of patients with MEN2B and can appear during early childhood. The earliest possible detection of these tumors can prevent a hypertensive crisis. The risk of malignancy is low (<5%).<ref>14</ref>

Adrenalectomy should be considered when patients have biochemical confirmation and an adrenal mass or enlargement on imaging. Bilateral adrenalectomy is reserved for bilateral adrenal masses. Patients become adrenal insufficient following bilateral adrenalectomy. Even patients who receive appropriate information on the management of their chronic adrenal insufficiency are at risk of addisonian crisis, which is a life-threatening emergency that may occur when the patient does not increase the replacement dosage when a major stress occurs. On the other hand, excessive steroid replacement is associated with premature osteoporosis, hypertension, and diabetes. [14]

 

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Patient Education

Adhering to a surveillance program lessens disease complications. Order genetic counseling for the patient so that gene testing and reproductive options can be discussed. For patient education information, see Thyroid Problems.

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