Multiple Endocrine Neoplasia (MEN)

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:

  1. Parathyroid glands
  2. Pancreatic islets
  3. 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.