Pediatric Multiple Endocrine Neoplasia - Types, Symptoms, Diagnosis, and Treatment

Introduction:

Multiple endocrine neoplasia is an inherited genetic disorder resulting in the growth of tumor cells in the endocrine glands. The endocrine system is a complex network of glands and tissues producing hormones that are released into the bloodstream. Multiple endocrine neoplasia was first reported in 1963 by Wermer, who noticed this condition in children and adults. In multiple endocrine neoplasia, there is an abnormal growth of the cells called the hyperplasia of the gland that can either be benign (non-cancerous) or malignant (cancerous) in nature. In children, the tumors commonly arise from the pituitary, thyroid, and adrenal glands. It can also arise from the germ cell layers and the neural crest cells called neuroendocrine tumors.

What Are the Types of Multiple Endocrine Neoplasia?

Multiple endocrine neoplasias are classified into two main types:

• Multiple Endocrine Neoplasia 1 (MEN 1): It is the most common variant, followed by familial medullary thyroid carcinoma. In addition, type 1 has an increased risk for medullary thyroid cancers, pheochromocytoma, or parathyroid cancers.

• Multiple Endocrine Neoplasia 2 (MEN 2): The Type 2 multiple endocrine neoplasias are further subdivided into 2A, 2B, and FMTC. Type 2B is formerly called type 3, and it is relatively uncommon. The other variant is FMTC, or familial medullary thyroid carcinoma, which develops into adulthood.

What Are the Other Names for Multiple Endocrine Neoplasia?

• Adenomatosis.

• Familial endocrine neoplasia.

• Multiple endocrine adenomatosis.

What Is the Inheritance Pattern of Multiple Endocrine Neoplasia?

All the subtypes of multiple endocrine neoplasia are autosomal dominant conditions. In an autosomal dominant condition, a single copy of the mutated or defective gene is sufficient to cause the defect in the individual. As it is an inherited condition, the parents affected by this condition can pass on the defect to their children. So, there is a 50 % chance for the child to acquire the disease.

What Is the Incidence of MEN Syndrome?

• Multiple endocrine neoplasia type 1 has an incidence of 1 in 30,000 people.

• The type 2 variant is rarely seen in 1 in 35,000 individuals.

• Males are more commonly affected than females.

• Although it is rare in children, it may also be seen in children less than ten years of age.

What Are the Glands Affected?

The affected body parts may vary in each type of MEN syndrome.

• In type 1, any one of the endocrine glands may be affected, such as the pancreas, parathyroid, and pituitary.

• In type 2 multiple endocrine neoplasia, more than two glandular involvements are seen.

• The thyroid gland is the most commonly affected and seen in almost all cases, followed by the adrenal glands in 50 % of the cases and the parathyroid in 20 % of the conditions.

What Causes Multiple Endocrine Neoplasia?

Multiple endocrine neoplasia type 1 is caused due to any gene mutations in chromosome 11q13. This gene is responsible for producing a protein called menin, a tumor suppressor gene. The tumor suppressor gene checks the growth and regulates the abnormal growth and multiplication of the cells. MEN type 1 is generally associated with tumors of the parathyroid, pituitary, and islets of the pancreas.

Multiple endocrine neoplasia type 2 is caused due to the mutations of the RET (Rearranged during transfection) gene. The RET gene provides information for protein production and is also involved in cell signaling. Any mutations of the RET gene result in the hyperactivity of the signaling process causing abnormal cell growth and division even in the absence of cell signals for cell division. It leads to the formation of tumor cells.

What Are the Signs and Symptoms of Multiple Endocrine Neoplasia?

The clinical presentation may vary slightly according to the type and severity of the syndrome.

MEN Type1:

MEN type 1 is also called Werner syndrome. Generally, for any child diagnosed with MEN -1, there are chances for cancer development, and they have to be assessed regularly, starting from the age of five until the end of their lives. In addition, they have a chance of developing hyperparathyroidism and are hence highly susceptible to kidney stone formations. The other common signs are:

• Weakness, lethargy, a sensation of always being tired.

• Decreased appetite.

• Nausea and vomiting.

• Increased thirst and frequency of urination.

• Constipation and decreased bowel movements.

• Hypercalcemia.

MEN Type 2:

Type 2 multiple endocrine neoplasia is also called Sipple syndrome. The symptoms are specific to the condition.

Medullary Thyroid Cancer:

• Trouble swallowing.

• Difficulty in breathing.

• Change in the voice and hoarseness is noticed.

• Presence of lumps in the throat and front of the neck.

Pheochromocytoma:

• Pain in the chest.

• Rapid and irregular heartbeats

• Headaches and dizziness.

• Increased sweating.

• Tremors.

Hyperparathyroidism:

• Increased blood calcium levels.

• Persistent pain in the abdomen.

• Weak, brittle, and painful bones.

• Trouble swallowing and change in the voice.

• Swelling or lump noticed in the neck.

• Recurrent kidney stone formation.

• Increased blood pressure.

What Are the Other Similar Conditions?

• Von- Hippel Lindau syndrome.

• Neurofibromatosis type 1.

• Tuberous sclerosis complex.

How to Diagnose Multiple Endocrine Neoplasia?

Multiple endocrine neoplasia is diagnosed based on the medical history and any known family history. Hence an accurate diagnosis should be made. They are most often diagnosed if the child is suspected of having any cancers, etc. If known family history is present, the child should be monitored right from the age of five, as they have a high chance of cancer development.

Other diagnostic procedures followed are:

• Biopsies: A fine needle aspiration or surgical biopsy is performed. A very thin needle is inserted into the abnormal growths, and the cells are examined under the microscope. This method rules out if there is any cancerous activity present in the cells.

• Magnetic Resonance Imaging Test: The imaging test helps in assessing the abnormalities present in the body.

• PET (Positron Emission Tomography) Scan: A special diagnostic imaging test performed to identify malignant cells. Radioactive glucose is given through an intravenous route. The malignant cells tend to take up more amount of glucose than the normal, healthy cells. It helps in identifying the presence of tumor cells in the body.

• Radioactive Iodine Scan: This scan rules out the presence of thyroid cancer cells and their growth. The thyroid cells take up the radioactive iodine, thus traveling through the bloodstream and getting deposited wherever the thyroid cells are seen in the body. Generally, the amount of iodine taken up by the abnormal thyroid cells is more compared to the normal cells. The areas that lack iodine content are referred to as cold spots.

• Venous Sampling of Parathyroid: Blood samples are collected from the vein near the parathyroid gland and checked for hormone levels. Elevated hormone levels in the blood are suggestive of hyperactive parathyroids.

• Urine Test: The urine test is performed to assess the levels of catecholamines. Higher levels of catecholamines are indicative of any organ damage or dysfunction. Very high levels suggest pheochromocytoma (a small adrenal gland tumor causing irregular secretion of hormones).

How Is Multiple Endocrine Neoplasia Treated?

• MEN Type 1: Surgery may be indicated to remove the hyperactive parathyroid glands since hyperparathyroidism is the main sign of MEN type 1. At least three parathyroid glands are removed along with the thymus.

• MEN Type 2: In children with type 2 multiple endocrine neoplasia, surgery of the thyroid gland may be necessary before the age of five to prevent the formation of cancers or to prevent the spread of cancers to other parts of the body.

• Targeted Therapy: This therapy identifies the cancer cells and destroys only them, and the healthy cells are unaffected. Generally, targeted therapy is preferred over chemotherapy or radiation therapy. It uses certain drugs or substances to kill cancer cells and prevent their growth.

• Pharmacological Therapy: Medications such as tyrosine kinase inhibitors are used to treat multiple endocrine neoplasia. The tyrosine kinase inhibitors block the signals required for the growth of the tumor cells.

Conclusion:

Educating the parents about the disease condition is very important. Generally, it is an inherited condition. Hence, proper genetic testing should be made mandatory for a positive medical history. It helps to assess the health of the child, thus preventing further complications. If there is no family history of multiple endocrine neoplasia, periodic check-ups may be required to reduce the risk of cancer in children suspected of having MEN syndrome.