This diagnosis is typified by hyperparathyroidism, pituitary tumours and pancreatic tumours, and may be confirmed by finding a mutation in the MENIN gene.
A family history may be diagnostic or suggestive of MEN1 and should be as extensive as possible, always including all second degree relatives.
Nearly all affected individuals will have parathyroid disease with hypercalcaemia, although asymptomatic isolated familial hypercalcaemia should be investigated for possible familial hypocalciuric hypercalcaemia.
Familial hypercalcaemia may also occur in MEN2a, so seek a history of thyroid cancer and phaeochromocytoma.
The penetrance of other clinical features varies.
Malaise, anaemia or any symptoms of hypercalcaemia may be indicators that a complication has developed and should prompt thorough screening.
Abdominal pain may be due to dyspepsia, peptic ulcer disease, constipation, or pancreatitis, all of which more commonly occur in the presence of hypercalcaemia, as does nausea and anorexia.
Severe dyspepsia, resistant peptic ulcer disease and diarrhoea and steatorrhoea are frequently seen with gastrinomas.
Watery diarrhoea is typical of a vasoactive intestinal peptide (VIPoma) secreting tumour.
Weight gain typically occurs with insulinomas, but weight loss is also an alarm symptom for pancreatic and other malignancies, and demands thorough investigation.
Multiple indigestion remedies contain calcium carbonate, and dietary supplements may also contain calcium and vitamin D which may lead to elevations in serum calcium.
Proton pump inhibitors need to be stopped for at least two weeks, and H2 (histamine 2 receptor) antagonists stopped for at least three days prior to testing serum gut levels in screening for pancreatic disease.
Multiple medications interfere with the measurement of serum steroid hormone levels, for example inhalers and topical preparations contain steroids and estrogen treatment causes an elevation of cortisol binding globulin and makes serum levels difficult to interpret. Multiple medications also interfere with prolactin release.
Long standing hypercalcaemia leads to a failure of urinary concentrating capacity - nephrogenic diabetes insipidus.
The commonest manifestation of this is increased thirst, followed by polyuria and nocturia.
Increased urinary calcium loss also predisposes to renal stone formation and hence renal colic.
All of these symptoms may occur with severe hypercalcaemia of any cause, however, they may also raise the suspicion of underlying malignancy.
Abdominal pain may be due to dyspepsia, peptic ulcer disease, constipation, or pancreatitis, all of which more commonly occur in the presence of hypercalcaemia.
Hyperparathyroidism leads to calcium loss from the skeleton and is a strong risk factor for osteoporosis.
Tiredness, depression and low energy are all common though non-specific symptoms of hypercalcaemia.
This is the commonest pituitary tumour.
Has the patient or their family noted any change in their facial appearance? Has their voice or mouth, hands or feet changed? Do they complain of increased sweating, or new snoring?
Has there been a change in their weight or body shape?
Have they developed diabetes, hypertension, depression, osteoporosis, acne, hirsuitism, oligomenorrhoea or muscle weakness?
It is worth specifically asking whether patients drive and, if so, whether they have had trouble noticing street signs on either side of the road as this may be the first instance in which field loss is noticed.
Visual field loss, for example homonymous hemianopia, indicates chiasmal impingement.
Assess for red flag symptoms: headaches present on waking and worse on coughing or leaning forward are more suggestive of increased intracranial pressure.
Headaches or lancing pain across one section of the head or face only are more suggestive of cranial nerve involvement particularly with disease in the cavernous sinus.
Oligomenorrhoea may occur with modest elevations of prolactin.
Amenorrhoea and hot flushes indicate loss of the gonadotropin release.
Vague symptoms such as these may indicate the development of hypopituitarism with ACTH or TSH deficiency.
Constipation could indicate loss of thyroid function.
Insulin and gastrin are the most common gut hormones produced by well differentiated endocrine tumours of the gastro-enteropancreatic tract.
Other clinically non functioning neuro-endocrine tumours may present with mass effects only.
Patients may complain of feeling intense hunger, followed by sweating, pallor, and anxiety then feeling dizzy, or frank loss of consciousness with hypoglycaemia.
Hypoglycaemic symptoms may occur at any time, but tend to be when fasting, and patients may have realised that they can be prevented by frequent consumption of carbohydrates.
Severe attacks in which anxiety is a major feature unrelated to food intake should raise the possibility of a phaeochromocytoma, not usually associated with MEN1.
Typically patients gain weight due to eating frequent carbohydrates to prevent or treat hypoglycaemia.
Gastrin secretion by pancreatic tumours classically causes severe indigestion and Zollinger-Ellison syndrome with multiple peptic ulcers.
Diarrhoea and steatorrhoea may also occur with gastrinomas.
Glucagon secreting tumours may be asymptomatic, however, they may cause glucose intolerance or diabetes mellitus, which may also be associated with somatostatin or VIP secreting tumours.
Weight loss is typical with glucagon secreting tumours.
Diarrhoea may accompany most gastro-enteropancreatic tumours.
Glucagonomas are classically associated with skin changes in areas exposed to friction: necrolytic migratory erythema, but may also cause glossitis.
Thrombolembolic disease is very commonly associated with glucagonomas.
Diarrhoea may occur with multiple pancreatic tumours including gastrinomas, but very high volume watery non steatorrhoea diarrhoea is suggestive of a VIP secreting tumour.
Diarrhoea and hypochlorhydria may lead to dehydration, weakness and hypokalaemic acidosis.
This may occur with VIP secretion, but is also associated with glucagon or somatostatin secreting tumours.
Typical 'carcinoid' flushing may occur with VIP secreting tumours.
Somatostatin secreting tumours are very rare neuro-endocrine tumours, 50% of which occur in the pancreas which classically present with gall stones.
This occurs with somatostatinomas as well as with glucagon or VIP secreting tumours.
Diarrhoea and steatorrhoea also occur with somatostatinomas.
Symptoms will depend on tumour location as they usually present with mass effects.
Other symptoms will depend on which, if any, peptides are secreted, for example ACTH, serotonin or gut peptides.
Dry flushes in which the patient feels a rush of heat through their body, and turns red, but does not sweat are typical in carcinoid syndrome. Menopausal flushes tend to be associated with generalised sweating.
Other neuro-endocrine tumours may also secrete peptides associated with diarrhoea.
Small bowel neuro-endocrine tumours may also be associated with a desmoplastic reaction in the mesentery, which may cause sub acute bowel obstruction or other changes in bowel habit.
Carcinoid flushes may be associated with acute bronchospasm and wheeze.
Neuro-endocrine tumours may lead to valve thickening and symptoms suggestive of right heart failure.
Thrombolembolic disease is very commonly associated with glucagonomas.
Non endocrine tumours may also be associated with MEN1 syndrome. These include facial angiofibromas, collagenomas and lipomas, as well as gonadal tumours, meningiomas, ependymonas and leiomyomas.
Phaeochromocytoma and paraganglioma are commonly associated with MEN2 though have also been described with MEN1.