Introduction
MEN = the occurrence of several distinct syndromes featuring functional tumours of multiple endocrine glands. In some cases, tumours are malignant; in others, they are benign.
MEN
- Tumours arising in >1 endocrine gland.
- Affected glands have similar embryological origin.
- Commonly familial – autosomal dominant inheritance.
Summary of MEN 1, 2a and 2b Tumours
Organ |
Frequency |
Clinical Manifestation |
Type 1 |
Functioning adenomas in:
Parathyroid
Enteropancreatic
Pituitary
Other:
Foregut carcinoids
Adrenal cortex adenomas
Cutaneous tumours |
95%
70%
50%
10%
25%
60% |
Hypercalcaemia
Gastrinoma, insulinoma, glucagonoma, VIPoma
Prolactinoma, acromegaly, Cushing’s
Thymic, bronchial, gastric
Non-functional tumours
Angiofibromas, collagenomas, lipomas |
Type 2a |
Medullary thyroid carcinoma
Adrenal medulla
Parathyroid hyperplasia |
100%
50%
50% |
Thyroid mass, diarrhoea, rasied plasma calcitonin, aggression
Phaeochromocytoma
Hypercalcaemia |
Type 2b |
2a without parathyroid hyperplasia plus:
Mucosal neuromas
|
|
Marphinoid appearance |
Type 1 MEN
MEN 1 often presents in the 3rd-5th decade.
- 95% of patients develop parathyroid hyperplasia/ adenoma à hypercalcaemia. Treatment is with parathyroidectomy to remove 3.5 of their 4 parathyroid glands.
- 70% of patients develop pancreatic tumours à gastrinoma, insulinoma, glucagonoma, VIPoma. Glucagonoma can be accompanied by ‘glucagon syndrome’ which comprises of a migrating rash, glossitis, cheilitis, anaemia, weight loss, high plasma glucagon and high plasma glucose. Treatment of pancreatic tumours is with PPIs.
- 40-60% of patients develop anterior pituitary tumours à prolactinoma or familial acromegaly. Treat prolactinoma with dopamine agonists to inhibit secretion (DA stimulates secretion from the pituitary).
There are rarely also tumours of:
- Carcinoid tumours of the thymus, lung or stomach.
- Adrenal cortex (commonly benign).
- Cutaneous tumours of the skin.
~40% of patients develop carcinoid syndrome, which presents with:
This is due to extensive secretion of serotonin, prostaglandins, kinins, gastrin etc.
Diagnosis of MEN 1 is on the basis of family HX and development of tumours in 2 of:
- Parathyroid glands
- Pancreatic islets
- Anterior pituitary gland
Genetic basis for MEN 1
- Mutations in the MEN gene on chromosome 11, which codes for menin, a nuclear tumour suppressor protein which regulates transcription through its interference with TFs and thereby stabilises the genome. It also assists in cell differentiation and proliferation and interacts with TFF-beta signalling.
- >1300 different mutations have been identified in affected families.
- All mutations associated with MEN 1 lead to loss of function of menin.
How can a loss of function mutation have autosomal dominant inheritance?
- A somatic mutation occurs in the normal allele, so now 2 defective alleles (i.e. inherited one that was already defective).
- Inactivation of the normal allele (2 copies of the gene on 2 chromosomes but one is inactivated and one is defective).
Type 2 MEN
2a
MEN 2a accounts for ~95% of MEN 2.
- 100% of patients have medullary thyroid carcinoma à aggression in patients. Early thyroidectomy required.
- ~50% of patients have a bilateral adrenal phaechromocytoma, which is usually benign.
- ~50% of patients have parathyroid hyperplasia (but <20% have hypercalcaemia!)
MEN Type 2b
MEN 2b accounts for ~5% of MEN 2.
- 100% of patients have medullary thyroid carcinoma.
- ~50% of patients have a bilateral adrenal phaechromocytoma, which is usually benign.
- There is no parathyroid hyperplasia in MEN 2b.
- Mucosal neuromas à GI symptoms, muscle hypotonia, chronic constipation due to hyperplasia of autonomic ganglia in the intestinal wall. Mucosal neuromas are visible as ‘bumps’ on the lips, cheeks, tongue, glottis, eyelids and visible corneal nerves, so patients may present with these.
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