Alternative names for multiple endocrine neoplasia type 2A

Sipple’s syndrome; Sipple syndrome; MEN 2a

What is MEN2A?

Multiple endocrine neoplasia type 2 (MEN2) is a rare inherited disorder in which medullary thyroid cancer, phaeochromocytoma and overactive parathyroid glands develop.

What causes MEN2A?

MEN2A is caused by an abnormality in the RET gene, found on chromosome 10. Knowing the exact abnormality in the RET gene can help predict the types of tumours/cancers a patient is at risk of developing. For example, some changes in the RET gene are associated with MEN2A, some with MEN2B, whereas others are associated with the development of hereditary thyroid cancer or familial medullary thyroid cancer only. Understanding this can help guide the management of people who are found to have these changes in the RET gene; in particular, to decide the best timing for thyroid surgery, and to consider what other conditions they should be screened for.

What are the signs and symptoms of MEN2A?

There are three types of hormone-secreting tumours that can develop in MEN2A:

1. Medullary thyroid cancer (MTC) – nearly all patients with MEN2A will develop medullary thyroid cancer by the age of 40 years. MTC develops from cells in the thyroid glandthat produce the hormone calcitonin. It may not cause any symptoms, or can cause a swelling or pain in the neck (in the thyroid gland). The cancer may spread elsewhere, commonly to the lymph nodes 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.
2. Phaeochromocytomas – up to 50% of patients with MEN2A with the highest risk mutationcan develop these tumours of the adrenal glands that release hormones such as adrenaline or noradrenaline into the bloodstream. High levels of these hormones can cause episodes of sweating, palpitations, headaches, feelings of anxiety and high blood pressure; they may be similar to panic attacks. Some patients have no symptoms. Sometimes the tumours affect both adrenal glands (bilateral). Other MEN2A gene mutations carry a much lower or even an almost zero risk of developing a phaeochromocytoma.
3. Primary hyperparathyroidism – up to 20–30% of patients with the highest risk mutation may develop overactive parathyroid glands. This causes a high level of parathyroid hormone, which in turn 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. Usually there are no symptoms but if present, symptoms include tiredness, depression, stomach ulcers, abdominal pain and non-specific aches and pains. If it is left untreated, osteoporosis and kidney stones can develop. Other MEN2A gene mutations carry a much lower or even an almost zero risk of developing primary hyperparathyroidism.

Other clinical variants include:

1. MEN2 with cutaneous lichen amyloidosis - collection of abnormal protein called amyloid which results in clusters of small skin-coloured, reddish brown scaly spots, which can merge together to form raised thickened areas especially on the shins and legs.
2. MEN2 with Hirschsprung disease – a condition where some of the nerves are missing in part of the gut and as a result, the gut cannot squeeze the poo out properly and this may result in a blockage.
3. Familial medullary thyroid cancer

How common is MEN2A?

MEN2A is a rare condition occurring in approximately 1 in 25,000 people.

Is MEN2A inherited?

MEN2A is an inherited condition due to an abnormality or ‘spelling mistake’ (mutation) in the RET gene, which can be passed on from parent to child. It is inherited in an 'autosomal dominant' way. This means it is not a sex-linked condition and that there is a 50% (1 in 2) chance that a child will inherit the abnormal gene, and therefore, MEN2A. A small number of MEN2A patients may not have a family history, and so are the first people to have the faulty gene in their family.  

How is MEN2A diagnosed?

Genetic testing – there is a genetic test for the abnormal RET gene, which is over 98% accurate. This test is offered to people who have clinical manifestations of MEN2A (diagnostic testing) and to relatives of people with known MEN2A (predictive testing). This should be performed through a Clinical Genetics service with appropriate genetic counselling.

The three different types of tumours are diagnosed and monitored in the following ways:

1. Medullary thyroid cancer (MTC) – once a diagnosis of MEN2A is made, a total thyroidectomy(removal of the thyroid gland) 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. Depending upon the underlying mutation, patients can have their level of risk assessed according to how early they are likely to develop MTC. Based on this, the timing of thyroid surgery (total thyroid removal) can be planned. Typically in MEN2A, patients are advised to undergo a total thyroidectomy before the age of 5 years but timing can vary depending on the type of mutation.

Once the thyroid gland has been removed then patients undergo lifelong surveillance, which includes a fasting calcitonin blood test. The samples have to be transferred to the laboratory on ice and processed immediately and so the tests have to be performed in the hospital.

If a patient has a thyroid lump then an ultrasound may be performed along with a biopsy where a thin needle can be used to sample cells from suspicious lumps in the thyroid and lymph nodes (fine needle aspiration). These samples are sent to specialists to be looked at. If MTC is diagnosed, further scans such as a computerised tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET) scan may be performed to help plan surgery, as more extensive surgery may be necessary.

2. Phaeochromocytomas – plasma metanephrines (metabolites secreted into the blood which help regulate blood pressure. Patient’s with Phaeochromocytomas typically have significantly increased concentrations in the blood) are an accurate method for diagnosis although some drugs can interfere with their measurements. A twenty-four hour urine collection for metanephrines is an alternative – a special bottle containing an acid preservative is needed for this test. If the blood or urine tests are abnormal, CTor MRI scans are often used to look for phaeochromocytomas in the adrenal glands. Specialised ‘nuclear medicine’ scans such as metaiodobenzylguanidine (MIBG) or PET scans are also sometimes used to identify phaeochromocytomas along with any evidence of malignancy, i.e. spread of these tumours (metastases).
3. Primary hyperparathyroidism – calcium and parathyroid hormone levels are tested through outpatient blood tests, which may have to be repeated at regular intervals. The diagnosis of primary hyperparathyroidism is made if the serum calcium is elevated together with the parathyroid hormone being high or inappropriately normal (it should be low if blood calcium is high).

If a patient is found to have MEN2A, lifelong surveillance is recommended. Patients should be cared for in a specialist centre under the guidance of an experienced multidisciplinary team. Screening is performed for the conditions listed above with a combination of blood tests and scans as appropriate. If a patient with MEN2A wishes to start a family, a repeat visit to the clinical genetics service is recommended to rediscuss the chances of their children being affected, to enable a partner to understand the implications of a diagnosis of MEN2A, and to consider antenatal genetic testing or to discuss the appropriate age to consider genetic testing of any baby, to guide thyroid surgery which may cure or prevent an otherwise life-limiting cancer diagnosis. 

How is MEN2A treated?

The exact treatment depends upon the type of tumours present:

1. MTC – essentially all patients who are found to have a RET gene mutation are advised to undergo total thyroid removal. For MEN2A this is typically recommended before the age of 5 years. This is to prevent the development of MTC. If a patient is found to already have MTC, then the operation may be more extensive, removing the thyroid gland as well as lymph nodes in the neck.
   
   If the cancer has spread to other parts of the body outside the neck, surgery or radiotherapy is sometimes given to the affected area. There are also some other options including drugs called tyrosine kinase inhibitors or radiolabelled peptide therapy, which may be offered to patients with widespread disease, and patients can also 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 classical symptoms of MTC, such as diarrhoea, flushing and pain. Examples of these treatments include loperamide to relieve the diarrhoea, or somatostatin analogue injections, which may relieve the diarrhoea, flushing and pain in some patients.
    
2. 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 stress hormones produced from the tumours are blocked, and that blood pressure is well controlled. In the UK, this involves a minimum of three 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. Extra intravenous fluids may also be given as part of the pre-operative preparation. It is crucial to prepare patients properly for surgery to safely remove a phaeochromocytoma and care of these patients should be undertaken in specialist centres that mange these patients regularly.
    
3. Primary hyperparathyroidism is usually treated by surgical removal of the affected parathyroid glands. Usually an operation will involve removal of some or all parathyroid glands and patients will then require life-long supplements of activated vitamin D and possibly calcium also to maintain a normal healthy blood calcium level.

Are there any side-effects to the treatment?

After thyroid surgery, patients require life-long thyroid hormone replacement with levothyroxine, usually requiring at least an annual blood test to ensure that treatment is optimal. More frequent tests may be required if the patient is planning a pregnancy as optimal maternal thyroid hormone replacement is crucial for foetal brain development.

A common significant side-effect following thyroid surgery is a low blood calcium (hypocalcaemia) due to damage to the adjacent parathyroid glands. This symptom can also occur following parathyroid surgery. Significant hypocalcaemia results in 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, life-long treatment of activated vitamin D and possibly calcium also may be necessary. This requires monitoring with blood tests to check calcium levels.

With thyroid surgery, there is also a small risk of damage to the recurrent laryngeal nerve, which affects the function of 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 be helpful if neck stiffness occurs.

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 due to adrenaline and noradrenaline release during surgery, 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 life-long 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 an increased risk of infections. They can also damage kidney function.

Somatostatin analogue injections can encourage the formation of gallstones in the gall bladder, and cause diarrhoea or stomach cramps.

Many therapies used in patients with widespread MTC disease have significant side-effects and careful counselling regarding the risk-benefit profile of all options should be reviewed with the patient by an expert in the field.

What are the longer-term implications of MEN2A?

The long-term outcome of MEN2A typically depends upon the MTC component of the disease. At one end of the spectrum this may be cured by preventative thyroid surgery in a young infant before MTC even develops and, at the other end, a patient may be first diagnosed in adulthood with MTC that has already spread to other parts of the body at time it is diagnosed. Patients who undergo an early preventative 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 any phaeochromocytoma development is detected early, as the high blood pressure caused by these tumours can cause serious complications such as a stroke and heart attacks. 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 MEN2A should be offered genetic tests to see if they also carry the abnormality in the RET gene. It is important that genetic screening is offered through a specialist service together with genetic counselling so that anyone undergoing the test understands the full implications. Input from patient support groups may be invaluable to patients and their families.

Are there patient support groups for people with MEN2A?

The Association for Multiple Endocrine Neoplasia Disorders (AMEND) patient support group can provide advice and support to patients and their families.