Multiple endocrine neoplasia type 2

MEN2 or Sipple's syndrome is caused by the ret oncogene and has three forms. The diagnosis usually refers to MEN2a, comprising medullary thyroid cancer (MTC), phaeochromocytoma and parathyroid tumours. MEN2b comprises MTC, phaeochromocytoma, Marfanoid habitus and mucosal ganglionneuromatosis. Isolated familial medullary thyroid cancer is also caused by ret mutations.

Baseline investigations - all patients

Full blood count

Useful indicator of general health and underlying disease.

Urea and electrolytes

Hypercalcaemia may cause dehydration and acute renal failure.

Liver function test

Useful indicator of general health and underlying disease.

Liver function should be tested at baseline before starting medical treatments.

Bone profile

This should be tested annually to screen for parathyroid disease.

Parathyroid hormone

This should be tested at baseline and then repeated only if calcium rises in MEN2a.

Fasting glucose

Hypoglycaemia may mimic the clinical features of a phaeochromocytoma.

Calcitonin

This is mandatory due to the high penetrance of medullary cell carcinoma with all forms of MEN2.

Chest radiograph

This should be performed at baseline and subsequently every three years.

Ultrasound neck

This should be performed at baseline as a screen for medullary cell carcinoma even in patients who have undergone prophylactic thyroidectomy, and to evaluate thyroid and parathyroid anatomy.

This, and further neck imaging, will need to be repeated when calcitonin rises or when clinically indicated.

2x24hr urinary metanephrines

Urinary metanephrines are the most sensitive and specific, widely available screen for phaeochromocytoma.

All patients with strongly positive results (>3x upper limit of normal) should be considered as having a phaeochromocytoma requiring immediate treatment and investigation.

Patients with results between one to three times the upper limit of normal require further assessment with a serum metanephrine in the first instance. False positives may be found within this range, for example from interfering medication or obstructive sleep apnoea.

Patients with normal results should be reassured as false negatives are very rare.

CT adrenals

This should be performed at baseline as a screen for adrenal disease and for future comparison. It should then be repeated every three years.

Further investigations - selected cases only

Baseline pituitary function

Prolactin, thyroid stimulating hormone, free thyroxine, 9am cortisol, growth hormone, insulin like growth factor-I, luteinising hormone, follicle stimulating hormone, estradiol/testosterone, and sex hormone binding globulin should be documented at baseline only.

Pituitary tumours are very rarely associated with MEN2 (frequently occurring in MEN1) and so this should not be repeated unless specifically indicated.

Electrocardiogram

ECG should be performed in all patients at baseline.

Discuss genetic testing

Genetic testing and family screening must be discussed and referral to a clinical geneticist offered to all patients.

Pentagastrin test

This should be considered if serum calcitonin and thyroid examination and ultrasound scan are all normal in a subject from an MEN2 family. This may aid decision making on timing of surgery, and may also be useful to confirm cure post operatively.

Plasma metanephrines

Serum metanephrines are usually taken in a patient after 15 minutes resting recumbent. It is highly sensitive and specific for phaeochromocytoma and is usually performed to confirm the diagnosis after a positive or borderline urinary collection.

Meta-iodobenzylguianidine scan

Phaeochromocytomas typically take up meta-iodobenzylguianidine (MIBG), and this scan is usually performed routinely prior to surgery.

MIBG scanning is also helpful to locate extra-adrenal disease and to determine whether there are multiple lesions.

Echocardiogram

This is frequently indicated in the assessment of a patient with a confirmed phaeochromocytoma to aid cardiac assessment.

Consider further cross sectional imaging if indicated

If the MIBG scan suggests increased uptake in extra-adrenal regions these should be imaged appropriately after discussion with a radiologist.