Alternative names for multiple endocrine neoplasia type 2B

MEN2, Sipple or Sipple’s syndrome; MEN 2b or Mucosal neuroma syndrome

What is MEN2B?

Multiple endocrine neoplasia 2b (MEN2B) is a rare inherited disorder characterised by the certain development of medullary thyroid cancer, plus the possible development of phaeochromocytomas and characteristic tumours (mucosal neuromas) of the lips, tongue and bowels. Parathyroid disease is extremely rare in MEN2B.

What causes MEN2B?

MEN2B is caused by a defect 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 faults in the RET gene are associated with MEN2A, some with MEN2B, whereas others are associated with the development of familial medullary thyroid cancer only. Understanding this can help guide the management of people who are found to have the gene fault; in particular to decide the best timing for thyroid surgery and to consider what other risks they should be screened for.

What are the signs and symptoms of MEN2B?

Patients with MEN2B usually present at a young age. Most people with multiple MEN2B are characteristically tall and thin with long fingers and toes, and may have a similar appearance to people with Marfan’s syndrome. Doctors may suspect MEN2B if a young child or baby has growth or eating problems affecting development (known as ‘failure to thrive’). A dentist or doctor may suspect MEN2B if they detect mucosal neuromas of the lips or tongue. These can lead to lips getting a swollen appearance or irregularities around the tongue. Sometimes MEN2B presents as an uncommon cause of abdominal swelling, constipation and/or diarrhoea. This is due to benign tumours of nerves in the bowel gut called ganglioneuromas causing the bowel not to function properly. hese tumours in gut may present as early as during infancy or childhood and may be seen in 4 out of 10 patients with MEN2B syndrome.  

There are three types of hormone-secreting tumours that can develop in MEN2b:

1. Medullary cancer of the thyroid (MTC) – all patients with MEN2B will develop medullary thyroid cancer; as compared with MEN2A the MTC develops earlier and in a more aggressive form in MEN2B. MTC develops from cells in the thyroid that produce the hormone calcitonin. It may not cause any symptoms, or can cause a swelling in the thyroid gland (goitre). 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. Phaeochromocytoma – up to 50% of patients with MEN2B will 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).
    
3. Primary hyperparathyroidism – overactive parathyroid glands may be seen in MEN2A but are extremely rare in MEN2B. 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 MEN2B?

MEN2B is a very rare condition and is estimated to occur in approximately one in every 1–4 million people.

Is MEN2B inherited?

MEN2B is an inherited conditions 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. 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, MEN2B. Quite a significant proportion of MEN2B patients may not have a family history as the mutation can occur ‘de novo’ in an individual.

How is MEN2B diagnosed?

Genetic testing – there is a genetic test for the defective RET gene which is over 98% accurate. This test is offered to people who have the 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 MEN2B 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. Depending upon the underlying mutation, patients can be risk stratified 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 MEN2B, patients are advised to undergo a total thyroidectomy before the age of 1 year.

   Once the thyroid gland has been removed then patients undergo life-long 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. A thin needle can be used to sample cells from suspicious lumps in the thyroid and lymph nodes (fine needle aspiration), and these samples are sent to specialists to be looked at. If MTC is diagnosed then 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. Phaeochromocytoma – plasma metanephrines are accurate 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, CT or 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. 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 suppressed if blood calcium is high).

If a patient is found to have MEN2B, life-long 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 MEN2B 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 MEN2B, 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 MEN2B treated?

The exact treatment depends upon the type of tumours present:

1. Medullary thyroid cancer (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. 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 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. 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. These are usually started in hospital. Patients also need to be admitted for three days or so before the scheduled surgery to optimise the preparation for surgery. Extra intravenous fluids may also be given as part of the preoperative 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 extremely rare in MEN2B but is usually treated by surgical removal of the affected parathyroid glands. Usually an operation will involve removal of 3½ or all 4 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 lifelong 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 pregnancy as optimal maternal thyroid hormone replacement is crucial for fetal 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 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.

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 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. They can also damage kidney function.

Somatostatin analogue injections can encourage the formation of gallstones in the gall bladder, and 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 MEN2B?

The long-term outcome of MEN2B depends very much on the MTC component of the disease. MEN2B is associated with aggressive medullary thyroid cancer at an early age and patients may have cancer that has spread already at diagnosis.

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 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 MEN2B should be offered genetic tests to see if they also carry the defect 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 MEN2B?

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