Multiple Endocrine Neoplasia syndromes
Last Review Date: September 7, 2019
The multiple endocrine neoplasia (MEN) syndromes are a group of genetically inherited diseases. It affects the body's network of hormone-producing glands called the endocrine system. MEN typically involves tumoours (neoplasia) in at least two endocrine glands; tunours can also develop in other organs and tissues. These groths can be noncancerous (benign) or cancerous (malignant). If the tumours become cancerous, the condition can be life threatening. Cancer may arise in multiple organs at the same time, or a person may develop one cancer, then a second cancer in another organ, many years later. These cancers also often arise in younger people and may be more aggressive than ‘sporadic’ cancers – those that do not have a genetic inheritance pattern.
The major forms of multiple endocrine neoplasia are called type 1, and type 2. These types are distinguised by the genes involved, the types of hormones made, and the characteristic signs and symptoms.
Type 1 is the most common and affects approximately 1 in 30,000 and is caused by a heritable defect in the MEN-1 tumour suppressor . If one of your parents has this syndrome, you have a 50 per cent chance of having the syndrome yourself. The syndrome most commonly affects the parathyroid gland (four small glands on the front of your thyroid), pancreas and pituitary gland (a small gland at the base of your brain). Tumours in these glands can lead to the overproduction of hormones. However, a patient with MEN-1 may also develop cancer of the small intestines, and lipomas (fatty lumps on your skin).
Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B (formerly called type 3), and familial medullary thyroid carcinoma (FMTC). In this syndrome there is a genetic mutation in the 'RET proto-oncogene' (see RET gene mutation). Among the subtypes of type 2, type 2A is the most common form, followed by FMTC. Type 2 A affects approximately 1 in 35,000 people. Type 2B is relatively uncommon, accounting for about 5 per cent of all cases of type 2.
- Type 2A people develop medullary thyroid cancer (MTC), and an over-active parathyroid gland.
- Type 2B is characterised by MTC, phaeochromocytoma and cancer on the lips or tongue.
The signs and symtoms of multiple endocrine neoplasia depend on the type of disease and the endocrine glands that affected by the tumour growth, as the normal function of the gland may be altered by the tumour. In most cases, the affected endocrine gland produces more hormones than usual, leading to excessive levels and effect of the hormones.
Someone who has MEN-1 syndrome is often asymptomatic. The most common sign of multiple endocrine neoplasia type 1 is overactivity of the parathyroid glands (hyperparathyroidism). Hyperparathyroidism disrupts the normal balance of the calcium in the blood, which can lead to kidney stones, thinning of the bones, nausea and vomiting, high blood pressure (hypertension), weakness and fatigue. However, the first health problems people often noticed are due to dysfunction of the parathyroid gland. By the age of 40, most affected people will have abnormally high levels of calcium in their blood and this can lead to kidney stones, osteoporosis or muscle aches and pains. They may also notice symptoms caused by cancers in other organs. This may include an upset stomach, due to increased acid secretion, and low blood sugar levels.
Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B (formerly called type 3), and familial medullary thryoid carcinoma (FMTC). These subtypes differ in their characteristic signs and symptoms and risk of specific tumours; for example, hyperparathyriodism occurs only in the type 2A, and medullary thyroid carcinoma is the only feature of FMTC. The signs and symptoms of multiple endocrine neoplasia type 2 are relatively consistent within any one family.
The most common presentation of this syndrome is a lump at the front of the neck that could be a sign of medullary thyroid cancer. Some people may first notice a racing heart or palpitations, sweating and anxiety. These symptoms are related to the development of a . Finally, some people may notice changes or growths on their tongue or lips.
The choice of tests ordered by a doctor may vary depending on how the problem first comes to be recognised. They may include:
- Calcium levels
Calcium levels will often be raised in someone who has cancer in their parathyroid. Deranged levels of parathyroid hormone cause this increase.
- Parathyroid hormone levels
A cancerous parathyroid gland will often produce an increased amount of parathyroid hormone.
- Renal (kidney) function tests
An increase in blood levels of calcium may lead to deposition of calcium in the kidney and subsequent damage. At the time of diagnosis, it may be important to rule out any kidney damage or stones.
- Insulin and C-peptide
Measuring levels of insulin and C-peptide can test for a cancer that arises in the pancreas. Prolactin and growth hormone levels. Some cancers in MEN-1 may arise in a small gland just below the brain – the pituitary gland. This can be detected by measuring prolactin and growth hormone levels.
- MEN1 gene mutation testing
Multiple endocrine neoplasia type 1 usually has an autosomal dominant pattern of inheritance.The MEN1 gene codes for a protein called menin. Menin acts as a tumour suppressor. If both copies of the MEN1 gene are faulty not enough protein is produced and cells in some endocrine organs divide and proliferate uncontrollably leading to tumour development. More than 1000 different mutations have been found in the MEN1 gene in patients with MEN-1. DNA testing, which can detect most of these mutations, is available in Australia, however this testing is not covered by Medicare.
- Fine needle
When someone has a lump in the neck, a sample is taken in a procedure that uses a fine needle and is guided by ultrasound. The small amount of tissue can give an indication of whether or not the lump is cancer.
- Urine and plasma metanephrine
If someone develops a cancer within their adrenal gland they will often produce elevated levels of chemicals such as metanephrine. High urine and plasma levels of these chemicals are used to diagnose phaeochromocytoma.
- Serum calcitonin levels
Calcitonin is produced by the c-cells in the thyroid gland. In cases of medullary thyroid cancer it will often be raised. Calcitonin levels, as well as a calcitonin stimulation test may be ordered to confirm MTC.
- Thyroid function tests
These are one of the first tests ordered when a doctor suspects a problem with your thyroid. It includes TSH, FT4 and FT3 and provides information about how your thyroid in functioning.
- RET gene mutation testing
Multiple endocrine neoplasia type is also inherited in an autosomal dominant pattern. In these cases, one copy of the mutated gene is sufficient to cause the disorder. The RET proto-oncogene codes for a signalling protein called RET that spans the cell membrane in various types of cells. There are more than 25 known mutations that cause this protein to become overactive and send signals into the cell promoting uncontrolled cell growth even when it has no signalling molecule bound to its outside region. DNA testing to detect these known mutations is available in Australia and is covered by Medicare in patients with a suspected diagnosis of multiple endocrine neoplasia type 2.
Imaging of the abdomen may be used to look for other cancers at the time of diagnosis.
People with MEN-2 often develop a lump in the neck and this can be investigated with the use of ultrasound. This imaging technique allows doctors to assess the location and characteristics of the lump and to help guide them in taking a sample for the lab to assess.
It is important to note that due to the complex nature of these syndromes, the tests ordered by your doctor may vary from those listed above.
This will vary depending on which organs are affected and the stage of the disease. It may involve both surgical and medical treatment.
- Surgery – Some cancers may be removed from places like the thyroid and parathyroid glands as well as the adrenal glands
- Medical treatment – In some cases surgery is not warranted and the doctor may advise taking medication rather than having a gland removed.
- Family screening should be considered
On this site
Tests: calcium, calcitonin, metanephrines, prolactin, parathyroid hormone, growth hormone, thyroid function tests, insulin, C-peptide, eGFR
Conditions: Osteoporosis, medullary thyroid cancer
Inside the lab: Genetic testing
Elsewhere on the web
Medline Plus – MEN type 1
Medline Plus – MEN type 2
Genetic Home Reference - MEN
Fauci, Braunwald, Kasper et al. Harrison’s Principles of Internal Medicine 17th Ed. Mcgraw Hill, USA: 2360-63
Tuttle R. Clinical manifestations, diagnosis, evaluation, and staging of medullary thyroid cancer. (internet)Up to date (updated august 2012) Available at: http://www.uptodate.com.ezproxy.library.uq.edu.au/contents/clinical-manifestations-diagnosis-evaluation-and-staging-of-medullary-thyroid-cancer?
Kumar V, Abbas A, Fausto N, Aster J. Robins and Cotran’s Pathological Basis of Disease 8th Ed. Philadelphia, USA: Saunders Elsevier; 2010. Ch 24