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