What are the other Names for this Condition? (Also known as/Synonyms)

• MEN Type 2
• Pheochromocytoma and Amyloid-Producing Medullary Thyroid Carcinoma
• Sipple Syndrome

What is Multiple Endocrine Neoplasia (MEN) Type 2? (Definition/Background Information)

• Multiple Endocrine Neoplasia (MEN) Type 2 is a syndrome involving tumors of the endocrine glands. It is an inherited genetic condition
• There are 2 types of Type 2 Multiple Endocrine Neoplasia - MEN 2A and MEN 2B
  • MEN 2A involves a type of thyroid cancer, called the medullary thyroid cancer, a benign (non-cancerous) tumor of adrenal gland, called the pheochromocytoma, and a benign tumor or overgrowth (hyperplasia) of the parathyroid gland
  • MEN 2B involves the medullary thyroid cancer, pheochromocytoma, muscle and bone related diseases, typical facial features that include broad forehead, swollen lips, and benign tumor of nerve tissues in the oral cavity and digestive tract
• Medullary thyroid cancer arises from the parafollicular C cells of thyroid gland, which secretes a hormone called calcitonin. Calcitonin plays a role in calcium metabolism and in the formation of bones
• Pheochromocytoma of the adrenal gland arises from the central part of the gland, called the adrenal medulla, which secretes adrenalin (a stress hormone). In pheochromocytoma, large amounts of adrenaline are secreted intermittently, which causes episodic increase in blood pressure and heart rate
• Tumor or overgrowth of the parathyroid gland produces excessive parathyroid hormones, which causes increased calcium levels, formation of kidney stones, and loss of bone mass
• MEN 2 Syndrome is associated with RET gene; mutation of RET gene causes over-expression of this gene, causing the symptoms. The defective gene may be inherited from the parent, or the gene mutation may occur randomly
• Suitable surgical procedures may be undertaken towards treating Multiple Endocrine Neoplasia Type 2. The prognosis is dependent upon early diagnosis and treatment of the disorder, including removal of the thyroid gland before the onset of cancer (if necessary)

Who gets Multiple Endocrine Neoplasia (MEN) Type 2? (Age and Sex Distribution)

Multiple Endocrine Neoplasia (MEN) Type 2 is a rare, familial genetic disorder. There is no predilection towards any age or sex.

What are the Risk Factors for Multiple Endocrine Neoplasia (MEN) Type 2? (Predisposing Factors)

• The only risk factor for Multiple Endocrine Neoplasia Type 2 is individuals with a positive family history of the condition. MEN Type 2 is a genetic disorder
• However, a family history of the condition is not observed among individuals with MEN 2B Syndrome. In such individuals, a de novo (new and spontaneous) mutation is observed in the RET gene

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Multiple Endocrine Neoplasia (MEN) Type 2? (Etiology)

MEN 2 Syndrome is caused by the mutation in the RET proto-oncogene on the chromosome 10; the proto-oncogene stimulates the proliferation of cancer cells.

• This mutation causes over-expression of the gene, which increases proliferation of the cells in the thyroid, parathyroid, and adrenal glands that turn cancerous
• MEN2 has an autosomal dominant inheritance pattern, implying that the genetic mutation occurs in only one copy of the gene (in any one parent)
• A child inheriting the RET gene from any one parent, has a very high probability of being affected by the disorder and may develop medullary thyroid cancer. Other signs and symptoms of MEN 2 Syndrome may manifest later in the child, depending on the severity of the condition

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly functioning gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring. 

What are the Signs and Symptoms of Multiple Endocrine Neoplasia (MEN) Type 2?

The signs and symptoms of Multiple Endocrine Neoplasia Type 2 disorder include:

Pheochromocytoma - a benign tumor of the adrenal gland that causes:

• High blood pressure
• Increased heart rate
• Episodic, excessive sweating
• Headaches

Thyroid and parathyroid associated signs and symptoms of MEN 2:

• Neck swelling
• Swollen and painless enlargements of lymph nodes in the neck
• Small painless growths in the eyes and mouth, called neuromas (especially in MEN 2B)
• High calcium level causing:
  • Constipation
  • Increased urination and increased thirst
  • Memory-related problems
• Depression
• Kidney stones and kidney failure in later stages
• Increased blood sugar level

How is Multiple Endocrine Neoplasia (MEN) Type 2 Diagnosed?

Depending on the signs and symptoms noted, a positive family and medical history (of Multiple Endocrine Neoplasia Type 2 Syndrome), and physical examination, the physician may order a variety of tests that include:

• Screening for RET mutations in all symptomatic patients and those with a positive family history of the disorder
• Baseline calcitonin level: If calcitonin level is observed as normal in a high-risk patient, then a stimulation test is performed by giving calcium or Pentagastrin
• Blood tests that include serum calcium and serum parathyroid hormone (PTH)
• Urine catecholamines
• 24 hour vanillylmandelic acid (VMA) in urine
• CT and MRI scans of the neck and abdomen
• MIBG scan - a scan specifically used to diagnose pheochromocytoma
• Radionuclide scanning to detect any metastasis of medullary thyroid cancer

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Multiple Endocrine Neoplasia (MEN) Type 2?

The possible complications of Multiple Endocrine Neoplasia Type 2 include:

• Metastasis of the medullary thyroid cancer
• Renal failure

How is Multiple Endocrine Neoplasia (MEN) Type 2 Treated?

Treatment measures for Multiple Endocrine Neoplasia Type 2 include the following:

• Surgical removal of the thyroid gland (total thyroidectomy) and removal of neck lymph nodes
• Unilateral or bilateral removal of the adrenal gland in cases of pheochromocytoma
• In cases of hyperparathyroidism, a subtotal parathyroidectomy (removal of parathyroid glands) is advised

How can Multiple Endocrine Neoplasia (MEN) Type 2 be Prevented?

• Currently, there are no specific methods or guidelines to prevent Multiple Endocrine Neoplasia (MEN) Type 2, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

MEN Type 2 can be diagnosed early by screening for RET mutations in those with a previous family medical history and other high-risk populations. Those tested positive for the mutations are advised removal of the thyroid gland as a precautionary measure.

What is the Prognosis of Multiple Endocrine Neoplasia (MEN) Type 2? (Outcomes/Resolutions)

• The prognosis of Multiple Endocrine Neoplasia Type 2 depends on the stage of the medullary thyroid cancer
• The prognosis is better, if the thyroid is removed before the cancer develops, or before it spreads to other parts of the body

Additional and Relevant Useful Information for Multiple Endocrine Neoplasia (MEN) Type 2:

• Multiple endocrine neoplasia type 1 (MEN type 1) is an inherited disorder of the endocrine glands. The disorder occurs in individuals, who are genetically predisposed to the condition

The following article link will help you understand multiple endocrine neoplasia type 1:

http://www.dovemed.com/diseases-conditions/multiple-endocrine-neoplasia-men-type-1/

Thanks and Gratitude:

We sincerely acknowledge and thank Dr. Kamalakkannan Chokkalingam for reviewing the Multiple Endocrine Neoplasia Type 2 article. His valuable input and feedback has helped enrich the contents of this article.

Dr. K. Chokkalingam DM FRCP
Consultant Physician (Diabetes and Endocrinology)
Nottingham University Hospitals
Nottingham NG72UH, United Kingdom