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.

Due to the association with medullary thyroid cancer, surveillance should be started in early childhood

Recommendations suggest age five is an appropriate age to start screening in patients testing positive for MEN2a.

Recommendations for screening and for prophylactic thyroidectomy vary in MEN2b, but should be as early as practical, due to the early and aggressive nature of thyroid cancers in this group.

Document the family tree and personal history in detail

A thorough family history, including all second degree relatives, should be documented at diagnosis and rechecked at every review to facilitate screening.

A family history may be diagnostic or suggestive of familial medullary thyroid cancer, MEN2a or MEN2b.

Are there any alarm symptoms that might suggest underlying malignancy or phaeochromocytoma? 

A change in bowel habit, anaemia or weight loss should alert the clinician to possible malignancy and warrants immediate investigation.

Any symptoms of catecholamine excess always demand immediate investigation.

Do they have any skin or oral changes? 

Mucosal neuromas may occur in MEN2b and an itchy lichenoid eruption may occur in MEN2a 'cutaneous lichen amyloidosis'.

Have they had episodes of bowel obstruction? 

Megacolon and intestinal obstruction may occur in MEN2b due to intestinal autonomic ganglion dysfunction.

Are they taking any prescribed or non prescribed medications? 

Almost all antidepressants may lead to increases in serum and urine catecholamines and their metabolites which may cause diagnostic confusion.

Multiple indigestion remedies lead to elevations in serum calcium.

Supplements may include calcium and vitamin D.

Symptoms suggestive of medullary cell thyroid cancer

Have they noted any new neck swelling or lymph nodes? 

Medullary thyroid cancer typically presents with local disease.

Are there any obstructive respiratory symptoms? 

Ask specifically about difficulty breathing in certain positions, snoring, or noisy breathing, which might indicate incipient stridor.

Are there any other obstructive symptoms? 

The patient may have difficulty or discomfort when swallowing, or need to drink during eating to help food pass at early stages of oesophageal impingement.

Has the patient noticed a change in their voice? 

A new hoarse voice suggests vocal cord palsy from involvement of the recurrent laryngeal nerve.

Has the patient developed any diarrhoea or other gastrointestinal symptoms? 

Diarrhoea may be the presenting symptom of medullary thyroid cancer with high calcitonin levels and is a marker of poor prognosis.

Intestinal obstruction, intestinal ganglioneuromatosis and megacolon may occur in MEN2b.

Abdominal pain may also be due to dyspepsia, peptic ulcer disease, constipation, or pancreatitis secondary to hypercalcaemia in MEN2a, or occur with phaeochromocytoma in MEN2a or MEN2b.

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 of carcinoid syndrome and may occur with high calcitonin levels.

In contrast, menopausal flushes tend to be associated with generalised sweating.

Have they lost weight? 

This is an alarm symtom for malignancy.

Symptoms suggestive of catecholamine excess

Have they ever been found to have high blood pressure? 

Intermittent or severe hypertension in a young person demands investigation for possible phaeochromocytoma.

Do they complain of generalised anxiety? 

Although typically this occurs in acute attacks, some patients with phaeochromocytoma describe a more generalised increase in anxiety.

Do they suffer with 'panic attacks' or other intermittent symptoms? 

Ask the patient to describe exactly what happens.

Typically, people with a phaeochromocytoma will describe episodes of sudden intense fear, with palpitations, anxiety, looking pale and clammy and sometimes collapsing.

Are there any triggers to attacks? 

Have any precipitants been noted, for example if they occur after fasting they may be due to hypoglycaemia, postural attacks may be due to orthostatic hypotension of any cause and sleep deprivation may trigger epileptiform attacks.

Phaeochromocytoma attacks tend to occur at any time, although specific triggers may provide a clue to the anatomical location of an extra-adrenal lesion. For example, attacks may follow micturition with bladder paragangliomas.

Is the onset and end of an attack sudden? 

Phaeochromocytoma attacks tend to be of sudden onset, and stop suddenly, whereas anxiety attacks may build and tend to be triggered by circumstances.

What happens at the end of an attack? 

Phaeochromocytoma attacks tend to start and stop abruptly. Epileptic seizures may be followed by a headache or exhaustion.

Do they look pale or flushed during an attack? 

Typically, the patient will look pale, and may be clammy. Flushing or redness implies an alternative cause, for example menopausal flushing, medullary carcinoma or carcinoid syndrome.

Is there a history suggestive of obstructive sleep apnoea or depression? 

Both these conditions may lead to increases in serum and urine catecholamines and their metabolites which may cause diagnostic confusion.

Has the patient developed any abdominal pain? 

Abdominal pain may also be seen with phaeochromocytomas.

Do they have symptoms suggestive of hypercalcaemia in MEN2a? 

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. 

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.

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.