Sipple’s syndrome; Sipple syndrome; MEN 2a.
What is multiple endocrine neoplasia type 2a
Multiple endocrine neoplasia type 2a is a rare inherited disorder resulting in medullary thyroid cancer, phaeochromocytoma and overactive parathyroid glands, resulting in a high calcium.
What causes multiple endocrine neoplasia type 2a?
Multiple endocrine neoplasia type 2a is caused by a defect in the RET gene, found on chromosome 10. The exact abnormality in the RET gene can determine the types of tumours/cancers a patient is at risk of developing. For example, some faults in the RET genes are associated with multiple endocrine neoplasia type 2a, while others are associated with the development of hereditary familial medullary thyroid cancer only. This can help diagnosis and also help in the management of people who are found to have the gene fault, by helping plan the best timing for thyroid surgery.
What are the signs and symptoms of multiple endocrine neoplasia type 2a?
There are three types of hormone-secreting tumours that can develop in multiple endocrine neoplasia type 2a:
Medullary cancer of the thyroid (MTC) – Nearly all patients with MEN2a will develop medullary thyroid cancer by the age of 40. MTC develops from cells in the thyroid gland that produce the hormone calcitonin. It may not cause any symptoms, or can cause a swelling in the thyroid gland. The cancer may spread elsewhere, commonly to the lymph glands in the neck, lungs and liver. 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 type2a will develop these tumours of the adrenal glands that release hormones such as adrenaline or noradrenaline into the bloodstream. They can occur in both adrenal glands in 60-80% of patients. High levels of these hormones can cause episodes of sweating, racing of the heartbeat, feelings of anxiety, chest tightness, headache and high blood pressure, similar to panic attacks. Some patients have no symptoms.
Parathyroid tumours – About 40% of patients with MEN2a will develop overactive parathyroid glands. This causes a high level of parathyroid hormone, which causes calcium to be taken out of the bones and put into the bloodstream, resulting in increased levels of calcium in the blood and urine. Symptoms include tiredness, depression, stomach ulcers, abdominal pain and non-specific aches and pains, and if left untreated can result in osteoporosis and kidney stones.
How common is multiple endocrine neoplasia type 2a?
Multiple endocrine neoplasia type 2a is a rare condition occurring in approximately 1 in 40, 000 people.
Is multiple endocrine neoplasia type 2a inherited?
Multiple endocrine neoplasia type 2a is an inherited condition due to an abnormality or ‘spelling mistake’ in the RET gene, which can be passed on from parent to child. It is inherited in an ‘autosomal dominant’ way, that is, there is a 50% (1 in 2) chance that a child will inherit the abnormal gene and therefore develop features of multiple endocrine neoplasia type 2a. About 50% of patients with MEN2a do not have a family history, and so are the first people to have the faulty gene in their family.
How is multiple endocrine neoplasia type 2a diagnosed?
Genetic Testing - There is a genetic test for the defective c-Ret gene, which is over 98% accurate. This test is offered to people who have the manifestations of multiple endocrine neoplasia type 2a andrelatives of people with known multiple endocrine neoplasia type2 (predictive testing). This should be performed through a Clinical Genetics service so implications for the test can be discussed in advance of testing, and further counselling offered, if necessary, as a positive result has implications for a patient and their family, and can often come as a shock.
The three different types of tumours are diagnosed and monitored in the following ways:
Medullary cancer of the thyroid – Once a diagnosis of MEN2a is made, a total thyroidectomy is recommended regardless of whether there is any abnormality in any scans or blood tests. This is to try and remove the thyroid gland early before MTC develops. Patients are advised currently to undergo total thyroidectomy from the age of 5.
Phaeochromocytoma - Plasma metanephrines are accurate for diagnosis although some drugs can interfere with their measurements. 24 hour urine collection for metanephrines is an alterative - a special bottle with acid is needed for this test. If the blood or urine tests are abnormal, CT or MRI scans are used to look for phaeochromocytomas in the adrenal glands. Specialised ‘nuclear medicine’ scans such as the metaiodobenzylguanidine (MIBG) or PET scans are also sometimes used to identify phaeochromocytomas and any evidence of spread of the tumours.
Parathyroid tumours - Calcium and parathyroid hormone levels are tested through outpatient blood tests, which may have to be repeated at regular intervals. Ultrasound or sesta MIBI (a nuclear medicine scan) may be requested to identify the location of the parathyroid glands.
If a patient is found to have MEN2a, lifelong surveillance is recommended with a specialist. Clinic appointments are usually every 6-12 months and screening is performed for the conditions listed above with a combination of blood tests and scans, as detailed above. If a patient with MEN2a wishes to start a family, a repeat visit to the clinical genetics service is recommended to discuss the chances of future children being affected, to enable a partner to understand the implications of a diagnosis of MEN2a and to discuss the appropriate age to consider genetic testing.
How is multiple endocrine neoplasia type 2a treated?
The exact treatment depends upon the type of tumours present:
Patients who are found to have the RET gene mutation are advised to undergo thyroid surgery. For MEN2a this is suggested to be at age 5 or under. This is to prevent the development of medullary thyroid cancer. If a patient is found to have MTC, the operation may be more extensive, removing the thyroid gland and lymph nodes in the neck under general anaesthesia.
If the 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. There are some new drugs called tyrosine kinase inhibitors, which may be offered to patients with widespread disease, and patients can be referred to specialist cancer centres if they would like to consider being involved in clinical trials.
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, which may relieve the diarrhoea, flushing and pain in some patients.
Phaeochromocytomas are surgically removed in all patients where possible. The preparation for surgery and surgery itself takes place in specialist hospitals. A period of preparation is required before surgery to ensure that the effects of the hormones produced from the tumours are blocked, and that blood pressure is well controlled. This involves a minimum of 2 weeks of taking drugs called alpha blockers such as phenoxybenzamine, and beta blockers such as propranolol or bisoprolol before a patient is ready for surgery. These are usually started in hospital. Patients also need to be admitted for 3 days or so before the scheduled surgery to optimise the preparation for surgery. Extra intravenous fluid may be given as part of the preoperative preparation. It is crucial to prepare patients properly for surgery to remove a pheochromocytoma but in centres that mange these patients regularly this is a safe operation to undergo.
Parathyroid tumours are usually treated by surgical removal of the affected parathyroid glands. Usually 3 ½ or 4 parathyroid glands are removed and patients may then require 1 alphacalcidol afterwards to maintain a normal calcium level.
Are there any side-effects to the treatment?
After thyroid surgery, patients require lifelong thyroid hormone replacement, usually requiring an annual blood test to monitor levels. The most common significant side-effect is low blood calcium (hypocalcaemia), which causes tingling of the fingers, toes and lips and sometimes cramping of the muscles. This may require a short admission to hospital for a calcium drip to normalise calcium and if the parathyroid damage is permanent, lifelong treatment with a drug called 1 alphacalcidol may be necessary. This requires monitoring with blood tests to check calcium levels. There is also a potential but rare risk of damage to the recurrent laryngeal nerve, which affects the vocal cords. Some patients require more extensive neck surgery such as a neck dissection, which can result in stiffness of the neck. Physiotherapy can help patients regain full function.
Phenoxybenzamine can cause a drop in blood pressure on standing, leading to fainting and feeling dizzy, particularly when standing up. It may also cause a slightly stuffy nose and coldness of the hands and feet. Rarely, it can cause problems with passing urine frequently.
Adrenal surgery can often be done by keyhole surgery and recovery is as for any abdominal operation. If a patient is not prepared adequately there may be risks, hence the need to be under the care of a specialist who has experience in managing this condition. However, this is very unusual in patients managed properly.
If both adrenal glands are removed, the patient will have 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 the cortisol and aldosterone hormones that are normally produced by the adrenal glands (see the article on Addison’s disease for further details).
Nuclear medicine treatments may cause fatigue and may affect the bone marrow causing anaemia and low platelet count, which can result in bleeding problems, and a low white cell count, which can result in increase risk of infections.
Octreotide injections can encourage the formation of gallstones in the gall bladder, and diarrhoea or stomach cramps.
If the patient has any concerns about the 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. Patients with MEN2a may have cancer that has spread already at diagnosis. Patients who undergo a prophylactic thyroidectomy, or have all the MTC removed at initial surgery have an excellent outlook.
It is also important that regular follow-up is carried out to ensure that a phaeochromocytoma is detected early, as the high blood pressure caused by these tumours can cause serious complications such as a stroke and heart attack. However, with regular surveillance in a specialist clinic, these issues can be addressed at an early stage before any problems occur.
Other members of the families of patients with multiple endocrine neoplasiatype 2a should be offered genetic tests to see if they carry the defect in the RET gene. If the defect is detected, preventative thyroidectomy before the age of 5, if possible, can be performed to prevent the development of thyroid cancer.
It is important that genetic screening is offered through a specialist service together with genetic counselling so that any one undergoing the test understands the implications for them and their families.
Reviewed: January 2015