Sipple’s syndrome; Sipple syndrome; MEN 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 thyroid-cancer/'>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.
There are three types of hormone-secreting tumours that can develop in multiple endocrine neoplasia type 2a:
Multiple endocrine neoplasia type 2a is a rare condition occurring in approximately 1 in 40,000 people.
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.
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 and relatives of people with known multiple endocrine neoplasia type 2 (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:
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.
The exact treatment depends upon the type of tumours present:
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.
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.
Last reviewed: Jan 2015