Multiple endocrine neoplasia type 2 (MEN 2)
Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary cancer syndrome that affects the endocrine glands, leading to the production of hormones in the body. It is categorized into three subtypes: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC), all of which are associated with medullary thyroid carcinoma (MTC), a rare thyroid cancer. In addition to MTC, MEN 2A and MEN 2B can lead to pheochromocytomas—adrenal tumors that produce stress hormones—and MEN 2A is also linked to parathyroid disorders, which can result in hyperparathyroidism. Unique to MEN 2B are mucosal neuromas and gastrointestinal ganglioneuromas, as well as distinctive facial features.
The underlying cause of MEN 2 is typically a mutation in the RET gene, which is necessary for normal cell growth. Symptoms may not appear until later in life, and those with a family history of MEN 2 are at a 50% risk of inheriting the syndrome. Diagnosis often involves genetic testing, blood and urine tests, and imaging studies to identify tumors. While MEN 2 cannot be prevented, early monitoring and surgical interventions can significantly improve outcomes for those affected.
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Multiple endocrine neoplasia type 2 (MEN 2)
ALSO KNOWN AS: MEN 2, MEN 2A, MEN 2B, Sipple syndrome, mucosal neuroma syndrome, familial medullary thyroid carcinoma
RELATED CONDITIONS: Medullary thyroid carcinoma, pheochromocytoma, parathyroid hyperplasia or adenoma, mucosal neuromas of the lips and tongue, gastrointestinal ganglioneuromas
DEFINITION: Multiple endocrine neoplasia type 2 (MEN 2) is a hereditary cancer syndrome that affects the endocrine glands, which produce hormones in the body. There are three types of MEN 2—MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). All three are associated with medullary thyroid cancer (MTC)—a cancerous tumor that grows from the C cells in the thyroid gland. MTC makes up 1 to 2 percent of thyroid cancers. MEN 2A and MEN 2B are also associated with pheochromocytoma—an adrenal gland tumor that releases stress hormones.
MEN 2A carries an increased risk for parathyroid hyperplasia, in which the parathyroid glands become enlarged and produce too much parathyroid hormone. There is also an increased risk of parathyroid adenoma, a benign tumor. Parathyroid hyperplasia and parathyroid adenoma both cause hyperparathyroidism, characterized by the secretion of excess parathyroid hormone.
MEN 2B is associated with mucosal neuromas (tumors growing from a nerve) of the lips and tongue, gastrointestinal ganglioneuromas (benign growths in the intestines), and a characteristic slender facial appearance with prominent, bumpy lips. The disease findings and the severity of the syndrome vary within and between families.
Risk factors: Because MEN 2 is hereditary, the main risk factor is having a family history of this syndrome. Each child of a person with MEN 2 has a 50 percent chance of inheriting the disease.
Etiology and the disease process: The underlying genetic cause of MEN 2 is a mutation, or a genetic change, in the RET gene. RET is a proto-oncogene, which means it usually functions in cell growth and differentiation. Mutations in RET cause it to become an active oncogene, turning normal cells into cancer cells.
Usually, each person has two normal copies of the RET gene. A mutation in one copy of the gene is sufficient to cause MEN 2, which is why this condition is referred to as autosomal dominant (autosomal means the RET gene is located on one of the twenty-two pairs of autosomes, the nonsex chromosomes). A person with MEN 2 has a RET gene mutation from the time of conception in the womb. However, symptoms of the disease may not manifest until later in life. Most mutations are inherited from a parent, but new mutations do occur. The age of onset for medullary thyroid cancer is usually early childhood in MEN 2B, early adulthood in MEN 2A, and middle age in familial medullary thyroid carcinoma.
Mutations in different parts of the RET gene lead to the three subtypes of MEN 2. Nearly all cases of MEN 2B are caused by one specific mutation. Certain mutations are associated with a higher incidence of pheochromocytoma and hyperparathyroidism.
Incidence: Approximately 1 in 35,000 people has MEN 2. Some researchers posit the incidence of MEN 1 and MEN 2 is high, but the conditions are underdiagnosed. About 50 percent of individuals with MEN 2 develop pheochromocytoma.
Symptoms: Symptoms of medullary thyroid cancer may include a thyroid nodule (lump on the throat) and enlarged in the neck. Pheochromocytomas release catecholamines (stress hormones) that can cause dangerously high blood pressure levels. Hyperparathyroidism can cause high calcium levels in the blood, nausea, fatigue, muscle pains, constipation, abdominal pain, kidney stones, and bone fractures. In MEN 2B, gastrointestinal ganglioneuromas can cause constipation or megacolon (abnormally large colon).
Screening and diagnosis: The diagnostic criteria for MEN 2 differ depending on the subtype. MEN 2A is diagnosed by the presence of two or more endocrine tumors (in one person or close blood relatives). MEN 2B is diagnosed in a person with mucosal neuromas on the lips and tongue, medullary thyroid cancer, and, in some cases, pheochromocytoma. Familial medullary thyroid carcinoma is diagnosed in families with four or more cases of medullary thyroid cancer without any other findings of MEN 2. Tools used to check for disease include blood, urine, and imaging tests. Blood tests may measure calcitonin levels (a hormone produced by medullary thyroid cancer), parathyroid hormone, and catecholamines. Testing urine can check for catecholamines and metanephrines released by pheochromocytomas. Blood and urine testing may also be done to assess for hyperparathyroidism. Imaging tests used in MEN 2 diagnosis include magnetic resonance imaging (MRI), computerized tomography (CT) scan, positron emission tomography (PET) scan, and endoscopic ultrasound of the pancreas.
Because mutations in the RET gene cause MEN 2, genetic testing is a valuable tool to confirm a suspected diagnosis or test a family member at risk for the disease with no symptoms. Molecular genetic testing detects RET gene mutations in approximately 98 percent of families with MEN 2A and MEN 2B and roughly 95 percent of families with familial medullary thyroid carcinoma.
Treatment and therapy: The only way to cure medullary thyroid cancer is to remove the thyroid gland (thyroidectomy) at a young age. A patient who has had a thyroidectomy must take thyroid hormone replacement therapy. Because the risk for cancer is so high, removing the thyroid gland is recommended for people who have a RET mutation, even if they do not yet have cancer. Surgery to remove the adrenal gland is necessary to treat patients with pheochromocytoma. Sometimes, pheochromocytomas occur in both adrenal glands. All or some of the four parathyroid glands may be removed to treat hyperparathyroidism.
Prognosis, prevention, and outcomes: Because MEN 2 is a genetic condition, its manifestations cannot be prevented. However, monitoring individuals at risk for the disease based on their family history or who are known to have a RET gene mutation can detect problems early and lead to more effective treatment and better outcomes. Such monitoring includes yearly blood testing for calcitonin levels, yearly blood pressure checks, and yearly urine testing for catecholamines and metanephrines. The medical team caring for patients decides the age at which monitoring should start.
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