• Encodes the protein menin (a 610-amino acid nuclear protein)
• Menin functions as a tumour suppressor — it normally acts as a brake on cell proliferation

Menin is involved in:

1. Transcriptional regulation: interacts with JunD (a transcription factor) to suppress cell growth; also interacts with mixed lineage leukemia (MLL) protein to regulate chromatin remodelling and histone methylation
2. Cell cycle control: helps maintain genomic stability
3. TGF-β signalling: menin facilitates TGF-β-mediated growth inhibition
4. DNA repair: involved in maintaining genomic integrity

• First hit: germline mutation inherited from a parent (present in every cell) — this alone is insufficient to cause a tumour
• Second hit: somatic mutation or loss of heterozygosity (LOH) of the remaining normal allele in an endocrine cell → complete loss of menin function → uncontrolled cell proliferation → tumour formation
• This explains:
  • Why tumours are multifocal: each endocrine cell independently can undergo a second hit
  • Why penetrance is variable: the second hit is stochastic (random)
  • Why different organs are affected at different ages: some tissues are more susceptible to LOH than others

Over 1,500 different MEN1 mutations have been described — there is no clear genotype-phenotype correlation (unlike MEN2), meaning you cannot predict which tumours will develop based on the specific mutation.

• "RET" stands for "REarranged during Transfection" — it was discovered because of chromosomal rearrangement during experimental transfection
• Encodes a receptor tyrosine kinase (RTK) expressed on neural crest-derived cells
• Normal function: RET is activated by glial cell line-derived neurotrophic factor (GDNF) family ligands → promotes cell survival, differentiation, and proliferation during embryonic development (particularly of neural crest cells, kidneys, and enteric nervous system)

• Unlike MEN1, RET mutations in MEN2 are activating (gain-of-function) mutations
• A single missense mutation is sufficient to constitutively activate the RET receptor without ligand binding → continuous, unregulated intracellular signalling → uncontrolled proliferation of neural crest-derived cells
• This is why MEN2 follows a dominant oncogene model — only one mutant allele is needed (no "second hit" required)
• Key downstream pathways activated: RAS/MAPK, PI3K/AKT, PLCγ, JAK/STAT → cell survival, proliferation, and migration

This is a critical concept for MEN2 and very different from MEN1. The specific codon mutated in RET determines:

1. Which clinical subtype (MEN2A vs MEN2B)
2. The aggressiveness of MTC
3. The timing of prophylactic thyroidectomy

i. Primary Hyperparathyroidism (earliest and most common, 95–100%)

• Polyuria and polydipsia — hypercalcaemia impairs renal concentrating ability (↓aquaporin-2 expression in collecting ducts → nephrogenic diabetes insipidus)
• Renal colic / flank pain — calcium phosphate / calcium oxalate stones form due to hypercalciuria
• Bone pain / fragility fractures — chronically elevated PTH → ↑osteoclast activity → bone resorption → osteoporosis / osteitis fibrosa cystica
• Abdominal pain / constipation — hypercalcaemia → ↓smooth muscle contractility in GI tract; also pancreatitis (calcium activates trypsinogen)
• Psychiatric symptoms — depression, confusion, cognitive impairment ("psychic groans") — calcium affects neuronal membrane excitability
• Nausea / anorexia — direct CNS and GI effects of hypercalcaemia
• Muscle weakness / fatigue — hypercalcaemia disrupts neuromuscular junction transmission

Mnemonic for hypercalcaemia: "Bones, stones, abdominal moans, and psychic groans"

ii. Pituitary Adenoma (15–42%)

• Prolactinoma (most common, ~60% of MEN1 pituitary tumours):
  • Women: galactorrhoea (prolactin stimulates breast milk production), amenorrhoea/oligomenorrhoea (prolactin suppresses GnRH → ↓LH/FSH), infertility
  • Men: erectile dysfunction, decreased libido, gynecomastia (often diagnosed later because symptoms are subtler → more commonly macroadenomas in men)
• GH-secreting adenoma: features of acromegaly — enlarged hands/feet, coarsened facial features, prognathism, excessive sweating, carpal tunnel syndrome, obstructive sleep apnoea
• ACTH-secreting adenoma: features of Cushing's disease — central obesity, moon face, buffalo hump, purple striae, proximal myopathy, hypertension, diabetes, easy bruising
• Non-functioning adenoma: mass effect only
• Mass effect (especially macroadenomas, which are more common in MEN1):
  • Bitemporal hemianopia — tumour compresses the optic chiasm from below
  • Headache — stretching of the diaphragma sellae
  • Hypopituitarism — compression of normal pituitary tissue → sequential loss of GH > LH/FSH > TSH > ACTH (in that order due to differential sensitivity)

iii. Pancreatic/Duodenal Neuroendocrine Tumours (30–80%)

• Gastrinoma / Zollinger-Ellison Syndrome (most common functional pNET in MEN1, ~54%):

  • Epigastric pain — multiple peptic ulcers in unusual locations (distal duodenum, jejunum) due to massive gastric acid hypersecretion (gastrin → parietal cell stimulation → 4-6× normal acid output) ^[4]
  • Chronic diarrhoea — (1) overwhelming acid inactivates pancreatic lipase → steatorrhoea; (2) acid damages small bowel mucosa → malabsorption; (3) hypergastrinaemia inhibits Na⁺/H₂O reabsorption ^[4]
  • Heartburn / reflux oesophagitis — from acid excess
  • GI bleeding — from multiple erosive ulcers
  • Weight loss — from malabsorption and chronic diarrhoea

• Insulinoma (~10% of MEN1 patients):

  • Neuroglycopenic symptoms: confusion, blurred vision, seizures, loss of consciousness — brain depends on glucose and is first to suffer
  • Autonomic/adrenergic symptoms: tremor, sweating, palpitations, hunger — catecholamine counter-regulatory response to hypoglycaemia
  • Whipple's triad: (1) symptoms of hypoglycaemia, (2) documented low blood glucose during symptoms, (3) resolution of symptoms with glucose administration
  • Symptoms typically occur fasting or post-exercise

• VIPoma (rare):

  • Watery diarrhoea (profuse, secretory, up to 3-5 L/day) — VIP stimulates intestinal chloride and water secretion
  • Hypokalaemia — massive faecal potassium losses
  • Achlorhydria — VIP inhibits gastric acid secretion (Verner-Morrison syndrome = "pancreatic cholera")

• Glucagonoma (rare):

  • Necrolytic migratory erythema — characteristic skin rash (pathognomonic); pathogenesis involves amino acid deficiency and zinc/fatty acid deficiency from glucagon-induced catabolism
  • Diabetes mellitus — glucagon is a counter-regulatory hormone that ↑hepatic gluconeogenesis and glycogenolysis
  • DVT — glucagon promotes a hypercoagulable state
  • Depression — mechanism not fully understood

• Non-functioning pNETs (20–55%): often detected incidentally on imaging; may cause symptoms from mass effect (abdominal pain, biliary obstruction)

iv. Other Tumours

• Thymic carcinoids: particularly in male smokers — can be aggressive; cervical thymectomy during parathyroidectomy may reduce risk
• Bronchial carcinoids: usually indolent
• Cutaneous lesions: often present before endocrine tumours manifest — can be an early diagnostic clue

i. Signs of Hyperparathyroidism / Hypercalcaemia

• Band keratopathy — calcium deposits in the cornea (medial and lateral limbus)
• Shortened QTc interval on ECG — calcium accelerates cardiac repolarization
• Hypertension — chronic hypercalcaemia causes vasoconstriction and direct smooth muscle calcium entry
• Proximal muscle weakness — hypercalcaemia impairs neuromuscular junction

ii. Signs of Pituitary Tumour

• Visual field defect (bitemporal hemianopia) — optic chiasm compression
• Galactorrhoea (expressible or spontaneous)
• Signs of acromegaly: large hands and feet, prognathism, frontal bossing, skin tags, macroglossia
• Signs of Cushing's disease: central obesity, moon face, buffalo hump, thin skin, purple striae, proximal myopathy
• Hypogonadism signs: in men — gynaecomastia, testicular atrophy; in women — absent secondary sexual characteristics (if prepubertal onset)

iii. Signs of Pancreatic NETs

• Epigastric tenderness (ZES — ulcer disease)
• Signs of hepatomegaly (if liver metastases — especially gastrinoma, 60-90% malignant)
• Necrolytic migratory erythema — annular, erythematous, blistering skin lesions that migrate, often on perineum, groin, buttocks, and lower extremities (glucagonoma)

iv. Cutaneous Signs (can be an early clue!)

• Angiofibromas (64% of MEN1 patients): small, skin-coloured to red papules on the face — resemble fibrous papules ^[1]
• Collagenomas (62%): skin-coloured, firm, subcutaneous plaques on the trunk ^[1]
• These cutaneous findings may precede endocrine tumour diagnosis and should prompt MEN1 screening

i. Medullary Thyroid Carcinoma (virtually 100%)

• Palpable thyroid nodule — typically bilateral, multicentric (cf. sporadic MTC which is unilateral) ^[5]
• Cervical lymphadenopathy — MTC spreads via lymphatics early; level VI nodes (central compartment) are the first site of metastasis ^[5]
• Diarrhoea (30% of patients) — calcitonin directly stimulates intestinal chloride and water secretion → secretory diarrhoea; this can be the presenting symptom
• Flushing — calcitonin and other peptides (prostaglandins, CGRP) cause vasodilatation
• Bone pain (if distant metastases)
• Hoarseness — recurrent laryngeal nerve invasion (suggests locally advanced disease)
• Dysphagia / dyspnoea — compression or invasion of trachea/oesophagus (late features)

ii. Phaeochromocytoma (~50% in MEN2A)

• Classic triad: paroxysmal headache, sweating, and palpitations ^[3]
• Paroxysmal hypertension — catecholamines (adrenaline and noradrenaline) cause vasoconstriction (α₁ receptors) and ↑heart rate/contractility (β₁ receptors)
• Postural hypotension (paradoxically) — chronic catecholamine excess → plasma volume contraction + desensitisation of adrenergic receptors
• Anxiety / panic attacks — adrenaline activates central and peripheral adrenergic pathways
• Pallor (NOT flushing) — α₁-mediated cutaneous vasoconstriction ("the 5th P of Phaeo")
• Weight loss — catecholamines increase basal metabolic rate
• Glucose intolerance / diabetes — catecholamines promote glycogenolysis and gluconeogenesis and inhibit insulin secretion

Mnemonic: The 5 P's of Phaeochromocytoma: Pressure (HTN), Pain (headache, chest pain), Palpitation, Perspiration, Pallor ^[3]

iii. Primary Hyperparathyroidism (10–25%)

• Usually mild and asymptomatic ^[1]
• When symptomatic: same features as MEN1 hyperparathyroidism (stones, bones, moans, groans) but typically milder

iv. Cutaneous Lichen Amyloidosis (rare but characteristic)

• Pruritic, pigmented, lichenoid skin lesion — typically over the upper back (interscapular region)
• Pathogenesis: amyloid deposits derived from keratin in the papillary dermis
• Associated with specific RET codon 634 mutations

v. Hirschsprung Disease (rare)

• Constipation, abdominal distension, failure to thrive in neonates/infants
• Pathogenesis: RET is essential for enteric nervous system development; certain RET mutations paradoxically cause both gain-of-function (in C cells) and loss-of-function (in enteric neurons) — hence Hirschsprung disease and MEN2A can coexist

• Thyroid mass: firm, non-tender, may be bilateral; may have palpable cervical lymphadenopathy (level VI, lateral neck)
• Hypertension (if phaeochromocytoma) — may be sustained or paroxysmal
• Tachycardia, tremor — catecholamine excess
• Orthostatic hypotension — volume depletion from chronic catecholamine excess
• Pallor during hypertensive paroxysms
• Retinal changes — hypertensive retinopathy if chronic HTN
• Interscapular pigmented pruritic plaques — cutaneous lichen amyloidosis (MEN2A with codon 634)

i. Medullary Thyroid Carcinoma (virtually 100%)

• Same symptoms as MEN2A but earlier onset (infancy/childhood) and more aggressive ^[1]
• MTC in MEN2B has the worst prognosis of all MEN-associated MTCs
• May already have lymph node and distant metastases at diagnosis in childhood

ii. Phaeochromocytoma (~50%)

• Same as MEN2A (5 P's)

iii. Mucosal Neuromas (pathognomonic for MEN2B)

• Typically involves lips and tongue ^[1]
• Bumpy, nodular lips — visible as small, glistening nodules on the vermilion border of the lips
• Enlarged, nodular tongue — nodules of neural tissue
• Thickened eyelids — neuromas on eyelid margins → everted eyelids (can resemble blepharochalasis)
• These may be present from birth or early infancy — often the FIRST clinical sign of MEN2B and should trigger immediate RET genetic testing

iv. Intestinal Ganglioneuromas

• Chronic constipation — ganglioneuromas in the intestinal wall disrupt normal peristalsis ^[1]
• Megacolon — chronic functional obstruction due to dysmotile bowel
• Abdominal distension, bloating
• Failure to thrive in children — from chronic GI dysmotility and poor feeding

v. Skeletal / Developmental

• Marfanoid habitus: tall stature, long limbs, arm span > height, long fingers (arachnodactyly)
  • BUT: no ectopia lentis (lens subluxation) and no aortic root abnormalities — this differentiates from true Marfan syndrome (FBN1 mutation) ^[1]
• Joint laxity
• Skeletal deformities: kyphosis, scoliosis, pes cavus
• ↓Upper-to-lower body ratio (long limbs relative to trunk) ^[1]

vi. Ocular

• Myelinated corneal nerves — visible on slit-lamp examination as prominent white nerve fibres on the cornea
• Dry eyes — neuronal dysfunction
• Prominent, thickened eyelid margins from mucosal neuromas

• Mucosal neuromas: glistening nodules on lips, tongue, buccal mucosa, conjunctivae — often the most striking and recognisable finding on examination
• Marfanoid habitus: tall, thin, long limbs, joint laxity
• Thyroid mass (bilateral, firm)
• Cervical lymphadenopathy
• Hypertension (if phaeo present)
• Abdominal distension (if ganglioneuromas causing megacolon)
• Myelinated corneal nerves on slit-lamp exam
• Skeletal deformities

• Gene: MEN1 at chromosome 11q13, encoding menin
• Method: Sanger sequencing or next-generation sequencing (NGS) of the entire coding region + splice sites; multiplex ligation-dependent probe amplification (MLPA) for large deletions
• Yield: ~80-90% of clinically defined MEN1 families have an identifiable MEN1 mutation; ~10-20% are mutation-negative (possible intronic/regulatory mutations or phenocopies)
• Interpretation: > 1,500 different mutations described; no genotype-phenotype correlation — you cannot predict which tumours will develop or their timing based on the specific mutation
• Cascade screening: all first-degree relatives should be offered testing once the familial mutation is identified
  • Mutation-positive: enter surveillance programme
  • Mutation-negative: can be discharged from surveillance (if the familial mutation is known)

• Gene: RET at chromosome 10q11.2
• Method: targeted sequencing of known hotspot exons (exons 10, 11, 13, 14, 15, 16); if negative and clinical suspicion remains high, full gene sequencing
• Yield: > 98% of clinically defined MEN2 families have an identifiable RET mutation
• Interpretation: strong genotype-phenotype correlation — the specific codon determines MEN2A vs MEN2B, aggressiveness, and management timing (see ATA table above)
• Genetic analysis for RET proto-oncogene mutation (Tyr kinase receptor) for MEN2 ^[5]
• Also screen asymptomatic relatives → prophylactic thyroidectomy (best done < 5-10y) ^[5]

Calcitonin if Hx or clinical suspicion of familial medullary carcinoma or MEN2 ^[8]

Why calcitonin is such a good tumour marker for MTC:

• C cells are the ONLY significant source of calcitonin in the body
• Calcitonin has a short half-life (~10 min) so levels respond quickly to changes in tumour burden
• Post-thyroidectomy, calcitonin should become undetectable — persistent or rising levels indicate residual/recurrent disease
• Postop: serum calcitonin and CEA 6mo post-op; ↑calcitonin → screen for residual or metastatic disease ^[5]

This is the investigation that must be done before any surgery in MEN2 patients.

Why metanephrines are superior to catecholamines:

• Phaeochromocytomas express COMT (catechol-O-methyltransferase) within the tumour cells
• COMT continuously converts noradrenaline → normetanephrine and adrenaline → metanephrine within the tumour itself, independent of catecholamine secretion into the bloodstream
• Therefore metanephrine levels are continuously elevated even between paroxysms, while catecholamine levels may be normal between episodes
• This gives metanephrines their near-perfect sensitivity

Screening tests for functional adrenal tumours: ONDST + spot ARR + 24h urine metanephrines ^[3]

Confirmation test (if borderline results):

• Clonidine suppression test: clonidine (α₂ agonist) normally suppresses central sympathetic outflow → ↓plasma normetanephrine. In phaeochromocytoma, tumour catecholamine production is autonomous → failure to suppress ^[3]

Localisation studies of hyperfunctioning parathyroid: USG + Sestamibi scan ^[3]

Why sestamibi works — from first principles: Sestamibi (⁹⁹ᵐTc-MIBI) is a lipophilic cation that enters cells and accumulates in mitochondria (driven by the mitochondrial membrane potential). Parathyroid adenomas/hyperplastic glands contain abundant oxyphilic cells (oncocytes) which are packed with mitochondria. Therefore sestamibi washes out of normal thyroid tissue quickly but is retained in parathyroid tissue. On dual-phase imaging, the persistent "hot spot" at 2 hours is the parathyroid lesion. False positive: Hurthle cell adenoma (also rich in mitochondria/oxyphilic cells) ^[3].

Special consideration in MEN:

• MEN1 and MEN2A typically have multigland hyperplasia (all 4 glands affected), not a single adenoma
• Sestamibi sensitivity is lower for multigland disease than for single adenomas (~50-60% vs ~80-90%)
• This is why bilateral neck exploration (BCE) is preferred in MEN1/2A, rather than focused/minimally invasive parathyroidectomy ^[3]

Why MIBG works — from first principles: MIBG (meta-iodobenzylguanidine) is structurally similar to noradrenaline. It is taken up by the noradrenaline transporter (NET / uptake-1) on the surface of chromaffin cells and stored in catecholamine storage vesicles. Since phaeochromocytomas are derived from chromaffin cells, they avidly take up and retain MIBG, producing a "hot spot" on scintigraphy. Labelling with ¹²³I (for diagnostic imaging) or ¹³¹I (for therapy) enables both diagnosis and targeted radionuclide therapy.

An undiagnosed or untreated phaeochromocytoma during anaesthesia can cause a massive catecholamine surge → hypertensive crisis (systolic BP > 250 mmHg), malignant arrhythmias (VT, VF), acute pulmonary oedema, intracranial haemorrhage, or cardiovascular collapse. The surgical manipulation itself, intubation, and anaesthetic agents can all trigger catecholamine release. This is why phaeochromocytoma is always addressed before any other surgery.

Medical therapy: pre-operative prevention of crisis by combined α/β-blockade ^[1]

Alternative α-blockers:

• Doxazosin (selective α₁-blocker): fewer side effects than phenoxybenzamine, easier to titrate, but reversible (shorter duration of action)
• Dipine CCBs (e.g. nifedipine, amlodipine): useful adjunct; direct vasodilator, no postural hypotension ^[1]
• Metyrosine (α-methylparatyrosine): inhibits catecholamine synthesis at the tyrosine hydroxylase step; used in combination with α-blockade for difficult-to-control cases ^[1]

Mx: similar to sporadic cases with alpha blockade followed by adrenalectomy (unilateral suffice) ^[1]

Why cortical-sparing matters in MEN2:

• In MEN2, phaeo is bilateral in 30-100% of cases → bilateral total adrenalectomy would leave the patient with permanent adrenal insufficiency (requiring lifelong glucocorticoid AND mineralocorticoid replacement)
• Addisonian crisis (acute adrenal insufficiency: hypotension, hypoglycaemia, hyperkalaemia, shock) can be life-threatening if the patient forgets to take steroids or becomes unwell
• Cortical-sparing surgery preserves enough cortex to maintain basal steroid production, avoiding this lifelong dependency

Postop complications: HTN crisis, hypotension, rebound hypoglycaemia → monitor BP, HR, H'stix closely postop ^[1]

Management of phaeochromocytoma crisis: classified as hypertensive urgency ^[1]

• ICU monitoring
• IV phentolamine (short-acting α-blocker): bolus 2-5mg IV, repeat as needed; or IV infusion
• Nitroprusside infusion: if phentolamine insufficient
• β-blocker (e.g. esmolol IV): ONLY after adequate α-blockade
• Magnesium sulphate IV: direct vasodilator + antiarrhythmic
• Emergency surgery if refractory

This is one of the most important and unique aspects of MEN2 management. Because virtually all MEN2 patients develop clinically apparent MTC ^[2], prophylactic removal of the thyroid before MTC develops (or while it's still at the C-cell hyperplasia stage) is potentially curative.

Monitor calcitonin with prophylactic thyroidectomy depending on risk of mutation and calcitonin level ^[1]:

Mx: total thyroidectomy + central LN dissection ^[1]

Postop: no need suppressive doses of T4 (not TSH-responsive), serum calcitonin/CEA screening ^[1]

No good adjuvant Tx for MTC ^[5] — it does not respond to radioactive iodine (MTC cells don't express NIS/thyroglobulin), and conventional chemotherapy has limited efficacy. However:

Management: indication of surgery same as sporadic; favours subtotal PTHectomy (3.5 glands) + cervical thymectomy (↓thymic carcinoid) ^[1]

Indications for surgery (same as sporadic PHPT) ^[1][3][12]:

• ALL symptomatic patients (renal stones, bone disease, neuromuscular symptoms) ^[12]
• Asymptomatic patients meeting criteria (mnemonic: CASR) ^[3]:
  • Ca: adjusted Ca ≥ 2.8 mmol/L (i.e. > 0.25 mmol/L above ULN)
  • Age < 50
  • Skeletal: DEXA T-score < -2.5 or vertebral fracture
  • Renal: CrCl < 60 mL/min, or 24h urine Ca > 10 mmol/L, or nephrolithiasis/nephrocalcinosis on imaging

Surgical approach — why NOT focused parathyroidectomy in MEN:

In MEN, focused parathyroidectomy is inappropriate because:

• The disease is multigland hyperplasia — removing one gland leaves 3 hyperplastic glands behind → guaranteed recurrence
• Sestamibi is less sensitive for multigland disease → may miss affected glands

MEN1 surgical options:

Why "3.5 glands" in MEN? The reasoning is pragmatic: you want to remove as much hyperplastic tissue as possible to control hypercalcaemia, while leaving enough parathyroid tissue to prevent permanent hypoparathyroidism (which requires lifelong calcium + vitamin D supplementation and carries risks of hypocalcaemic seizures, arrhythmias, and cataracts). The frozen section of the excised half-gland confirms you are indeed leaving parathyroid tissue behind (not a lymph node or fat) ^[3].

Post-operative complications specific to parathyroidectomy in MEN ^[3]:

Mx: similar to MEN1, NOT for prophylactic parathyroidectomy during thyroidectomy (usually asymptomatic) ^[1]

Key differences from MEN1:

• Usually mild and asymptomatic → most patients do NOT require surgery
• If symptomatic or meeting surgical criteria, same approach as MEN1 (subtotal parathyroidectomy)
• During thyroidectomy for MTC, the surgeon should inspect but NOT routinely remove normal-appearing parathyroid glands — removing asymptomatic normal glands causes unnecessary hypoparathyroidism
• If inadvertently devascularised during thyroidectomy → autotransplant into the forearm or SCM

Mx: generally prefer medical treatment by high-dose PPI due to multifocality → low cure rate by OT ^[1]

Why medical over surgical for MEN1-associated gastrinoma?

• MEN1 gastrinomas are multifocal (dozens of microadenomas in the duodenal wall and pancreas) ^[1][6]
• 50-88% sporadic and 70-100% MEN1-associated gastrinomas are in the duodenum ^[6] — scattered along the wall
• Surgical cure rate is very low (~0-10%) because you simply cannot remove them all without destroying the entire duodenum and pancreas
• PPI effectively controls the clinical consequences (ulcers, diarrhoea) even though the tumour persists
• Surgery is reserved for large ( > 2cm), dominant tumours to prevent or treat metastatic spread

Surgical treatment: advised for ALL patients ^[4]

Unlike gastrinoma, insulinoma in MEN1 is usually a dominant single tumour (even if multiple are present) causing the hypoglycaemia, and surgical cure is achievable.

Management: in general resect if > 1-2cm or functional, otherwise observe ^[6]

• In MEN1, many non-functioning pNETs are < 1cm and indolent → surveillance with annual imaging
• Surgery (distal pancreatectomy or enucleation) is considered for tumours > 2cm or with evidence of growth (risk of lymph node metastasis increases significantly above 2cm)
• Debulking surgery for metastatic disease to improve quality of life and enable medical therapy

• These are rare even in MEN1
• Principles: symptom control (octreotide) + surgical resection if resectable
• Metastatic: targeted therapy (everolimus, sunitinib), PRRT (¹⁷⁷Lu-DOTATATE), chemotherapy