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.
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.
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.
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.
Mucosal neuromas may occur in MEN2b and an itchy lichenoid eruption may occur in MEN2a 'cutaneous lichen amyloidosis'.
Megacolon and intestinal obstruction may occur in MEN2b due to intestinal autonomic ganglion dysfunction.
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.
Medullary thyroid cancer typically presents with local disease.
Ask specifically about difficulty breathing in certain positions, snoring, or noisy breathing, which might indicate incipient stridor.
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.
A new hoarse voice suggests vocal cord palsy from involvement of the recurrent laryngeal nerve.
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.
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.
This is an alarm symtom for malignancy.
Intermittent or severe hypertension in a young person demands investigation for possible phaeochromocytoma.
Although typically this occurs in acute attacks, some patients with phaeochromocytoma describe a more generalised increase in anxiety.
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.
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.
Phaeochromocytoma attacks tend to be of sudden onset, and stop suddenly, whereas anxiety attacks may build and tend to be triggered by circumstances.
Phaeochromocytoma attacks tend to start and stop abruptly. Epileptic seizures may be followed by a headache or exhaustion.
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.
Both these conditions may lead to increases in serum and urine catecholamines and their metabolites which may cause diagnostic confusion.
Abdominal pain may also be seen with phaeochromocytomas.
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.
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.
All of these symptoms may occur with severe hypercalcaemia of any cause, however, they may also raise the suspicion of underlying malignancy.