Multiple endocrine neoplasia type 1

This diagnosis is typified by hyperparathyroidism, pituitary tumours and pancreatic tumours, and may be confirmed by finding a mutation in the MENIN gene.

Document the family tree and personal history in detail

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.

Does the patient feel well or have they developed new non specific symptoms? 

Malaise, anaemia or any symptoms of hypercalcaemia may be indicators that a complication has developed and should prompt thorough screening.

Has the patient developed any gastrointestinal symptoms, anorexia or weight change? 

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.

Are they taking any prescribed or non prescribed medications? 

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.

Are there any symptoms suggestive of hypercalcaemia? 


Is there any history of excessive thirst, nocturia or other symptoms suggestive of renal colic? 

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.


Has the patient lost any weight, developed nausea or anorexia? 

All of these symptoms may occur with severe hypercalcaemia of any cause, however, they may also raise the suspicion of underlying malignancy.


Has the patient developed any other gastrointestinal symptoms? 

Abdominal pain may be due to dyspepsia, peptic ulcer disease, constipation, or pancreatitis, all of which more commonly occur in the presence of hypercalcaemia.


Have there been any bony symptoms: back pain or previous fractures suggestive of osteoporosis? 

Hyperparathyroidism leads to calcium loss from the skeleton and is a strong risk factor for osteoporosis.


Has there been any mood change? 

Tiredness, depression and low energy are all common though non-specific symptoms of hypercalcaemia.

Symptoms of pituitary disease


Are there features to suggest elevated prolactin: galactorrhoea, breast swelling, oligomenorrhoea, erectile dysfunction or loss of libido? 

This is the commonest pituitary tumour.


Are there any features of GH excess? 

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? 


Are there any features of cortisol excess? 

Has there been a change in their weight or body shape? 

Have they developed diabetes, hypertension, depression, osteoporosis, acne, hirsuitism, oligomenorrhoea or muscle weakness?


Has the patient noticed any visual symptoms? 

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.


Has the patient developed a new headache or neuralgia? 

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.


Has there been any change in menstrual cycle or new hot flushes? 

Oligomenorrhoea may occur with modest elevations of prolactin.

Amenorrhoea and hot flushes indicate loss of the gonadotropin release.


Does the patient feel well in themselves? Have they noticed loss of energy, fatigue, nausea, dizziness or weight loss? 

Vague symptoms such as these may indicate the development of hypopituitarism with ACTH or TSH deficiency.


Has there been any change in bowel habit? 

Constipation could indicate loss of thyroid function.

Symptoms suggestive of pancreatic or neuroendocrine tumours

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.

Insulinomas


Have there been any 'funny turns' suggestive of hypoglycaemia? 

Patients may complain of feeling intense hunger, followed by sweating, pallor, and anxiety then feeling dizzy, or frank loss of consciousness with hypoglycaemia.


What triggers lead to these attacks? What's the timing? 

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.


Have they gained weight? 

Typically patients gain weight due to eating frequent carbohydrates to prevent or treat hypoglycaemia.

Gastrinomas


Have they developed severe dyspepsia or peptic ulcers? 

Gastrin secretion by pancreatic tumours classically causes severe indigestion and Zollinger-Ellison syndrome with multiple peptic ulcers.


Has there been any other change in bowel habit? 

Diarrhoea and steatorrhoea may also occur with gastrinomas.

Glucagonomas


Have they developed new or worsening glucose intolerance? 

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.


Have they become anorexic, anaemic or lost weight? 

Weight loss is typical with glucagon secreting tumours.


Have they developed diarrhoea or other change in bowel habit? 

Diarrhoea may accompany most gastro-enteropancreatic tumours.


Have they developed a new rash in areas exposed to friction or around the mouth? 

Glucagonomas are classically associated with skin changes in areas exposed to friction: necrolytic migratory erythema, but may also cause glossitis.


Do they have a history of thromboembolic complications? 

Thrombolembolic disease is very commonly associated with glucagonomas.

Vasoactive intestinal peptide secreting tumours: VIPomas


Have they developed profuse, watery diarrhoea? 

Diarrhoea may occur with multiple pancreatic tumours including gastrinomas, but very high volume watery non steatorrhoea diarrhoea is suggestive of a VIP secreting tumour.


Have they developed proximal myopathy or generalised weakness? 

Diarrhoea and hypochlorhydria may lead to dehydration, weakness and hypokalaemic acidosis.


Have they developed new or worsening glucose intolerance? 

This may occur with VIP secretion, but is also associated with glucagon or somatostatin secreting tumours.


Have they developed flushing? 

Typical 'carcinoid' flushing may occur with VIP secreting tumours.

Somatostatinoma


Are there any symptoms suggestive of gall stones? 

Somatostatin secreting tumours are very rare neuro-endocrine tumours, 50% of which occur in the pancreas which classically present with gall stones.


Have they developed new or worsening glucose intolerance? 

This occurs with somatostatinomas as well as with glucagon or VIP secreting tumours.


Has there been any change in bowel habit? 

Diarrhoea and steatorrhoea also occur with somatostatinomas.

Symptoms of other neuro-endocrine tumours


Neuro-endocrine or carcinoid tumours may also occur in MEN1 at other sites, for example the small or large bowel, bronchial tree or thymus

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.


Does the patient complain of flushing episodes? 

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.


Does the patient have diarrhoea, abdominal pain or other gastrointestinal symptoms? 

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.


Does the patient complain of episodic wheeze or other cardiac or respiratory symptoms? 

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.

Symptoms of other tumours


Adrenocortical tumours are also associated with MEN1

These will classically present with symptoms of glucocorticoid excess, or with an adrenal mass on imaging.


Dermatological, gonadal and neurological tumours may also be associated with MEN1

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.

Symptoms suggestive of catecholamine excess


Have they ever been found to have high blood pressure, or complain of anxiety attacks or collapses? 

Phaeochromocytoma and paraganglioma are commonly associated with MEN2 though have also been described with MEN1.