MEN and other Familial Endocrine Disease

DEFINITION

MEN 1 = Multiple Endocrine Neoplasia I
MEN 2 = Multiple Endocroine Neoplasia II

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EPIDEMIOLOGY

See below

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AETIOLOGY

See below

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BIOLOGICAL BEHAVIOUR

MEN 1
Aetiology
Mutation of the MEN1 tumour suppressor gene (Cr11q13)
[Tumour suppressor gene implies loss of function].
MEN1 produces Menin, which suppresses transcription.
Genetics
Autosomal dominant
Highly penetrant; variable expression
90% inherited; 10% sporadic
Manifestations
Triple P tumours:
- parathyroid: 90% by age 50; commonly 4-gland hyperplasia
- pituitary (anterior): 40%; commonly prolactinomas
- pancreatic (endocrine): 80%; multiple adenomas, islet cell hyperplasia, often gastrinomas (ZES); also can be insulinomas, VIPomas, PPIomas, etc.
And more rarely Triple C tumours:
- carcinoids (foregut): 4%
- cortical (adrenocortical) (hyperplasia, adenoma, carcinoma): at least 5%
- cutaneous lipomas: 1%

MEN 2
Aetiology
RET proto-oncogene (Cr10)
- this encodes a receptor tyrosine kinase

 MEN 2A
MPH tumours
- medullary thyroid Ca (90%)
- phaeochromocytoma (50%)
- hyperparathyroidism (30%); commonly 4-gland hyperplasia.
- Hirschprungs association
- Lichen planus amyloidosis

MEN 2B
MMP tumours

Rarest, most virulent
50% inherited, 50% de-novo
- average dx by age 10
Distinguished by developmental defects and absence of hyperparathyroidism; all pts have neurogangliomas.
- medullary thyroid Ca (most)
- phaeochromocytoma (50%)
- no parathyroid lesions
- skin lesions: neuromas, Cafe-au-lait
- musculoskeletal abnormalities: marfinoid, pes cavas, pes excavatum
- other: mucosal neuromas of oral cavity and conjunctiva, ganglioneuromatosis in GI tract, medullated corneal nerve fibres

--> prophylactic thyroidectomy for gene carriers (at 2y).


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MANIFESTATIONS

As per above

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INVESTIGATIONS

As per above
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MANAGEMENT

Screening

Men1

Gene analysis offered
Test all with isolated gastrinomas (25% have MEN1)
Lifelong surveillance
- biochem: annual PTH and Ca
- markers: insulin, gastrin, glucose, VIP, pancreatic peptide, glucagon, somatostatin
- pituitary: annual prolactin and IGF1
- annual chromogrannin A
- radiological: 3-5yearly MRI of pancreas and foregut

Men2
Risk stratify by position of mutation on RET gene
- Risk level 1 = MEN2B and some MEN2A
--> remove thyroid at 6m
- Risk level 2 and 3 = certain MEN RET mutations
--> 2 = remove thyroid <5y
--> 3 = not needed before 10y old.
Post op surveillance with calcitonin
- if high, MRI or PET
Screen all tumours


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REFERENCES