Sipple Syndrome - Multiple Endocrine Neoplasia Type 2

Introduction

Sipple syndrome (multiple endocrine neoplasia type 2) is a collection of medical conditions caused by endocrine system cancers. Tumors can be benign or cancerous (cancer). They are most commonly found in endocrine organs (such as the thyroid, parathyroid, and adrenal glands). MEN2 is a subtype of MEN (multiple endocrine neoplasias). MEN type 2 has three subtypes: type 2A, type 2B, and familial medullary thyroid cancer (FMTC). Approximately 90 percent of all cases are of type 2A. Regardless of the subtype, people with MEN type 2 are more likely to develop familial medullary thyroid cancer (FTMC).

What Is Sipple Syndrome (MEN2)?

Sipple syndrome is a rare genetic condition affecting the endocrine glands, causing medullary thyroid cancer, pheochromocytoma, and parathyroid gland cancer. It can also create noncancerous (benign) tumors in the parathyroid and adrenal glands. High levels of hormones produced by the afflicted endocrine glands might lead to various medical concerns, such as high blood pressure, kidney stones, and itchy skin. A mutation (change) in the RET (rearranged during transfection) gene causes Sipple syndrome. Males and females are equally affected by MEN2. It affects nearly one in 35,000 people in the overall population. It is also known as MEN2A, MEN2A syndrome, multiple endocrine adenomatosis type 2A, or multiple endocrine neoplasia type 2A syndrome.

What Causes Sipple Syndrome?

Sipple syndrome is caused by a change (mutation) in the RET gene. The RET gene is an oncogene or a gene that contributes to the development of cancer. When functioning normally, the RET protein encoded by the RET gene performs multiple essential activities, including cell division control and cell death regulation (apoptosis). RET gene-activating mutations cause uncontrolled cell growth, resulting in tumor development in target tissues. The RET gene produces a protein involved in the transforming growth factor-beta (TGF-beta) signaling system. Variations in the RET gene can impact nerve tissues across the body since the TGF-beta system operates in nervous tissues throughout the body.

Sipple syndrome is an autosomal dominant disease. A single copy of a mutant RET gene can cause the disease. The RET mutation can be inherited from one of the parents, or it can develop as a spontaneous genetic change (new mutation) that happens at the embryo stage for no apparent reason. The probability of passing the faulty gene from the affected parent to offspring is 50 percent for each pregnancy, with male and female children equally at risk.

What Are the Signs and Symptoms of Sipple Syndrome?

Nearly all individuals with Sipple syndrome develop medullary thyroid cancer (MTC), generally at a young age. The thyroid, adrenal, and parathyroid glands are the three endocrine glands most often affected by Sipple syndrome.

• Thyroid Tumors - Medullary thyroid carcinoma (MTC) is the most common clinical symptom of Sipple syndrome. Early signs of MTC can be noticed in children. If MTC is not diagnosed and treated during childhood, most people will have a neck mass or pain between the ages of 15 and 20. MTC is a highly aggressive type of cancer that can spread to other organs through the lymph nodes or circulation. The first indication of MTC is frequently a solid tumor in the thyroid or abnormal expansion of adjacent lymph nodes.

• Adrenal Gland Tumors - Pheochromocytoma (PHEO) is a rare form of adrenal gland tumor that grows from chromaffin cells, which generate hormones that the body requires to function normally. High blood pressure, excessive sweating, frequent headaches, anxiety, loss of skin color, and nervousness are the symptoms associated with PHEO. High blood pressure caused by PHEO usually does not respond to treatment.

• Hyperparathyroidism - This condition is characterized by a persistently elevated level of circulating parathyroid hormone (PTH) and associated hypercalcemia. Persistently high serum calcium levels may eventually result in kidney damage, kidney stones, or bone demineralization and an increased risk of bone fractures. Apart from these symptoms, hypercalcemia due to hyperparathyroidism can also result in muscular or bone pain, weakness, nausea, constipation, indigestion, ulcers, and high blood pressure.

How Is Sipple Syndrome Diagnosed?

Diagnosis of Sipple syndrome is based on detailed patient history, family history, clinical evaluation, and identification of specific features. The characteristic feature of this syndrome is the presence of two more endocrine tumors (MTC, parathyroid hyperplasia, or PHEO). Sipple syndrome can be diagnosed using a variety of tests. Some of these tests are designed to identify high levels of certain hormones in the blood. Elevated hormone levels can indicate certain endocrine cancers.

• Elevated levels of calcitonin indicate the presence of MTC.

• High levels of PTH can indicate the presence of a parathyroid tumor.

• Elevated levels of catecholamines can suggest the presence of an active PHEO.

• A range of imaging (X-ray) scans may also be used to determine the size and location of tumors.

• The clinical diagnosis of Sipple syndrome can be confirmed by genetic testing by identifying a mutation in the RET gene.

What Are the Treatment Options for Sipple Syndrome?

The treatment of Sipple syndrome may require the combined efforts of a team of professionals. Treatment is specific to the individual's symptoms. It may include surgical excision of tumors and medications to counteract the effects of elevated hormones or replace hormones that are no longer produced by the body.

• Thyroidectomy, or surgical thyroid removal, is the conventional treatment for those with MEN2. Thyroid surgery is frequently performed as a prophylactic strategy. Individuals will require lifelong hormone replacement therapy for thyroid hormones. Total thyroidectomy and central compartment lymph node dissection should be performed for medullary thyroid cancer. Additional lymph node dissection can also be done based on preoperative imaging.

• Surgery is the most common treatment for those with PHEO. Surgical removal of one or both adrenal glands is usually done. Laparoscopic laparotomy is the most often used surgical method for treating PHEO. A small incision is created in the belly, and a small tube (laparoscope) is inserted through the incision to remove the tumor.

• Primary hyperparathyroidism (PHPT) is often mild. It can be managed with calcimimetics or, more commonly, surgical excision of the parathyroid gland followed by re-implantation of ceratin-healthy parathyroid tissue into the arm. As there is a possibility of a benign tumor reoccurring in healthy parathyroid tissue, transferring that tissue into the arm would save affected patients from undergoing surgery in the same location.

• Familial genetic screening is indicated to detect at-risk individuals who may develop the disease. It helps in early management with prophylactic thyroidectomy, providing them the highest chance of cure.

Conclusion

Sipple syndrome (multiple endocrine neoplasia type 2) is a rare genetic polyglandular cancer condition characterized by medullary thyroid carcinoma (MTC) pheochromocytoma, parathyroid gland cancer, and an elevated chance of developing other specific malignancies in other endocrine glands. Endocrine tumors can release an abnormally large amount of hormones into the circulation, causing various symptoms.