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

Type 1 MEN

MEN 1 often presents in the 3^rd-5^th 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:

• Flushing
• Diarrhoea
• Palpitations
• Hypotension
• Right sided heart failure

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.

• 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.
• Marfan-like signs due to CT defects (abnormal fibrillin-1, which is a ligand for TGF-beta).

Genetics of MEN 2

• Mutation in the Ret proto-oncogene, a receptor tyrosine kinase, which is located on chromosome 10.
• The Ret gene acts as a tumour initiator. It plays a role in central and peripheral nerve development and function.
• The mutant present in MEN 2 is constitutively active without a ligand, resulting in uncontrolled tumour initiation.
• Tests for ret mutations are revolutionising MEN2 treatment by enabling a prophylactic thyroidectomy to be done before neoplasia occurs, usually before 3 years of age.

Remember: most medullary thyroid carcinomas and phaeochromocytomas result from spontaneous new mutations, e.g. of ‘ret’ – only ~10% are due to MEN.

Management

• MEN is the most treatable form of pancreatic neoplasia, and a treatable cause of hypercalcaemia – so look out for it!
• Management involves surgical excision of the tumours wherever possible, along with symptomatic treatment as outlined above, relating to the specific endocrine glands affected.
• Due to the autosomal dominant inheritance of the disease, family members should be screened by measurement of serum calcium in MEN 1, and by genetic testing for Ret mutations in MEN 2.
• Patients known to have MEN require constant surveillance to check for their acquisition of any additional features of the syndrome, which may indicate their development of an additional tumour. This may happen many years after their initial presentation and diagnosis.

References

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