Sipple’s syndrome; Sipple syndrome; MEN 2a.
What is multiple endocrine neoplasia type 2a
Multiple endocrine neoplasia type 2a causes more than one of the body’s hormone-secreting glands to develop tumours. Examples of the affected glands are the thyroid gland, the parathyroid glands (just next to the thyroid gland in the neck) and the adrenal glands.
What causes multiple endocrine neoplasia type 2a?
Multiple endocrine neoplasia type 2a is caused by a defect in a gene called ‘c-Ret’.
What are the signs and symptoms of multiple endocrine neoplasia type 2a?
There are three main types of tumours that appear in multiple endocrine neoplasia type 2a and these can cause different symptoms:
Medullary cancer of the thyroid - Nearly all patients with multiple endocrine neoplasia type 2a will develop medullary thyroid cancer by the age of 40. This condition develops from cells in the thyroid gland that produce the hormone calcitonin. The symptom is a swelling in the thyroid gland (goitre). The cancer may spread elsewhere, commonly to the lymph glands in the neck and cause swelling of the neck. The cancer may also cause diarrhoea, flushing and neck pain due to the overproduction of calcitonin and other active substances.
Phaeochromocytoma - One in two patients with multiple endocrine neoplasia type 2a will develop these tumours of the adrenal glands which release excess hormones such as adrenaline or noradrenaline into the bloodstream. These tumours are usually non-cancerous in multiple endocrine neoplasia type 2a patients. They can be very difficult to diagnose and produce no symptoms. However, in some people the excessive levels of hormones can cause episodes of sweating, racing of the heartbeat, feelings of anxiety, headache and high blood pressure, similar to panic attacks.
Parathyroid tumours - Between one in six to one in three patients with multiple endocrine neoplasia type 2a will have problems with overgrowth of the parathyroid glands which will cause the release of too much parathyroid hormone (primary hyperparathyroidism). This causes calcium to be taken out of the bones and put into the bloodstream, resulting in increased levels of calcium (hypercalcaemia) in the blood and urine. A parathyroid tumour can cause no symptoms. It may, however, cause the following problems - tiredness, irritability, stomach ulcers, pancreatitis, indigestion, kidney stones, osteoporosis (brittle bones) and constipation.
More rarely, patients with multiple endocrine neoplasia type 2a may develop Hirschsprung’s disease, where the large bowel fails to develop the nerve cells that control the ability to contract and move faeces. This shows as chronic constipation and obstruction of the large bowel.
How common is multiple endocrine neoplasia type 2a?
Multiple endocrine neoplasia type 2a is a rare condition. It occurs in approximately one in every 20,000 to 30,000 people.
Is multiple endocrine neoplasia type 2a inherited?
Multiple endocrine neoplasia type 2a is an inherited condition due to a defect in the c-Ret gene. This defect can be passed on from parent to child. There is a 50:50 chance that a child will inherit the defect, and therefore, multiple endocrine neoplasia type 2a, from their parent.
How is multiple endocrine neoplasia type 2a diagnosed?
There is a genetic test for the defective c-Ret gene. This test is offered to people who have the symptoms of multiple endocrine neoplasia type 2a and are therefore suspected to have this condition, or to the relatives of people with known multiple endocrine neoplasia type 2a. This is a simple blood test and is performed at an NHS Regional Genetics Centre outpatient clinic, after suitable counselling regarding the implications of the test.
The three different types of tumours are diagnosed and monitored in the following ways:
Medullary cancer of the thyroid - Most tests for this condition are done as an outpatient. This is diagnosed using ultrasound scans of the neck. A thin needle can be used to sample cells from suspicious lumps in the thyroid and lymph glands (fine needle aspiration) and these samples are sent to specialists to be looked at. A simple blood test can also be used to detect calcitonin levels. These can all be used to guide diagnosis and further treatment.
Phaeochromocytoma - Most tests for phaeochromocytomas are done as an outpatient. Computed tomography (CT) or magnetic resonance imaging (MRI) scans are used to look for phaeochromocytomas and any evidence of growth of the tumours. Specialised ‘nuclear medicine’ scans such as the metaiodobenzylguanidine (MIBG) or positron emission tomography (PET) scans are also sometimes used to identify phaeochromocytomas and any evidence of spread of the tumours. To look for evidence of excessive adrenaline or noradrenaline secretion, patients may be asked to collect urine over 24 hours or to have a blood test.
Parathyroid tumours causing primary hyperparathyroidism - Calcium and parathyroid hormone levels are tested through outpatient blood tests which may have to be repeated at regular intervals.
How is multiple endocrine neoplasia type 2a treated?
Exact treatment depends on the type of tumours present:
Medullary cancers of the thyroid are usually treated by surgical removal of the thyroid gland and lymph nodes (if affected) under general anaesthesia, if possible. Patients can eat and drink almost immediately after waking up from the operation. They need to stay in hospital for approximately three to five days. If cancer has spread to other parts of the body outside the neck, surgery or radiotherapy is sometimes given to the affected area. If the cancer has spread to places where it is not possible for surgery to remove the tumours, nuclear medicine treatments such as radioactive MIBG or octreotide may be used to slow down the growth of the tumours. This is usually given as an inpatient in specialist hospitals.
Treatment can also be given to relieve the symptoms such as diarrhoea, flushing and pain. Examples of these treatments include loperamide to relieve the diarrhoea, or octreotide injections to relieve the diarrhoea, flushing and pain.
Phaeochromocytomas are usually removed by surgery. The surgery takes place as an inpatient in specialist hospitals. A special period of preparation may be required just before surgery to ensure the blood pressure is well controlled and does not rise or fall excessively. This involves admission for three days or so before the scheduled surgery for injections of blood pressure medications. Blood pressure tablets can also be prescribed to ensure that the blood pressure is controlled. Most tumours can be removed using keyhole surgery. However, in some cases this may not be possible.
Parathyroid tumours are usually treated by surgical removal of the affected parathyroid gland(s), which may be done at the same time as removal of the thyroid glands (thyroidectomy).
Are there any side-effects to the treatment?
In thyroid and parathyroid surgery, the most common side-effect is low blood calcium (hypocalcaemia) which causes tingling of the fingers, toes and lips and sometimes cramping of the muscles. There is also a potential but rare risk of voice box or nerve damage. Patients have to take lifelong thyroid hormone supplements, as well as calcium and vitamin D supplements. This requires monitoring with blood tests at regular intervals.
In rare cases, adrenal surgery can cause sudden surges in blood pressure during removal of the tumour and this could cause a stroke, heart attacks or heart failure. However, these risks have been dramatically reduced since the introduction of drugs to control the blood pressure.
If both adrenal glands are removed, the patient will need to take lifelong replacement steroid medication. The two main drugs that a patient must take after removal of both adrenal glands are hydrocortisone and fludrocortisone. They replace cortisol and aldosterone hormones which are normally produced by the adrenal glands.
Nuclear medicine treatments are usually well tolerated, but if many treatments are given, this may cause the bone marrow to stop producing blood cells. This can cause a lack of red blood cells which carry oxygen, or a lack of white blood cells, which protect against infections.
If given, the blood pressure medications can cause an excessively low blood pressure, leading to fainting and feeling dizzy, particularly when standing up. Some of the medications may also cause a slightly stuffy nose and coldness of the hands and feet.
Octreotide injections can encourage the formation of gallstones in the gall bladder.
If the patient has any concerns about the side-effects of treatment, they should discuss them with their doctor.
What are the longer-term implications of multiple endocrine neoplasia type 2a?
The long-term outcome of multiple endocrine neoplasia type 2a depends very much on how much the medullary thyroid cancer has spread. It is also important that regular follow-up is carried out to ensure that any phaeochromocytomas are caught early, as the high blood pressure caused by these tumours can cause serious complications such as a stroke and heart attack.
Other members of the families of patients with multiple endocrine neoplasia type 2a should be offered genetic tests to see if they carry the defect in the c-Ret gene. If the defect is detected in younger children under the age of five, preventative thyroidectomy before the age of five can be offered to prevent the development of thyroid cancer, but the implication of this operation would be that the children need to take lifelong thyroid hormone replacement.
Written: March 2011. Review due: March 2013