Sipple syndrome

Definition

The multiple endocrine neoplasia (MEN) syndromes are three related disorders affecting the thyroid and other hormonal (endocrine) glands of the body. MEN has previously been known as familial endocrine adenomatosis.

Description

The three forms of MEN are MEN1 (Wermer's syndrome), MEN2A (Sipple syndrome), and MEN2B (previously known as MEN3). Each is an autosomal dominant genetic condition which predisposes to hyperplasia (excessive growth of cells) and tumor formation in a number of endocrine glands.

Causes & symptoms

MEN1 patients experience hyperplasia or tumors of several endocrine glands, including the parathyroids, the pancreas, and the pituitary. The most frequent symptom of MEN1 is hyperparathyroidism. Overgrowth of the parathyroid glands leads to over secretion of parathyroid hormone, which leads to elevated blood calcium levels, kidney stones, weakened bones, and nervous system depression. Almost all MEN1 patients show parathyroid symptoms by age 40.

Tumors of the pancreas known as gastrinomas are also common in MEN1. Excessive secretion of gastrin (a hormone secreted into the stomach to aid in digestion) by these tumors can cause upper gastrointestinal ulcers. The anterior pituitary and the adrenal glands can also be affected. Unlike MEN2, the thyroid gland is rarely involved in MEN1 symptoms.

Patients with MEN2A and MEN2B experience two main symptoms, medullary thyroid cancer (MTC) and a tumor of the adrenal gland medulla known as pheochromocytoma. MTC is a slow-growing cancer, but one that can be cured in less than 50% of cases. Pheochromocytoma is usually a benign tumor that causes excessive secretion of adrenal hormones, which, in turn, can cause life-threatening hypertension and cardiac arrhythmia.

The two forms of MEN2 are distinguished by additional symptoms. MEN2A patients have a predisposition to increase in size (hypertrophy) and to develop tumors of the parathyroid gland. Although similar to MEN1, less than 20% of MEN2A patients will show parathyroid involvement.

MEN2B patients show a variety of additional conditions: a characteristic facial appearance with swollen lips; tumors of the mucous membranes of the eye, mouth, tongue, and nasal cavity; enlarged colon; and skeletal abnormalities. Symptoms develop early in life (often under five years of age) in cases of MEN2B and the tumors are more aggressive. MEN2B is about ten-fold less common than MEN2A.

MEN1 is caused by mutation at the PYGM gene. PYGM is one of a group of genes known as tumor suppressor genes. A patient who inherits one defective copy of a tumor suppressor gene from either parent has a strong predisposition to the disease because of the high probability of incurring a second mutation in at least one dividing cell. That cell no longer possesses even one normal copy of the gene. When both copies are defective, tumor suppression fails and tumors develop.

Both types of MEN2 are caused by mutations in another gene, known as RET. A mutation in only one copy of the RET gene is sufficient to cause disease. A number of different mutations can lead to MEN2A, but only one specific genetic alteration leads to MEN2B.

For all types of MEN, the children of an affected individual have a 50% chance of inheriting the defective gene.

Diagnosis

Classical diagnosis of MEN is based on clinical features and on testing for elevated hormone levels. For MEN1, the relevant hormone is parathyroid hormone. For both types of MEN2, the greatest concern is development of medullary thyroid cancer. MTC can be detected by measuring levels of the thyroid hormone, calcitonin. Numerous other hormone levels can be measured to assess the involvement of the various other endocrine glands.

Diagnosis of MEN2B can be made by physical examination alone. However, MEN2A shows no distinct physical features and must be identified by measuring hormone levels or by finding endocrine tumors.

Since 1994, genetic screening using DNA technology has been available for both MEN1 and MEN2. This new methodology allows diagnosis prior to the onset of symptoms.

In the past, there was no way of definitively identifying which children had inherited the defective gene. As a result, all children had to be considered at risk. In the case of MEN2A and MEN2B, children would undergo frequent calcitonin testing. Molecular techniques now allow a positive distinction to be made between children who are and are not actually at risk.

Children who are identified as carriers of the RET gene can be offered total thyroidectomy on a preventative (prophylactic) basis to prevent the development of MTC.

Treatment

No comprehensive treatment is available for genetic conditions such as MEN. However, some of the consequences of MEN can be symptomatically treated.

Pheochromocytoma in both types of MEN 2 can be cured by surgical removal of this slow growing tumor.

Treatment of MTC is by surgical removal of the thyroid, although doctors may disagree at what stage to remove the thyroid. After thyroidectomy, the patient will receive normal levels of thyroid hormone orally or by injection.

Even when surgery is performed early, metastatic spread of the cancer may have already occurred. Since this cancer is slow growing, metastasis may not be obvious. Metastasis is very serious in MTC because chemotherapy and radiation therapy are not effective in controlling its spread.

Prognosis

Diagnosed early, the prognosis for the MEN diseases is reasonably good, even for MEN2B, the most dangerous of the three forms. Even in the absence of treatment, a few individuals with MEN2A mutations will never show any symptoms at all. Analysis of at-risk family members using molecular genetic techniques will lead to earlier treatment and improved outcomes.

Prevention

One of the most serious consequences of MEN is MTC, which can be prevented by thyroidectomy. There is no preventive measure to block the occurrence of genetic mutations such as those that cause MEN.

Key Terms

Endocrine

A term used to describe the glands that produce hormones in the body.

Hyperplasia

An overgrowth of normal cells within an organ or tissue.

Medullary thyroid cancer (MTC)

A slow-growing tumor associated with MEN.

Neoplasm

An abnormal formation of tissue; for example, a tumor.

Pheochromocytoma

A tumor of the medullary of the adrenal gland.

Further Reading

For Your Information

Periodicals

• Gardner, David G. "Recent Advances in Multiple Endocrine Neoplasia Syndromes." Advances in Internal Medicine (1997): 597-625.
• Moley, Jeffrey F. "The Molecular Genetics of Multiple Endocrine Neoplasia Type 2A and Related Syndromes." Annual Review of Medicine 48(1997): 409-420.

  Organizations

• Canadian MEN Society. P.O. Box 100, Meola, Saskatchewan SOM 1XO. (306) 892-2080.

Gale Encyclopedia of Medicine. Gale Research, 1999.