Multiple endocrine neoplasia

At a glance

• Autosomal dominant syndromes with tumours in two or more endocrine glands. Each child of a carrier has a 50% chance of inheriting the variant.
• MEN1: parathyroid, duodenopancreatic neuroendocrine tumours (NETs) and anterior pituitary. Gene: MEN1 (menin), a tumour suppressor.
• MEN2: medullary thyroid cancer (MTC) in nearly all, plus phaeochromocytoma, and hyperparathyroidism in MEN2A. Gene: RET, an activating proto-oncogene.
• MEN1 care is surveillance and selective surgery. MEN2 care is prophylactic thyroidectomy timed by codon.
• Before any operation in MEN2 or new MTC, exclude phaeochromocytoma.
• The 2025 international MEN1 guideline (Brandi, Lancet Diabetes Endocrinol, 55 recommendations) replaced the 2012 Endocrine Society surveillance schedule. eviQ's Australian protocol now follows it. For MTC, the ATA 2015 guideline is still the current ATA version.

Classification

Syndrome	Gene	Main tumours	Other features
MEN1	MEN1 (loss of function)	Parathyroid (95%), duodenopancreatic NET (30 to 70%, over 80% by age 80), pituitary (30 to 40%)	Thymic and bronchial NETs, adrenal cortical nodules, angiofibromas, collagenomas, lipomas, meningioma
MEN2A	RET (gain of function)	MTC (over 90%), phaeochromocytoma (up to 50%), hyperparathyroidism (20 to 30%)	Cutaneous lichen amyloidosis (C634), Hirschsprung disease (exon 10 cysteine codons)
MEN2B	RET, almost always M918T	Early aggressive MTC, phaeochromocytoma (about 50%)	Mucosal neuromas, marfanoid habitus, intestinal ganglioneuromatosis, medullated corneal nerves. No hyperparathyroidism
MEN4	CDKN1B	MEN1-like: hyperparathyroidism and pituitary adenoma	Milder, later onset, fewer NETs
MEN5	MAX	Phaeochromocytoma and paraganglioma	Pituitary adenoma, hyperparathyroidism

Familial MTC alone is now treated as a variant of MEN2A.

Genetics

• MEN1 follows Knudson's two-hit model: a germline variant plus a somatic hit in each gland, which is why tumours are multiple and recur. There is no genotype-phenotype correlation, so every carrier gets the same surveillance. Penetrance for any clinical feature is over 50% by 20 and over 95% by 40 (Brandi 2021). About 10% are de novo.
• Up to 30% of people with clinical MEN1 have no detectable MEN1 variant (eviQ). Think of phenocopies: CDKN1B, CASR, CDC73, AIP.
• RET has a strong genotype-phenotype link. The ATA groups variants as highest risk (M918T), high risk (C634, A883F) and moderate risk (most others).
• Most MEN2B cases are new mutations, so the family history is often blank.

Who to test

• MEN1 (Brandi 2025, AACE 2025): clinical or familial MEN1, a first-degree relative of a carrier, hyperparathyroidism under 30 or multigland, gastrinoma or multiple pancreatic NETs at any age, or two MEN1-type tumours short of the clinical criteria. Consider it for a solitary pancreatic NET under 40, a thymic, bronchial or gastric NET under 40 (AACE 2025), and for young adults with a functioning pituitary adenoma or a macroadenoma (not a microprolactinoma in a woman).
• RET: every patient with MTC, including apparently sporadic disease (about 25% are hereditary), and anyone with features of MEN2.
• Offer pre-test genetic counselling through a familial cancer service, then cascade testing. In a known family, test before starting biochemical surveillance so non-carriers can be discharged.

Pitfall: a single "sporadic" parathyroid adenoma at 24 is MEN1 until proven otherwise.

MEN1: the tumours

Hyperparathyroidism

• Multigland hyperplasia or adenomas, with earlier onset than sporadic disease. It presents like any primary hyperparathyroidism (see Hypo- and hypercalcaemia).
• Operate if symptomatic, if target organs are affected (Fifth International Workshop criteria), or in adults with calcium consistently more than 0.25 mmol/L above the upper limit. Mild asymptomatic disease can be watched.
• Index operation: subtotal (3 to 3½ gland) parathyroidectomy with transcervical thymectomy, by an experienced surgeon. The thymectomy removes ectopic parathyroid tissue and lowers thymic NET risk, though it doesn't clear all thymus.
• Pre-operative localisation doesn't change the operation in MEN1. Recurrence is common over the following decade, and hypoparathyroidism is the trade-off of more extensive surgery.
• Cinacalcet for those unfit for, or awaiting, surgery.
• Hypercalcaemia raises gastrin, so the timing of parathyroidectomy matters in gastrinoma.

Duodenopancreatic NETs

Tumour	Points to know
Non-functioning pancreatic NET	Commonest. Surgery above 2 cm or with rapid growth. Tumours of 2 cm or less are watched with serial MRI while stable
Gastrinoma	Commonest functioning type, peak 30 to 50. Usually multiple small duodenal tumours; surgery rarely cures. High-dose PPI controls acid. About a quarter of Zollinger-Ellison cases have MEN1 (see Peptic ulcer disease)
Insulinoma	Often presents before 30, can occur in childhood. Fasting hypoglycaemia; diagnosis as in Hypoglycaemia. Resect
Glucagonoma, VIPoma, somatostatinoma	Rare

• Fasting gastrin is raised by PPIs, H. pylori, atrophic gastritis and hypercalcaemia. Gastrinoma needs gastrin over 10 times the upper limit with gastric pH under 2, and PPIs should only be stopped under specialist care.
• SSTR PET (Ga-68 DOTATATE) before any duodenopancreatic surgery. Routine EUS biopsy isn't recommended.

Pituitary and thoracic tumours

• Prolactinoma is the commonest pituitary tumour, then non-functioning and somatotroph adenomas. Manage as for sporadic tumours (Brandi 2025); MEN1 tumours respond to dopamine agonists as sporadic ones do.
• Thymic NETs occur mostly in men who smoke, are aggressive and are often metastatic at diagnosis. Bronchial NETs are usually indolent; small ones (under 1 to 2 cm) can be watched.
• Adrenal nodules in 20 to 40%, mostly non-functioning cortical lesions, managed as incidentalomas.

MEN1 surveillance (Brandi 2025, eviQ)

For genetic carriers and obligate carriers. Begin with a paediatric endocrinology consultation around age 5.

Target	Test	Start	Interval
Hyperparathyroidism	Serum calcium (PTH no longer needed for screening)	Consider from 10	1 to 3 yearly in children, yearly in adults
Insulinoma	Ask about hypoglycaemic symptoms	5	Yearly
Pancreatic NET	MRI abdomen	10 to 15	2 to 3 yearly if negative
Gastrinoma	Fasting gastrin	18	Yearly
Pituitary	Growth and puberty; prolactin and IGF-1	5 (clinical), 10 (bloods)	Yearly in adults
Pituitary	MRI	Optional from 15, routine in adults	3 to 5 yearly; can stop imaging at 75
Thymic and bronchial NET	CT chest	20 to 25	3 to 5 yearly

• Chromogranin A and routine pancreatic hormone panels have gone. With negative imaging, extra biochemistry adds little.
• MRI is preferred for abdomen and pituitary to limit lifetime radiation. CT is kept for the chest, where MRI misses small nodules.
• AACE 2025 differs: yearly PTH, calcium and phosphate from age 5 to 8, chest CT or MRI from 8 to 15, and abdominal CT or MRI every 1 to 3 years from 16. Australian practice follows Brandi 2025 through eviQ.
• Older schedules (Endocrine Society 2012) used yearly broad biochemistry and pituitary MRI from age 5. Expect to see them in older exam material.

MEN2

Medullary thyroid cancer

• From parafollicular C cells, preceded by C-cell hyperplasia. Markers: calcitonin and CEA.
• Presents as a nodule or neck nodes, sometimes with diarrhoea or flushing from high calcitonin. See Thyroid nodules for nodule work-up.
• Before thyroidectomy: calcitonin, CEA, neck ultrasound, metanephrines, calcium, and germline RET.
• Calcitonin over about 500 ng/L, or extensive neck disease, means looking for distant spread before surgery: CT neck and chest, liver MRI or 3-phase contrast CT, and bone imaging (ATA 2015).
• Treatment: total thyroidectomy with central neck dissection; lateral dissection depends on nodes and calcitonin. C cells don't take up iodine, so radioactive iodine and TSH suppression have no role.
• Follow-up: calcitonin and CEA at 3, 6 and 12 months, then yearly once undetectable. Calcitonin doubling time predicts outcome.
• Advanced progressive disease: selective RET inhibitors. In LIBRETTO-531 (NEJM 2023), first-line selpercatinib beat cabozantinib or vandetanib for progression-free survival (HR 0.28).
• Australia: selpercatinib is TGA-registered for RET-mutant MTC. Check the current PBS Schedule for its MTC listing and any linked RET-testing requirement.

Prophylactic thyroidectomy (eviQ, ATA)

ATA risk	Typical variant	Thyroidectomy	Surveillance if not yet operated
Highest	M918T (MEN2B)	In the first year of life	Not applicable
High	C634, A883F	By age 5	Calcitonin and neck ultrasound yearly from 3
Moderate	Most others	Usually 5 to 10, later only if calcitonin and ultrasound stay normal	Yearly from 5

Prophylactic surgery is total thyroidectomy alone. Add central neck dissection only if calcitonin is over 40 ng/L or nodes are seen (ATA 2015), because it raises the risk of hypoparathyroidism in young children.

Phaeochromocytoma and hyperparathyroidism

• MEN2 phaeochromocytomas are adrenal, often bilateral (over time in about half), rarely malignant, and adrenergic: plasma metanephrine rises, not just normetanephrine.
• Screen yearly with plasma free or urine fractionated metanephrines from 11 (highest and high risk) or 16 (moderate risk), earlier if hypertensive. Image only after a positive biochemical test.
• Remove a phaeochromocytoma before thyroid or parathyroid surgery, after alpha-blockade (see Systemic hypertension). Cortical-sparing adrenalectomy can avoid lifelong steroid dependence when disease is bilateral.
• Hyperparathyroidism: yearly PTH and serum calcium (albumin-corrected and ionised) from 11 (high risk) or 16 (moderate). eviQ keeps PTH here, unlike MEN1 screening. Usually milder than in MEN1; remove only enlarged glands. None in MEN2B.

Special situations

• Pregnancy: screen MEN2 carriers for phaeochromocytoma before conception and when pregnant; an undiagnosed tumour can cause a hypertensive crisis in labour. Prolactinomas in MEN1 are managed as usual. Offer counselling about preimplantation genetic testing and prenatal diagnosis.
• Older people: pituitary MRI can stop at 75 in MEN1 if prior imaging was clear. Weigh surveillance burden against life expectancy.
• Rural and remote patients: surveillance needs a named coordinating clinician and an expert centre MDT. Missed follow-up is a stated reason eviQ gives for not delaying thyroidectomy in moderate-risk RET carriers.
• GLP-1 receptor agonists are avoided with personal or family history of MTC or MEN2 (see Type 2 diabetes).

Pitfalls

• Doing a focused one-gland parathyroidectomy in MEN1 because sestamibi showed one hot spot.
• Operating on MTC before metanephrines and finding the phaeochromocytoma on the table.
• Treating MTC with radioactive iodine, or reading thyroglobulin rather than calcitonin and CEA.
• Testing only "familial" MTC for RET. Test every case.
• Calling a raised gastrin a gastrinoma in someone taking a PPI.
• Expecting MEN2B to have a family history, or to cause hyperparathyroidism.
• Forgetting the thymus. Thymic NETs are aggressive and a major cause of MEN1 death, especially in men who smoke.
• Assuming a negative MEN1 test excludes a syndrome. Test for phenocopies (CDKN1B, CASR, CDC73, AIP).