Sipple’s syndrome; Sipple syndrome; MEN 2a
Multiple endocrine neoplasia type 2A (MEN2A) is a rare inherited disorder resulting in medullary thyroid cancer, phaeochromocytoma and overactive parathyroid glands, characterised by a high calcium level.
MEN2A 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 hereditary thyroid-cancer/'>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.
There are three types of hormone-secreting tumours that can develop in MEN2A:
MEN2A is a rare condition occurring in approximately 1 in 40,000 people.
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.
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 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:
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 is found to have MEN2A, lifelong surveillance is recommended. Patients should be cared for in a specialist centre under the guidance of an experiencedmultidisciplinary 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.
The exact treatment depends upon the type of tumours present:
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 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 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.
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 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.
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 extensively at diagnosis. 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 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 MEN2A 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.
Last reviewed: Feb 2018