MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES

Prepared by:Sajad Abd Al-Rudha Ali

What is meant by NEOPLASIA???

The term Neoplasia refers to a new, excessive growth of cells that is not under physiologic control, like tumors or mass lesions. It’s Unlike cancer that implies only malignancy tumors, Neoplasms can be classified as either benign or malignant.

Multiple endocrine neoplasia syndromes are autosomal dominant mutations in the genes that regulate the growth of the cells, in which the endocrine glands develop non cancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors in at least two endocrine glands. Almost all of the cases are inherited and they affect an estimated 1 in 30,000 people and it affects men and women equally.

According to the difference in the characteristic signs, symptoms and risk of specific tumors; this syndrome is occurred in two patterns:-

Type 1 Disease (Werner’s syndrome) : People with this type of disease have a tumor or excessive growth or activity in more than one of the following glands:

Parathyroid gland Pituitary gland Pancreas gland Thyroid gland (less often affected) Adrenal gland (less often affected).

Type 2 Disease (Sipple’s syndrome) : This is subdivided into:

Type 2A Disease: People with this type of disease have a tumor or excessive growth or activity of two or three of the following glands:

Parathyroid Thyroid Adrenal gland. Type 2B Disease: It’s developed at an early age in infants

as young as 3 months, this type is characterized by: Medullary Thyroid Carcinoma MTC Pheochromocytomas Growths around nerves (neuromas) Marfan’s syndrome.

Pathophysiology Mutations in the MENIN and RET genes cause multiple

endocrine neoplasia. Mutations in the MENIN gene (a gene that’s located on

chromosome 11)cause multiple endocrine neoplasia type1. This gene provides instructions for producing a protein called MENIN . Menin acts as a tumor suppressor, which means it normally keeps cells from growing and dividing too rapidly or in an uncontrolled way. Although the exact function of MENIN is unknown, it is likely involved in cell functions such as copying and repairing DNA and regulating the activity of other genes. If mutations inactivate both copies of the MENIN gene, it is no longer able to control cell growth and division. The loss of functional MENIN allows cells to divide too frequently, leading to the formation of tumors characteristic of multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 2 results from mutations in the RET gene( a gene that’s located on chromosome 10). This gene provides instructions for producing a protein that is involved in signaling within cells. The RET protein triggers chemical reactions that instruct cells to respond to their environment, for example by dividing or maturing. Mutations in the RET gene over activate the protein's signaling function, which can trigger cell growth and division in the absence of signals from outside the cell. This unchecked cell division can lead to the formation of tumors in endocrine glands and other tissues.

If you inherit one defective copy of a MENIN gene from either parent, there's a high probability of having a second mutation in at least one dividing cell. Then, that cell no longer possesses even one normal copy of the gene. When both copies are defective, tumors develop.

Both types of MEN2 are caused by mutations in the RET gene. A mutation in only one copy of the RET gene is enough to cause the disease.

Symptoms Its effect depends on which glands are affected. MEN1

patients will have hyperplasia or tumors of several endocrine glands, including the parathyroids, the pancreas, and the pituitary. The most common symptom of MEN1 is hyperparathyroidism, which leads to elevated blood calcium levels, kidney stones, weakened bones, and depression of the nervous system. Usually The symptoms appear at the age 40.

Patients with MEN2A and MEN2B will have two main symptoms-medullary thyroid cancers (MTC) and a tumor of the adrenal gland medulla known as pheochromocytoma. Medullary thyroid carcinoma forms from the C-cells of the thyroid. C-cells make the hormone calcitonin , which is involved in regulating the calcium levels in the blood and calcium absorption by the bones, It is a slow-growing cancer, it can be cured in less than 50% of the 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.

MEN2B patients are also characterized by 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.

tumors of the mucous membranes of the tongue

There are other symptoms that vary from person to another like: Abdominal pain Anxiety Black, tarry stools Bloated feeling after meals Burning, aching, or hunger discomfort in the upper abdomen or lower chest that is relieved by

antacids, milk, or food Decreased sexual interest, loss of body or facial hair (in men) Fatigue Headache Lack of menstrual periods, infertility, or failure to produce breast milk (in women) Loss of appetite Loss of coordination Loss of underarm or pubic hair Mental changes or confusion Muscle pain Nausea and vomiting Sensitivity to the cold Unintentional weight loss Vision problems weakness

Diagnosis When checking for a misdiagnosis of MEN or confirming a

diagnosis of MEN it’s useful to consider what other medical conditions might be possible misdiagnosed or other alternative conditions relevant to diagnose.

Diagnose is based on clinical features and testing for elevated hormone levels.

The occurrence of one endocrine condition does not immediately lead to a suspicion of MEN syndromes. Diagnoses is based on the occurrence of one or more endocrine conditions and a family history of MEN1 or MEN2.

Magnetic resonance imaging or computed tomography scan of the cranial nerves, also in the abdomen may show pancreatic tumor.

Genetic tests are done to people who have one of the tumors associated with multiple endocrine neoplasia and in family members of people already diagnosed with one of the syndromes.

Screening of the family members is particularly important because about half of the children of people with a multiple endocrine neoplasia syndrome inherit the disease.

Diagnostic tests must be used to carefully evaluate each affected endocrine gland. For example, radioimmunoassay showing increased levels of gastrin in patients with peptic ulceration and Zollinger-Ellison syndrome suggests the need for follow-up studies for MEN I because 50% of patients with Zollinger-Ellison syndrome have MEN.

Also you can diagnose MEN by testing serum glucagon, insulin, and parathyroid hormone

Treatment Treatment depends upon the type of tumor that is present( its

location, staging, and any hormone abnormality that may present)

No cure is known for any of the multiple endocrine neoplasia syndromes. Doctors treat the changes in each gland individually. A tumor is treated by removing it surgically when possible, Hormone replacement therapy is given when glands are removed or do not produce enough hormones.

If removal is not possible (and before removal), doctors tend to give drugs to correct the hormone imbalance caused by gland over activity. For example: Bromocriptine may be used instead of surgery for pituitary tumors that release the hormone prolactin. Other medicine such as omperazole to reduce the risk of ulcers, diazoxide for elevating blood glucose and octreotide for the inhibition f growth hormones.

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