EndocrinologyTier 2Disease (DEADMAN)

Multiple endocrine neoplasia

Description

The four syndromes at a glance

	Gene	Inheritance	Core tumours
MEN1	MEN1 (menin) - tumour suppressor	AD	Parathyroid + Pituitary + Pancreas ("3 Ps")
MEN2A	RET - proto-oncogene	AD	MTC + phaeochromocytoma + hyperparathyroidism
MEN2B	RET (M918T)	AD (~50% de novo)	MTC + phaeochromocytoma + mucosal neuromas + marfanoid
MEN4	CDKN1B (p27)	AD	MEN1-like, milder, later

*MEN1 = suppressor -> two hits, so tumours are multifocal and appear over decades*
*MEN2 = oncogene -> single activating hit, so a specific codon predicts a specific age of MTC onset*
MTC and phaeochromocytoma are shared by 2A and 2B; 2A has parathyroid disease, 2B has neuromas and marfanoid habitus instead

MEN1 - the 3 Ps and more

Primary hyperparathyroidism >90% - usually the first manifestation, often in the 20s-30s
Enteropancreatic NET 30-70% - gastrinoma (commonest, usually duodenal and multiple), insulinoma, VIPoma, glucagonoma, non-functioning
Pituitary 10-40% - prolactinoma commonest, also GH-, ACTH-secreting and non-functioning
Also: thymic and bronchial carcinoid (thymic carcinoid in male smokers - the leading MEN1-specific cause of death), adrenocortical tumours, angiofibromas, collagenomas, lipomas, meningioma

MEN2B - recognise the phenotype

Mucosal neuromas (lips, anterior tongue), thickened corneal nerves, marfanoid habitus (without lens dislocation or aortic disease), intestinal ganglioneuromatosis (constipation, megacolon), no parathyroid disease
The phenotype is visible in infancy - the diagnosis is often made too late

Epidemiology

MEN1 prevalence ~1:30,000; ~10% de novo mutations
MEN2 ~1:35,000; MEN2A ~95% of MEN2; MEN2B ~5%, of which ~50% are de novo
Medullary thyroid carcinoma: ~25% hereditary, 75% sporadic
- ~40-50% of "sporadic" MTC carries a somatic RET mutation
MEN4 very rare

Aetiopathogenesis

MEN1

MEN1 on 11q13 encodes menin - a nuclear scaffold protein regulating transcription (MLL histone methyltransferase complex), cell cycle and genome stability
Tumour suppressor -> Knudson two-hit: germline first hit, somatic loss of the second allele in the target tissue
- -> multifocal, multiglandular, metachronous tumours with no genotype-phenotype correlation
*No genotype-phenotype correlation in MEN1* - contrast MEN2

MEN2

RET on 10q11.2 - a receptor tyrosine kinase for GDNF family ligands, expressed in neural crest derivatives
Activating (gain-of-function) mutations -> constitutive dimerisation and signalling
*Codon determines phenotype and the age at which MTC develops* - this is what drives the timing of prophylactic surgery

ATA risk	Codon	MTC onset
Highest	M918T (MEN2B)	Infancy - operate in the first year
High	C634 (MEN2A), A883F	Early childhood - operate by age 5
Moderate	Other (e.g. 609, 611, 618, 620, 768, 804)	Later; operate based on calcitonin

~95% of MEN2A mutations lie in exon 10 or 11 (cysteine-rich extracellular domain, codons 609-634)
Loss-of-function RET mutations cause Hirschsprung disease - the same gene, the opposite effect. Hirschsprung can coexist with MEN2A codon 609/618/620
MTC arises from parafollicular C cells (neural crest) -> calcitonin and CEA, and is preceded by C-cell hyperplasia

Diagnosis

When to suspect

Every patient with medullary thyroid carcinoma must have germline RET testing - even with no family history
Primary hyperparathyroidism under 40, multiglandular, or recurrent -> MEN1 testing
Any phaeochromocytoma - germline panel in everyone
Multiple duodenal/pancreatic NETs, recurrent peptic ulceration (Zollinger-Ellison), prolactinoma in a young patient with hypercalcaemia

Clinical diagnosis of MEN1

Two of the three main tumour types, OR
One, plus a first-degree relative with MEN1, OR
A germline MEN1 mutation (even if asymptomatic)

Biochemical markers

MTC: calcitonin and CEA
- Calcitonin doubling time is the strongest prognostic marker in follow-up
- Falsely raised by PPIs, renal failure, neuroendocrine tumours, smoking; procalcitonin is an alternative
Phaeochromocytoma: plasma free metanephrines - *always exclude and treat before any neck surgery*
Parathyroid: calcium + PTH
MEN1 pancreatic: fasting gastrin (off PPI), chromogranin A, glucagon, VIP, pancreatic polypeptide, insulin/C-peptide with a 72h fast if hypoglycaemic
Pituitary: prolactin, IGF-1

Surveillance of gene carriers

MEN1 - annual from childhood/adolescence
- Calcium/PTH, gastrin, chromogranin A, prolactin, IGF-1, fasting glucose/insulin
- Pituitary MRI and pancreatic MRI/EUS every 1-3 years; CT chest for thymic carcinoid
MEN2 - annual calcitonin and CEA, plasma metanephrines from age 8-16 depending on codon, calcium/PTH (2A)

Management

MEN2 - medullary thyroid carcinoma

*Prophylactic total thyroidectomy, timed by RET codon*
- M918T (MEN2B): within the first year of life
- C634: by age 5 (or earlier if calcitonin rises)
- Moderate-risk codons: from age 5, guided by annual calcitonin - may be deferred into adolescence or later
Exclude and block a phaeochromocytoma before any operation - unblocked, induction of anaesthesia can be fatal
Established MTC: total thyroidectomy + central compartment node dissection (+/- lateral)
- MTC does not take up iodine and does not respond to TSH suppression - radioiodine and thyroxine suppression are useless
Advanced/progressive metastatic MTC
- Selective RET inhibitors - selpercatinib (or pralsetinib) - are the preferred systemic therapy for RET-mutant disease
  - Far better response and tolerability than the multikinase inhibitors they displaced
- Cabozantinib or vandetanib where a RET inhibitor is unavailable or has failed
- Resistance emerges (solvent-front RET mutations, MAPK reactivation) - trial-based combinations under study
Lifelong levothyroxine replacement (not suppression), calcium/PTH monitoring

MEN2 - other components

Phaeochromocytoma: alpha blockade then cortical-sparing bilateral or unilateral adrenalectomy (preserve cortex - these patients are young and often bilateral)
Hyperparathyroidism (2A): usually mild; subtotal parathyroidectomy or resection of enlarged glands

MEN1

Primary hyperparathyroidism
- Subtotal (3.5-gland) parathyroidectomy or total parathyroidectomy with autotransplantation, plus transcervical thymectomy (supernumerary glands, thymic carcinoid)
- Single-gland excision fails - the disease is multiglandular from the start; recurrence is the rule
- Operate before pancreatic surgery - hypercalcaemia drives gastrin secretion
Gastrinoma: high-dose PPI controls acid; surgery is controversial because tumours are multiple and duodenal
Insulinoma: enucleation or resection - the one pancreatic NET where surgery is clearly curative
Non-functioning pancreatic NET: resect if >2 cm or growing
Prolactinoma: cabergoline as usual
Thymic carcinoid: aggressive, poorly responsive; prophylactic thymectomy at parathyroid surgery

Genetic counselling

Cascade testing of first-degree relatives, with predictive testing in childhood where a result changes management (MEN2 always does; MEN1 from about age 5)

Associations

Hirschsprung disease - loss-of-function RET; coexists with MEN2A exon 10 codons
Cutaneous lichen amyloidosis - MEN2A, codon 634, interscapular; often precedes MTC
Zollinger-Ellison syndrome - ~25% of gastrinomas are MEN1
Carney complex (PRKAR1A) and McCune-Albright - other multi-gland syndromes to distinguish
von Hippel-Lindau, NF1, SDHx - the other phaeochromocytoma syndromes
Familial isolated hyperparathyroidism, HPT-jaw tumour syndrome (CDC73)
Familial medullary thyroid carcinoma - MTC alone, moderate-risk RET codons

Natural history & complications

MEN1
- Near-complete penetrance by age 50; hyperparathyroidism usually first, in the 20s-30s
- Life expectancy reduced by ~10-15 years; deaths from malignant pancreatic NET and thymic carcinoid, not from hypercalcaemia
- Hyperparathyroidism recurs after surgery in a large minority
MEN2
- MTC penetrance approaches 100% and determines prognosis
- MEN2B MTC is present in infancy and metastasises early - the single strongest argument for phenotype recognition at birth
- Cure requires surgery before nodal spread; prophylactic surgery in a gene carrier is essentially curative
- Phaeochromocytoma in MEN2 is rarely metastatic but frequently bilateral and metachronous
- MTC 10-year survival: >95% node-negative, ~40-50% with distant metastases
Both syndromes need lifelong surveillance in a specialist multidisciplinary centre

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