Case Study # 27

Multiple Endocrine Neoplasia Type 2 (MEN2)
-Uha Reddy, SOM 2007

Learning Objectives:

• Differentiate between the 3 syndromes of MEN2: MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC).
• Describe the common tumors associated with each syndrome.
• Discuss the genetics of MEN2 with particular emphasis on the RET protein.
• Discuss the role of genetic testing in MEN2.

Case Study:

Mrs. E is a 29-year old female who presents to your office for the first time. She is the youngest of four children and her eldest brother was recently diagnosed with medullary thyroid cancer at the age of 34. Her father was also diagnosed with medullary thyroid cancer at a young age. Because her father was adopted, she does not know any of the family history on his side. Mrs. E is concerned about her family’s health and wants to know if cancer runs in her family. In addition, Mrs. E and her husband of 2 years are currently trying to have a child and Mrs. E asks you if her child will be at increased risk for cancer.

Questions:

1. What is the prevalence of MEN2?
2. What are the 3 syndromes of MEN2? And which tumors are associated with each syndrome?
3. What are the characteristics of medullary thyroid cancer?
4. How is MEN2 inherited? And what are the important gene(s)/protein(s) involved in the development of MEN2?
5. What is the role of genetic testing in MEN2?

1. What is the prevalence of MEN2?

According to the National Cancer Institute, the prevalence of MEN2 is ~ 1 in 30,000 people.

2. What are the 3 syndromes of MEN2? And which tumors are associated with each syndrome?

The 3 syndromes of MEN2 are MEN2A, MEN2B, and familial medullary thyroid cancer (FMTC).

MEN2A syndrome is associated with medullary thyroid cancer, pheochromocytoma, parathyroid hyperplasia, and cutaneous lichen amyloidosis. Medullary thyroid cancer is the most common tumor of MEN2A; it is present in more than 90% of patients. Pheochromocytoma is a tumor of the adrenal gland, which produces excess amounts of epinephrine and norepinephrine. This tumor is less common than medullary thyroid cancer in MEN2A, but it is still present in 40-50% of patients. Parathyroid hyperplasia is found in 10-20% of patients with MEN2A. When parathyroid hyperplasia is associated with MEN2A, it typically involves multiple glands. Finally, cutaneous lichen amyloidosis is also linked to the MEN2A syndrome. This condition involves the skin and typically presents as a skin lesion on the extremities or upper back, which shows amyloid deposits on histological examination.  

MEN2B syndrome is also associated with medullary thyroid cancer and pheochromocytoma. However, parathyroid hyperplasia and cutaneous lichen amyloidosis are not features of MEN2B. Instead, MEN2B is associated with other conditions such as mucosal neuromas (particularly on the lips and tongue), intestinal ganglioneuromas, and Marfanoid body habitus. In MEN2B, medullary thyroid cancer tends to be more aggressive and present earlier than in MEN2A. In addition, it occurs in almost 100% of patients. 

Familial medullary thyroid cancer (FMTC) can be simply defined as a limited version MEN2A, associated only with medullary thyroid cancer. These two syndromes have a strong genetic link, which will be explained below.  Because it is often difficult to distinguish between FMTC and MEN2A, certain criteria have been established and must be met before a diagnosis of FMTC can be made. In order to make the diagnosis, a thorough family history must be elicited. (1) There must be more than 10 family members with medullary thyroid cancer, (2) several of the affected family members must be over the age of 50, and (3) not even one family member can be affected by another MEN2A tumor. Concern about missing a pheochromocytoma or other MEN2A tumor is the reason for the strict FMTC criteria.

3. What are the characteristics of medullary thyroid cancer?      

Medullary thyroid cancer is a tumor of the parafollicular cells, or C cells, of the thyroid gland. The main function of the parafollicular cells is to produce calcitonin, a peptide which helps regulate calcium levels in the body by inhibiting bone resorption. In medullary thyroid cancer, there is often hyperplasia and extension of the parafollicular cells with a corresponding rise in calcitonin levels.

4. How is MEN2 inherited? And what are the important gene(s)/protein(s) involved in the development of MEN2?

All 3 syndromes of MEN2 are inherited in an autosomal dominant pattern. The gene, which has been implicated in these syndromes, is located on the long arm of chromosome 10 (10q11.2). This gene, the RET proto-oncogene, is responsible for the production of the RET protein, which is a tyrosine kinase receptor. The RET protein can be found in many types of cells including the parafollicular cells of the thyroid, neurons, and cells of the adrenal medulla. In these cells, the RET protein is involved in activities such as growth and development.

There are 3 major components of the RET protein: the extracellular domain which includes a cysteine-rich portion adjacent to the cell membrane, the transmembrane domain, and the intracellular domain composed of two tyrosine kinases (TK1 and TK2). Mutations in the RET proto-oncogene alter the function of these domains. In MEN2A and FMTC, the genetic mutations typically involve exons 10 or 11 in the RET proto-oncogene, which consists of a total of 21 exons. These mutations affect the cysteine-rich portion of the extracellular RET domain. In MEN2B, more than 95% of patients are found to have a mutation in exon 16, which affects the TK2 intracellular domain of the RET protein. The genetic mutations involved in MEN2A, MEN2B, and FMTC lead to an increase in the function of the RET protein. Because of the RET protein’s activities, these mutations facilitate unregulated growth and development and lead to the production of tumors. 

5. What is the role of genetic testing in MEN2?
 
According to the National Cancer Institute, medullary thyroid cancer accounts for only 2-3% of thyroid cancer in the United States. However, the prognosis of medullary thyroid cancer is poorer than the prognoses of other more common types of thyroid cancer such as papillary and follicular thyroid cancer. For medullary thyroid cancer, the average 5-year survival rate is 83%. In order to prevent patients at risk for MEN2 from developing medullary thyroid cancer, genetic testing is recommended by a variety of organizations including the American Society of Clinical Oncology and the National Cancer Institute. Patients who are considered at risk for MEN2 include all first-degree relatives of a patient with known MEN2. If a patient is found to have 1 of the 3 MEN2 syndromes, then typically prophylactic thyroidectomy is recommended.
 
In Mrs. E’s case, her father should undergo genetic testing first in order to determine if he has one of the RET mutations. If the testing shows that her father does have a RET mutation and thus, MEN2, then Mrs. E and her siblings should be tested for that same mutation.

In patients with medullary thyroid cancer, it is not always clear whether the case is sporadic or familial. Therefore, the question of whether to proceed with genetic testing for the individual and his or her family is debatable. However, certain characteristics make it more likely for the case to be familial; these characteristics include a family history of medullary thyroid cancer, diagnosis at a young age (before age 35), and bilateral thyroid disease.

For Mrs. E and her family, genetic testing is appropriate because of her family history and her brother’s young age at diagnosis.
 
Mrs. E can learn more about MEN2 and its genetics at the following websites:

Genetics Home Reference (A service of the U.S. National Library of Medicine)
http://ghr.nlm.nih.gov/condition=multipleendocrineneoplasia

National Cancer Institute – Multiple Endocrine Neoplasia Type 2
http://www.cancer.gov/cancertopics/pdq/genetics/medullarythyroid/HealthProfessional/page2

Online Mendelian Inheritance in Man (OMIM)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

In addition, Mrs. E can create a personalized record of her family’s health history by visiting the following website:

My Family Health Portrait (A tool from the U.S. Surgeon General)
https://familyhistory.hhs.gov

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