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Q1: Classification and the gene-gland pairings (2 min)
Examiner: Name the multiple endocrine neoplasia syndromes. For each, give the gene, the chromosome, the direction of the molecular defect, and the gland triad.
Expected answer:
- MEN 1 (Wermer) — MEN1 gene (menin), chromosome 11q13, tumour SUPPRESSOR (loss-of-function, Knudson two-hit); the 3 P's: Primary hyperparathyroidism (commonest, earliest, multi-gland hyperplasia), Pituitary adenoma (prolactinoma commonest), Pancreatic neuroendocrine tumour (gastrinoma/ZES commonest; insulinoma second).
- MEN 2A (Sipple) — RET proto-oncogene, chromosome 10q11.2, gain-of-function (extracellular cysteine, codon 634); medullary thyroid carcinoma (near 100 percent), phaeochromocytoma (~50 percent, often bilateral), parathyroid hyperplasia (~20 percent).
- MEN 2B — RET codon 918 (M918T, tyrosine kinase domain, highest ATA risk); aggressive MTC, phaeo, mucosal neuromas, marfanoid habitus, ganglioneuromatosis; NO parathyroid disease.
- MEN 4 — CDKN1B (p27/Kip1), a MEN 1 phenocopy; suspect when MEN1 sequencing is negative.
- All autosomal dominant; the decisive discriminator is that medullary thyroid cancer belongs to MEN 2 (RET), never MEN 1.
Q2: Investigations (3 min)
Examiner: A 25-year-old presents with a thyroid nodule; biopsy confirms medullary thyroid carcinoma. How do you confirm the syndrome, and what surveillance does a RET carrier enter?
Expected answer:
- RET germline sequencing is indicated in EVERY newly diagnosed MTC patient (~25 percent is hereditary) — confirm the mutation in the proband.
- Cascade testing of all first-degree relatives FROM BIRTH (50 percent risk; de-novo in ~25 percent of MEN 2B).
- Surveillance biochemistry (annual, from age 5 or earlier): basal (and stimulated) calcitonin (C-cell disease/MTC), plasma or 24-h urine fractionated metanephrines (phaeo), serum calcium and PTH (parathyroid, MEN 2A only).
- MTC markers = calcitonin and CEA (NOT thyroglobulin); calcitonin doubling time under 6 months predicts poor prognosis.
- For MEN 1, MEN1 gene sequencing then surveillance from age 5: calcium/PTH, prolactin/IGF-1, fasting glucose/insulin/gastrin/chromogranin, pituitary MRI every 3 years, abdominal imaging.
Q3: Management (3 min)
Examiner: Walk me through the management of a confirmed RET codon 634 carrier aged 4, and of a MEN 1 patient with gastrinoma.
Expected answer:
- MEN 2A codon 634 carrier, age 4: prophylactic total thyroidectomy with central neck dissection by about age 5 (ATA high-risk, level C); MTC penetrance is near 100 percent and can already be present. ALWAYS exclude phaeochromocytoma before any surgery — phenoxybenzamine 10 mg twice daily x 10 to 14 days, beta-blocker only after alpha-blockade. Annual calcitonin/CEA, metanephrines, calcium/PTH.
- MEN 1 gastrinoma (ZES): high-dose PPI (omeprazole 40 to 80 mg/day) to control acid; octreotide (somatostatin analogue, octreotide LAR 20 to 30 mg IM q4wk) for hormonal and tumour control; surgical resection of localised duodenal/pancreatic gastrinoma if no metastases. For metastatic SSTR-positive disease: Lu-177 DOTATATE PRRT, everolimus, sunitinib, trans-arterial embolisation of hepatic metastases. Treat the other MEN 1 tumours (parathyroidectomy for hyperparathyroidism, cabergoline for prolactinoma, enucleation for insulinoma).
Q4: The non-negotiable rules and prognosis (2 min)
Examiner: What are the two rules you must never break in MEN 2, and what determines prognosis?
Expected answer:
- Rule 1: ALWAYS exclude and treat phaeochromocytoma BEFORE any surgery in MEN 2 (alpha-blockade first — phenoxybenzamine 10 mg twice daily x 10 to 14 days; beta-blocker only after alpha). An undiagnosed phaeo under anaesthesia is fatal.
- Rule 2: Offer PROPHYLACTIC THYROIDECTOMY to RET carriers, timed by ATA mutation risk — MEN 2B (codon 918) in INFANCY, MEN 2A (codon 634) by about age 5, moderate-risk codons individualised to calcitonin.
- Prognosis: MEN 2B worst (aggressive infantile MTC); MEN 2A good with prophylactic thyroidectomy and phaeo surveillance; MEN 1 depends on pancreatic NET burden (malignant gastrinoma/thymic carcinoid the principal causes of death). Calcitonin doubling time is the best MTC prognostic marker. Lifelong, family-wide surveillance is mandatory — the patient never leaves follow-up.