MULTIPLE ENDOCRINENEOPLASIA SYNDROMESPrepared 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 underphysiologic control, like tumors or masslesions. It’s Unlike cancer that implies onlymalignancy tumors, Neoplasms can beclassified as either benign or malignant.
Multiple endocrine neoplasia syndromesare autosomal dominant mutations in thegenes that regulate the growth of the cells,in which the endocrine glands develop noncancerous (benign) or cancerous(malignant) tumors or grow excessivelywithout forming tumors in at least twoendocrine glands. Almost all of the casesare inherited and they affect an estimated 1in 30,000 people and it affects men andwomen equally.
According to the difference in the characteristic signs,symptoms and risk of specific tumors; this syndrome isoccurred in two patterns:-Type 1 Disease (Werner’s syndrome) : People with this type ofdisease have a tumor or excessive growth or activity in morethan 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 atumor or excessive growth or activity of two or three of thefollowing glands: Parathyroid Thyroid Adrenal gland.Type 2B Disease: It’s developed at an early age in infantsas young as 3 months, this type is characterized by: Medullary Thyroid Carcinoma MTC Pheochromocytomas Growths around nerves (neuromas) Marfan’s syndrome.
PathophysiologyMutations in the MENIN and RET genes cause multipleendocrine neoplasia. Mutations in the MENIN gene (a gene that’s located onchromosome 11)cause multiple endocrine neoplasia type1.This gene provides instructions for producing a protein calledMENIN . Menin acts as a tumor suppressor, which means itnormally keeps cells from growing and dividing too rapidly orin an uncontrolled way. Although the exact function of MENINis unknown, it is likely involved in cell functions such ascopying and repairing DNA and regulating the activity ofother genes. If mutations inactivate both copies of the MENINgene, it is no longer able to control cell growth and division.The loss of functional MENIN allows cells to divide toofrequently, leading to the formation of tumors characteristic ofmultiple endocrine neoplasia type 1.
Multiple endocrine neoplasia type 2 results from mutationsin the RET gene( a gene that’s located on chromosome 10).This gene provides instructions for producing a protein that isinvolved in signaling within cells. The RET protein triggerschemical reactions that instruct cells to respond to theirenvironment, for example by dividing or maturing. Mutationsin the RET gene over activate the proteins signaling function,which can trigger cell growth and division in the absence ofsignals from outside the cell. This unchecked cell division canlead to the formation of tumors in endocrine glands and othertissues.
If you inherit one defective copy of a MENIN gene fromeither parent, theres a high probability of having a secondmutation in at least one dividing cell. Then, that cell nolonger possesses even one normal copy of the gene. Whenboth copies are defective, tumors develop. Both types of MEN2 are caused by mutations in the RETgene. A mutation in only one copy of the RET gene isenough to cause the disease.
Symptoms Its effect depends on which glands are affected. MEN1patients will have hyperplasia or tumors of several endocrineglands, including the parathyroids, the pancreas, and thepituitary. The most common symptom of MEN1 ishyperparathyroidism, which leads to elevated blood calciumlevels, kidney stones, weakened bones, and depression of thenervous system. Usually The symptoms appear at the age 40. Patients with MEN2A and MEN2B will have two mainsymptoms-medullary thyroid cancers (MTC) and a tumor ofthe adrenal gland medulla known as pheochromocytoma.Medullary thyroid carcinoma forms from the C-cells of thethyroid. C-cells make the hormone calcitonin , which isinvolved in regulating the calcium levels in the blood andcalcium 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 causesexcessive secretion of adrenal hormones, which, in turn,can cause life-threatening hypertension and cardiacarrhythmia. MEN2B patients are also characterized by swollen lips;tumors of the mucous membranes of the eye, mouth,tongue, and nasal cavity; enlarged colon; and skeletalabnormalities. Symptoms develop early in life, often underfive years of age.
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 byantacids, 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 adiagnosis of MEN it’s useful to consider what other medicalconditions might be possible misdiagnosed or otheralternative conditions relevant to diagnose. Diagnose is based on clinical features and testing for elevatedhormone levels. The occurrence of one endocrine condition does notimmediately lead to a suspicion of MEN syndromes.Diagnoses is based on the occurrence of one or moreendocrine conditions and a family history of MEN1 or MEN2. Magnetic resonance imaging or computed tomography scan ofthe cranial nerves, also in the abdomen may show pancreatictumor.
Genetic tests are done to people who have one of thetumors associated with multiple endocrine neoplasia andin family members of people already diagnosed with one ofthe syndromes. Screening of the family members is particularly importantbecause about half of the children of people with amultiple endocrine neoplasia syndrome inherit the disease. Diagnostic tests must be used to carefully evaluate eachaffected endocrine gland. For example, radioimmunoassayshowing increased levels of gastrin in patients with pepticulceration and Zollinger-Ellison syndrome suggests theneed for follow-up studies for MEN I because 50% ofpatients 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( itslocation, staging, and any hormone abnormality that maypresent) No cure is known for any of the multiple endocrine neoplasiasyndromes. Doctors treat the changes in each glandindividually. A tumor is treated by removing it surgically whenpossible, Hormone replacement therapy is given when glandsare removed or do not produce enough hormones. If removal is not possible (and before removal), doctors tendto give drugs to correct the hormone imbalance caused bygland over activity. For example: Bromocriptine may be usedinstead of surgery for pituitary tumors that release thehormone prolactin. Other medicine such as omperazole toreduce the risk of ulcers, diazoxide for elevating blood glucoseand octreotide for the inhibition f growth hormones.