Multiple endocrine neoplasia type 2b

Multiple endocrine neoplasia type 2b is a rare inherited disease causing the development of tumours in the thyroid, adrenal and parathyroid glands, and mucosal tumours.

Alternative names for multiple endocrine neoplasia type 2b

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

What is multiple endocrine neoplasia type 2b?

Multiple endocrine neoplasia 2b is a rare inherited disorder resulting in medullary thyroid cancer, phaeochromocytoma and overactive parathyroid glands resulting in a high calcium. In addition, patients with MEN2b can also develop characteristic tumours (neuromas/ganglioneuromas) of the lips, tongue and bowels.

What causes multiple endocrine neoplasia type 2b?

MEN2b 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 MEN2b. This can help in diagnosis and also help in management of people who are found to have the MEN2b gene fault.

What are the signs and symptoms of multiple endocrine neoplasia type 2b?

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 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 a person has characteristic tumours called mucosal neuromas in the lips or tongue. Sometimes MEN2b shows itself 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.  

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

  1. Medullary cancer of the thyroid (MTC) – all patients with multiple endocrine neoplasia type 2b will develop medullary thyroid cancer, often by the age of 1, and it is often a very aggressive form. 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 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.
  2. Phaeochromocytoma – one in two patients with MEN2b 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.
  3. Parathyroid tumours – about 40% of patients with MEN2a will develop overactive parathyroid glands. Rarely, patients with multiple endocrine neoplasia type 2b 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 2b?

MEN2a is a very rare condition occurring in approximately 1 in 40, 000 people. MEN2b is rarer than MEN2a, and is estimated to occur in approximately one person in every 1–4 million people.

Is multiple endocrine neoplasia type 2b 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, that is there is a 50% (1 in 2) chance that a child will inherit the abnormal gene and therefore develop features of MEN2. About 50% of patients with MEN2b do not have a family history, and are the first people to have the faulty gene in their family. MEN2b is a more aggressive type of MEN2 and is associated with different RET gene changes than MEN2a.

How is multiple endocrine neoplasia type 2b 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 MEN2b and relatives of people with known MEN2b (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:

  1. Medullary cancer of the thyroid – once a diagnosis of MEN2b is made then a total thyroidectomy is recommended by the age of 1 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.

    Once the thyroid gland has been removed then patients undergo lifelong surveillance, which includes a fasting calcitonin blood test. This has to be sent to the lab on ice and frozen in the lab rapidly and so has to be done in a hospital. Patients also need lifelong thyroxine replacement.

    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 glands (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. Twenty-four hour urine collection for metanephrines is an alternative – a special bottle with acid is needed for this test. If the blood or urine tests are abnormal then 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.
  3. 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 MEN2b then 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 MEN2b wishes to start a family then 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 MEN2b and to discuss the appropriate age to consider genetic testing.

How is multiple endocrine neoplasia type 2b treated?

The exact treatment depends upon the type of tumours present:

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.

  1. Medullary thyroid cancer is managed by surgical removal of the thyroid gland and lymph nodes in the neck under general anaesthesia, if possible. 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. 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.
  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 hormones produced from the tumours are blocked, and that blood pressure is well controlled. This involves a minimum of two 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 fluid may be given as part of the preoperative preparation. It is crucial to prepare patients properly for surgery to remove a phaeochromocytoma but in centres that mange these patients regularly this is a safe operation to undergo.  
  3. Parathyroid tumours are usually treated by surgical removal of the affected parathyroid glands. Usually 3½ or 4 parathyroid glands are removed and patients may then require 1 alphacalcidol after 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 to 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, which are normally produced by the adrenal glands (see the article on Addison’s disease, for more information).

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 increased 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 2b?

The long-term outcome of MEN2b depends very much on how much the medullary thyroid cancer has spread. 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 phaeochromocytomas are 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 carry the defect in the RET gene. If the defect is detected, preventative thyroidectomy before the age of 2, 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 anyone undergoing the test understands the implications for them and their families. 

Last reviewed: Jan 2015