Key Facts

Multiple Endocrine Neoplasia syndromes are autosomal dominant inherited conditions predisposing to tumours in specific endocrine organs. Early detection through genetic screening and regular surveillance is critical.

Epidemiology

• MEN1: prevalence ~1 in 30,000; equal sex distribution
• MEN2A: prevalence ~1 in 35,000
• MEN2B: prevalence ~1 in 1,000,000 (rarest but most aggressive)
• All types show near-complete penetrance by age 50

Aetiology

• MEN1: loss-of-function mutation in menin tumour suppressor gene (chromosome 11q13)
• MEN2A and MEN2B: gain-of-function mutations in RET proto-oncogene (chromosome 10q11)
• Specific RET codon mutations correlate with aggressiveness and phenotype
• De novo mutations: ~50% of MEN2B, ~10% of MEN2A, ~10% of MEN1

Pathophysiology

• MEN1: menin acts as tumour suppressor; loss of function leads to unregulated cell proliferation in parathyroids, pituitary, and pancreatic islets
• MEN2: RET constitutive activation of tyrosine kinase receptor leads to uncontrolled growth of thyroid C cells, adrenal medulla, and parathyroid glands
• Two-hit hypothesis applies to MEN1; RET mutations in MEN2 are activating (gain-of-function)

MEN1 (Wermer Syndrome)

• Primary hyperparathyroidism (90-100%): often first manifestation, presents age 20-25; hypercalcaemia, renal stones, bone disease
• Pancreatic neuroendocrine tumours (30-80%): gastrinoma (Zollinger-Ellison syndrome – peptic ulcers, diarrhoea), insulinoma (hypoglycaemia), glucagonoma, VIPoma
• Pituitary adenoma (30-40%): prolactinoma most common; also GH-secreting (acromegaly), ACTH-secreting (Cushing)

MEN2A (Sipple Syndrome)

• Medullary thyroid carcinoma (>95%): often bilateral, presents age 5-25
• Phaeochromocytoma (50%): often bilateral; episodic hypertension, headache, sweating, palpitations
• Primary hyperparathyroidism (20-30%): usually mild
• Associated with Hirschsprung disease in some families

MEN2B

• Medullary thyroid carcinoma (>95%): earliest onset and most aggressive
• Phaeochromocytoma (50%)
• Mucosal neuromas: lips, tongue, eyelids (pathognomonic)
• Marfanoid habitus: tall, thin, long limbs
• Intestinal ganglioneuromatosis: constipation, megacolon

Red Flags

• Recurrent peptic ulcers resistant to PPI → consider Zollinger-Ellison (MEN1)
• Thyroid nodule + family history of thyroid cancer → screen for MEN2
• Hypertensive crisis during surgery → undiagnosed phaeochromocytoma in MEN2

Bloods

• Calcium, PTH: hyperparathyroidism screening
• Calcitonin: MTC marker (MEN2)
• Plasma/24h urine metanephrines: phaeochromocytoma screening
• Fasting gastrin: Zollinger-Ellison syndrome (MEN1)
• Fasting glucose, insulin, C-peptide: insulinoma (MEN1)
• Prolactin, IGF-1: pituitary adenoma screening (MEN1)
• Chromogranin A: general neuroendocrine tumour marker

Imaging

• CT/MRI abdomen: pancreatic tumours (MEN1)
• MRI pituitary: pituitary adenoma (MEN1)
• Neck ultrasound: thyroid nodules (MEN2), parathyroid adenoma
• CT/MRI adrenals: phaeochromocytoma
• MIBG scan or DOTATATE PET: functional adrenal/neuroendocrine imaging

Special Tests

• Genetic testing: RET proto-oncogene (MEN2), MEN1 gene (MEN1) – essential for family screening
• Pentagastrin/calcium stimulation test: MTC screening (less used now with improved calcitonin assays)
• Endoscopic ultrasound (EUS): pancreatic tumour detection in MEN1

MEN1

• Hyperparathyroidism: subtotal (3.5 gland) parathyroidectomy when symptomatic
• Gastrinoma: high-dose PPIs (omeprazole 40-120mg); surgical resection if localised
• Insulinoma: surgical enucleation
• Pituitary adenoma: treat as sporadic (transsphenoidal surgery, dopamine agonists for prolactinoma)
• Regular surveillance with annual biochemistry and 3-5 yearly imaging

MEN2A

• Prophylactic thyroidectomy: timing based on RET mutation risk category
  • Highest risk (codon 918): within first 6 months of life
  • High risk (codons 634, 883): by age 5
  • Moderate risk: when calcitonin rises or by age 10
• Phaeochromocytoma: laparoscopic adrenalectomy; alpha-blockade (phenoxybenzamine 10-20mg BD) before surgery
• Hyperparathyroidism: parathyroidectomy only if symptomatic
• Lifelong levothyroxine and calcitonin monitoring post-thyroidectomy

MEN2B

• Prophylactic thyroidectomy within first 6 months of life (or at diagnosis)
• Manage phaeochromocytoma as for MEN2A

Referral Criteria

• All suspected MEN patients → specialist endocrine centre
• Genetic counselling for all affected families
• Pre-symptomatic genetic testing for at-risk relatives

• MEN1: life expectancy reduced by ~10 years; pancreatic NET and thymic carcinoid are leading causes of death
• MEN2A: excellent prognosis with prophylactic thyroidectomy; 10-year survival >95% if MTC detected early
• MEN2B: worst prognosis; MTC often metastatic at diagnosis if thyroidectomy delayed
• Phaeochromocytoma is life-threatening if unrecognised during surgery
• Regular surveillance allows early detection and significantly improves outcomes
• Genetic screening of family members is life-saving

MEN Syndrome Comparison

RET Mutation Risk Categories for Thyroidectomy Timing