Multiple Endocrine Neoplasia (MEN) Syndromes

Meet the patient

A 28-year-old woman is referred to the thyroid surgeon for a firm neck nodule and a palpable cervical node. Fine-needle aspiration returns medullary thyroid carcinoma. Her father had a thyroid operation in his thirties and died suddenly at forty-two, "a heart attack, they said." Her blood pressure in clinic is 160/100, and the nurse notes she has been pale and sweaty.[1][2]

Before anyone books a thyroidectomy, one question must be answered — the question that defines this whole disease: has anyone excluded a phaeochromocytoma? An undiagnosed phaeo under anaesthesia is a classic, preventable death, and in a MEN 2 patient the thyroid operation is precisely where it hides. Everything below exists to keep her safe on the table and to find the syndrome in her family.[1][11]

What MEN actually is — two genes, opposite directions, one discriminator

MEN is the paradigm of hereditary endocrine cancer: one germline mutation, several glands, a lifetime of tumours. The syndromes are autosomal dominant, so every child of an affected parent carries a 50 percent risk, and finding one endocrine tumour in a young patient obliges you to hunt for the others in the patient and across the family.[1][2]

Two genes dominate, and they fail in opposite molecular directions. MEN 1 is loss of a tumour SUPPRESSOR — the MEN1 gene encoding menin on chromosome 11q13. MEN 2 is activation of a PROTO-oncogene — the RET receptor tyrosine kinase on chromosome 10q11.2. A fifth syndrome, MEN 4, is loss of CDKN1B (p27) and mimics MEN 1 but is far rarer. The clinical skill is to read the pattern, confirm it genetically, then act — prophylactic thyroidectomy in MEN 2 RET carriers, lifelong surveillance in MEN 1.[1][5]

Etymology for viva gold: Wermer (MEN 1) and Sipple (MEN 2A) are the clinicians who first described the clusters; drop the eponym and the gene in the same breath and you sound like you have been to a genetics clinic. menin and RET (REarranged during Transfection) are the two words that decide almost every MEN question.[2]

The four syndromes face-off — read the triad, name the gene

Recognising the gland triad at the bedside makes the genetic diagnosis. Each syndrome is defined by a gene, a cluster of tumours and a penetrance pattern — and the triad is so stereotyped that a confident clerk can call it before the bloods return.[1][2]

[1]

The ATA RET mutation risk categories refine MEN 2 management. The American Thyroid Association sorts RET mutations into highest (ATA-D — the MEN 2B M918T codon 918, where MTC can be aggressive in infancy), high (ATA-C — the C634R codon 634 typical of MEN 2A), and moderate (ATA-A/B — codons such as 609, 611, 618, 620, 630, 768, 790, 791, 804, 891). That risk level sets the age at which prophylactic thyroidectomy is offered — the practical translation of molecular genetics into surgical timing.[3][7]

Why MEN 1 loses a brake and MEN 2 floors an accelerator — the molecular fork

MEN is the cleanest illustration in medicine of the two opposing mechanisms of inherited cancer. Understand the direction of the molecular defect and the inheritance, the penetrance and — in MEN 2 — the codon-specific timing of surgery all fall into place.[1][5]

MEN 1 — loss of the MEN1 tumour suppressor. A germline loss-of-function mutation in one MEN1 allele is inherited; a second somatic hit (the Knudson two-hit hypothesis) then knocks out the remaining wild-type allele in a parathyroid, pituitary or pancreatic endocrine cell. With both copies gone, the cell loses menin — a nuclear protein that brakes proliferation through transcription-factor and chromatin complexes — and clonal expansion follows in parathyroid chief cells, anterior pituitary secretory cells and pancreatic islet neuroendocrine cells. The same two-hit logic explains why the tumours are multi-gland and metachronous.[4][6]

MEN 2 — activation of the RET proto-oncogene. RET encodes a receptor tyrosine kinase expressed on parafollicular C cells of the thyroid, adrenal chromaffin cells and, to a lesser extent, parathyroid chief cells — exactly the cells that give rise to the MEN 2 tumours. Unlike MEN 1, only a single activating mutation is needed; no second hit is required because the mutant receptor is already switched on. The mutations cluster in two functional regions:[1][3]

• Extracellular cysteine-rich domain, codon 634. Substituting a cysteine leaves a free thiol that drives ligand-independent receptor dimerisation and switches on the kinase. Codon 634 (C634R) is the classic MEN 2A mutation and carries the full triad.
• Intracellular tyrosine kinase domain, codon 918. The M918T substitution in the catalytic core alters substrate specificity and is the most potent activating mutation — essentially diagnostic of MEN 2B, with MTC arising in utero or infancy.[7]

Downstream, constitutive RET signalling drives the RAS-RAF-MEK-ERK and PI3K-AKT pathways. The specific codon sets the phenotype (Machens genotype-phenotype correlations): codon 634 gives MEN 2A, codon 918 gives MEN 2B, and moderate-risk codons give familial medullary thyroid carcinoma or attenuated MEN 2A. That is the molecular basis for risk-adapted prophylactic thyroidectomy.[7]

MEN 4 — loss of CDKN1B (p27). CDKN1B encodes p27, a cyclin-dependent kinase inhibitor that restrains the G1-to-S transition. Loss-of-function germline mutations reproduce a MEN 1-like phenotype and should be suspected when a patient has a MEN 1 phenotype but negative MEN1 sequencing.[5][8]

The clinical faces — Wermer's three Ps, Sipple's triad, and the child you diagnose by looking

The clinical face of MEN is several separate endocrine syndromes stacked in one patient or family. Each tumour produces its own classic picture; the diagnostic leap is to see the pattern.[1][2]

MEN 1 — the three Ps across a lifetime. Primary hyperparathyroidism is earliest and commonest (about 90 percent by age 50), arising from multi-gland hyperplasia and presenting with renal stones, bone pain, fatigue, polyuria, abdominal groans and psychic moans; because it is multi-gland, it appears younger and recurs more often than sporadic disease. Pituitary adenoma occurs in 30 to 40 percent, with prolactinoma the commonest subtype (galactorrhoea, amenorrhoea, infertility, erectile dysfunction, mass effect with bitemporal hemianopia). Pancreatic neuroendocrine tumour most often means gastrinoma and Zollinger-Ellison syndrome (refractory peptic ulceration and diarrhoea); insulinoma is second, with Whipple's triad of fasting neuroglycopaenia.[4][10]

MEN 2A — Sipple's triad. Medullary thyroid carcinoma is the first manifestation in nearly all carriers (penetrance near 100 percent), presenting as a thyroid nodule or cervical lymphadenopathy, sometimes with diarrhoea and flushing from tumour calcitonin. Phaeochromocytoma develops in about half — often bilaterally — producing the classic triad of episodic headache, sweating and palpitations with paroxysmal or sustained hypertension. Primary hyperparathyroidism is milder than in MEN 1 (about 20 percent, multi-gland).[1][2]

MEN 2B — the child you diagnose by walking to the bed. The phenotype is unmistakable. Aggressive medullary thyroid carcinoma appears in infancy and is the leading cause of death. Mucosal neuromas stud the lips, anterior tongue, buccal mucosa, eyelids and conjunctiva, giving prominent, everted, bumpy lips. Marfanoid habitus (tall stature, long limbs, arachnodactyly, pectus, kyphoscoliosis) overlaps with Marfan — but MEN 2B has no aortic root dilatation and no lens dislocation. Ganglioneuromatosis of the gut causes chronic constipation and megacolon, often mislabelled as Hirschsprung disease. Phaeochromocytoma completes the picture.[1][2]

The classic trap — the MEN 2B child labelled Marfan or Hirschsprung. A child with marfanoid habitus and constipation may carry a RET codon 918 mutation, and the MTC can already be metastatic. A young adult with recurrent renal stones alone may have MEN 1 hyperparathyroidism; refractory peptic ulceration may be MEN 1 gastrinoma; any bilateral phaeochromocytoma deserves a hereditary workup (MEN 2, VHL, NF1, SDHx). And every patient with medullary thyroid cancer — any age, any family history — must be offered RET testing, because about a quarter of MTC is hereditary.[1][3]

The differential face-off — is the thyroid cancer hereditary? Is the phaeo syndromic?

The differentials split into three questions: is the thyroid cancer hereditary, is the hyperparathyroidism familial, is the phaeo syndromic? Answer each with the right test.[1][2]

About 25 percent of all medullary thyroid cancer is hereditary (MEN 2 or FMTC). The discriminating test is germline RET sequencing, indicated in every newly diagnosed MTC patient regardless of family history; sporadic MTC is usually a single RET-negative (often somatic M918T) tumour in an older adult. Sporadic primary hyperparathyroidism is a single parathyroid adenoma in a middle-aged woman, whereas MEN 1 is multi-gland hyperplasia, younger onset, recurrence after surgery, and pituitary or pancreatic company. Bilateral, multifocal, young-onset or extra-adrenal phaeo points to MEN 2 (RET), VHL, NF1 or the SDHx paraganglioma syndromes.[1][9]

[2]

The one-line discriminator beneath: a marfanoid habitus with aortic disease or lens dislocation is Marfan; the same habitus with mucosal neuromas and a thyroid nodule is MEN 2B.[2]

The bedside round — phenotype, family map, and the one question before any operation

Bedside assessment in MEN does three jobs: recognise the phenotype, enumerate the tumours, and map the family — then make the operation safe.[1][2]

• Recognise the phenotype. In suspected MEN 2B, inspect the face and mouth — thickened bumpy lips, mucosal neuromas on tongue and eyelids, the long-limbed marfanoid build are pathognomonic. In suspected MEN 1, look for galactorrhoea and visual fields (prolactinoma), and the signs of hypercalcaemia and peptic ulceration. In suspected MEN 2, take the blood pressure (phaeo), palpate the thyroid and cervical nodes (MTC), and ask about episodic headache, sweating and palpitations.
• Map the family. A three-generation pedigree is mandatory — thyroid cancer at a young age, phaeochromocytoma, hyperparathyroidism, renal stones, peptic ulcer disease, sudden cardiac death and pituitary disease all count. A de-novo mutation has a negative family history, so a negative family history does not exclude MEN.
• Make the operation safe. Before any operation — or invasive procedure, or labour — in a MEN 2 patient, exclude phaeochromocytoma with plasma or 24-hour urine fractionated metanephrines. An undiagnosed phaeo under anaesthesia is one of the classic preventable deaths in medicine.[1][11]

Confirm the gene, then map the tumours — the fixed diagnostic ladder

Genetic testing is the cornerstone — once a pathogenic mutation is found in the proband, predictive testing of relatives turns high-risk anxiety into a focused, age-defined programme. Investigation has two goals: confirm the syndrome genetically, and define the tumour burden biochemically and radiologically.[1][4]

[1] [3] [4]

MEN 1 surveillance runs from age 5. A confirmed or at-risk carrier enters annual surveillance: serum calcium and intact PTH (the commonest, earliest tumour), prolactin and IGF-1 (pituitary), fasting glucose, insulin, gastrin, chromogranin A, glucagon, VIP and pancreatic polypeptide (enteropancreatic NET). A pituitary MRI every three years and abdominal cross-sectional imaging every one to three years complete the screen; basal and stimulated gastrin with a secretin stimulation test localises gastrinoma.[4][6]

MEN 2 surveillance runs from age 5 or earlier. A confirmed RET carrier has annual basal and stimulated calcitonin for C-cell disease and MTC, plasma or 24-hour urine fractionated metanephrines for phaeo (from age 5 in MEN 2A), and serum calcium and PTH in MEN 2A only. Neck ultrasound and CT or MRI of the adrenals image the relevant glands.[1][3]

Medullary thyroid cancer is tracked with calcitonin and CEA — NOT thyroglobulin. Thyroglobulin follows papillary and follicular thyroid cancer, which arise from follicular cells, not the parafollicular C cells that give rise to MTC. Calcitonin doubling time is the single best prognostic marker: a doubling time under 6 months predicts a poor outcome, while over 24 months predicts an indolent course.[3][13]

MEN 1 — treat each of the three Ps, and screen the family from age five

Definitive management of MEN 1 is syndrome-specific, lifelong, and built on one principle: treat each tumour, prevent what you can, and screen the family forever.[4][6]

Primary hyperparathyroidism is the commonest manifestation and is surgically treated. Because the disease is multi-gland hyperplasia, the operation of choice is subtotal parathyroidectomy — a 3.5-gland resection leaving about 50 mg of the most accessible gland in situ — with transcervical thymectomy, or total parathyroidectomy with forearm autotransplantation. The aim is durable normocalcaemia without permanent hypoparathyroidism; recurrence is commoner than in sporadic disease, so an experienced endocrine surgeon is essential.[4][9]

Pituitary adenoma. Prolactinoma is treated first-line with the dopamine agonist cabergoline (0.5 to 2 mg twice weekly, titrated to prolactin and tumour shrinkage); transsphenoidal surgery is reserved for macroadenoma with chiasmal compression or dopamine-agonist resistance. Acromegaly and Cushing disease follow their standard pathways.[4][6]

Enteropancreatic neuroendocrine tumours. Gastrinoma (Zollinger-Ellison syndrome) is controlled medically with a high-dose proton pump inhibitor — omeprazole 40 to 80 mg per day — which prevents peptic complications; octreotide (a somatostatin analogue) helps both hormonal and tumour control, and surgical resection of localised duodenal or pancreatic gastrinoma is considered when metastases are absent. Insulinoma is treated by surgical enucleation (or partial pancreatectomy for multiple lesions) once localised; diazoxide (300 to 1200 mg per day in divided doses) suppresses insulin secretion for refractory hypoglycaemia. Functional metastatic disease is managed with somatostatin analogues, everolimus, sunitinib or peptide-receptor radionuclide therapy.[4][10]

[4] [10]

MEN 2 — prophylactic thyroidectomy by codon, and exclude the phaeo before any cut

In MEN 2, medullary thyroid carcinoma is the leading cause of death, so management centres on preventing or curing it surgically — and on never letting a hidden phaeo kill the patient on the table.[1][3]

[1]

The definitive operation for MTC is total thyroidectomy with central neck (level VI) dissection; lateral neck dissection (levels II to V) is added for nodal disease. C-cell tumours do not take up radioiodine — ablation is useless — and do not respond to TSH suppression like differentiated thyroid cancer, so postoperative levothyroxine is for replacement, not suppression. Advanced or metastatic MTC is treated with the tyrosine kinase inhibitors cabozantinib or vandetanib, the first effective systemic therapies.[1][3]

Prophylactic thyroidectomy in RET carriers is the paradigm of hereditary cancer prevention, and the ATA 2015 guideline times it by mutation risk:[3][7]

[3]

Phaeochromocytoma is treated by adrenalectomy after adequate preoperative alpha-blockade. The classical regimen is phenoxybenzamine — a non-competitive, irreversible alpha-blocker — 10 mg twice daily, titrated every 2 to 3 days, given for 10 to 14 days preoperatively with liberal salt and fluid to expand intravascular volume; a beta-blocker (propranolol 20 to 40 mg three times daily) is added only after alpha-blockade for tachycardia. Modern practice increasingly uses selective alpha-1 blockers such as doxazosin 2 to 8 mg daily, and a large US study reported that phenoxybenzamine is no longer the standard agent in many centres — but the principle of alpha before beta is universal.[11][12]

The consultant confession: the codon sets the clock — operate on a MEN 2B infant in the first months and you may cure the MTC; wait until school age and you may be treating metastases. The calendar is part of the prescription.[3][7]

[1] [3] [11]

Phaeo crisis and the alpha-before-beta rule — the first fifteen minutes

A catecholamine crisis in a MEN 2 patient is a hypertensive emergency, and the first drug is an alpha-blocker, never a beta-blocker. It is precipitated by anaesthesia induction, tumour handling, opiates, contrast or abdominal palpation — and it may be the first sign of the disease.[1][11]

Undiagnosed phaeo under anaesthesia — especially during thyroidectomy in an unscreened MEN 2 patient — is the classic fatal pitfall. If intraoperative hypertension explodes, abort the procedure, give IV phentolamine, admit to ICU, and complete alpha-blockade before any re-operation. This is exactly why every MEN 2 patient is screened for phaeo before any surgery.[1][11]

How MEN patients come to harm — the preventable list

Most deaths in MEN are preventable, and they cluster around five avoidable errors.[1][2]

• Operating on a MEN 2 patient without excluding the phaeo first — the classic anaesthetic death; a beta-blocker given first converts a crisis into an unopposed-alpha catastrophe.
• Missing the MEN 2B child by labelling it Marfan or Hirschsprung — the MTC is already metastatic by the time the tongue neuromas are finally noticed.
• Treating one tumour and ignoring the syndrome — a young patient with multi-gland hyperparathyroidism, bilateral phaeo, MTC or gastrinoma must be tested for MEN and the family screened.
• Following MTC with the wrong marker — thyroglobulin tracks follicular tumours, not C-cell MTC; use calcitonin and CEA, and remember MTC does not take up radioiodine.
• Late or absent genetic testing — failing to RET-test every MTC patient (about a quarter is hereditary) or to cascade-screen relatives (MEN 2 from birth, MEN 1 from age 5).[1][3]

Prognosis — the codon sets the clock, calcitonin tells the time

Prognosis depends on the syndrome and the dominant tumour, and in MEN 2 the codon is the clock. MEN 2B has the worst prognosis — aggressive MTC arising in infancy, often metastatic at diagnosis — and survival has improved only with early genetic diagnosis and prophylactic thyroidectomy in the first months of life. MEN 2A has a good prognosis when RET carriers undergo prophylactic thyroidectomy and lifelong phaeo surveillance. MEN 1 prognosis is dominated by the pancreatic NET burden — malignant gastrinoma and thymic carcinoid are the main cancer-related deaths, while primary hyperparathyroidism and prolactinoma are eminently manageable.[1][4]

For medullary thyroid cancer, the calcitonin doubling time is the single best prognostic marker: under 6 months predicts a poor outcome (five-year disease-specific mortality around 25 to 50 percent), while over 24 months predicts an indolent course. Postoperative calcitonin and CEA are followed lifelong.[3][13]

Disposition is lifelong and family-wide. Every MEN patient stays in structured endocrine surveillance for life, and the diagnosis triggers a cascade genetic testing programme reaching parents, siblings and children. The modern multidisciplinary endocrine cancer service — endocrinology, endocrine surgery, genetics, thyroid surgery, nuclear medicine, oncology and reproductive medicine — is the right setting.[1][6]

Children, families, pregnancy, and the de-novo trap

Children with RET mutations are the paradigm of preventive surgery in hereditary cancer. Prophylactic thyroidectomy is timed by ATA risk — MEN 2B (codon 918) in infancy, MEN 2A (codon 634) by about age 5, and moderate-risk mutations individualised to the calcitonin trajectory. Lifelong levothyroxine replacement (and calcium with calcitriol if hypoparathyroid) is required; paediatric anaesthetic and endocrine expertise is essential.[3][7]

Family screening and genetic counselling. All MEN syndromes are autosomal dominant with a 50 percent risk to children. Predictive testing of at-risk children — MEN 2 from birth, MEN 1 from age 5 — is offered with pre- and post-test counselling on psychosocial, reproductive, employment and insurance implications; pre-implantation genetic testing is available for affected adults planning a family.[1][4]

The de-novo trap. About a quarter of MEN 2B and a smaller fraction of MEN 2A and MEN 1 arise de novo. The parents test negative and need no surveillance — but every child of the proband still carries a 50 percent risk, so the index case is the gateway to cascade screening, not a dead end.[1]

Pregnancy. In MEN 2, exclude and treat phaeochromocytoma before conception or early in pregnancy — a phaeo crisis in labour is potentially fatal; prophylactic thyroidectomy is normally completed before reproductive age. In MEN 1, watch for prolactinoma enlargement under oestrogen and monitor hypercalcaemia. Older adults with newly diagnosed MEN have surveillance scaled to comorbidity, but phaeo exclusion before any surgery remains non-negotiable at any age.[1][4]

MEN 4 (CDKN1B / p27) is suspected when a patient has a clinical MEN 1 phenotype but negative MEN1 sequencing; surveillance mirrors the MEN 1 programme, and the genetic counselling cascade is distinct. Familial medullary thyroid carcinoma (FMTC) is a milder MEN 2 variant in which MTC is the only tumour — phaeo screening continues because some families later declare phaeo and "tip" into MEN 2A.[5][8]

Evidence, controversy, and regional deltas

The American Thyroid Association 2015 Revised Guidelines for Medullary Thyroid Carcinoma (Wells et al) are the practice-defining document for MEN 2 — they establish the RET mutation risk categories (highest ATA-D, high ATA-C, moderate ATA-A/B) that drive prophylactic thyroidectomy timing, the calcitonin-based surveillance schedule, and total thyroidectomy with central neck dissection. Machens genotype-phenotype work underpins the codon-specific surgical timing.[3][7]

For MEN 1, the Endocrine Society and European Society of Endocrinology 2012 clinical practice guidelines (Thakker et al, JCEM) defined the surveillance and management framework, and the 2025 best-practice update (Brandi et al, Lancet Diabetes and Endocrinology) consolidates the contemporary multidisciplinary approach.[4][6]

The live controversy is the choice of preoperative alpha-blockade. Traditional teaching and van der Zee's 2014 review favour non-competitive phenoxybenzamine for its complete, irreversible blockade. A 2023 US national study of 552 patients (Kuo et al) reported that phenoxybenzamine is no longer the standard agent — selective alpha-1 blockers such as doxazosin are now more commonly used in many centres — but the alpha-before-beta principle is universal.[11][12]

Where the evidence is weak. The exact age of prophylactic thyroidectomy in moderate-risk RET carriers (individualised to calcitonin trajectory); the preferred preoperative alpha-blocker (phenoxybenzamine versus doxazosin); the timing and extent of surgery for MEN 1 hyperparathyroidism (subtotal versus total with autotransplant); and the place of Lu-177 DOTATATE PRRT and TKIs in the long-term algorithm for metastatic NET and MTC.[7][9][12]

The mantra, and the mnemonics

[1] [3]

The mantra: MTC means RET — exclude the phaeo before any operation, prophylactic thyroidectomy by codon risk.[1][3]

Ward-round test — three stems, thirty seconds each

Stem 1 — the thyroidectomy booked without a phaeo screen (answer)

A 28-year-old with biopsy-proven medullary thyroid carcinoma is listed for total thyroidectomy. Her blood pressure is 160/100 and her father died suddenly at forty-two. The registrar has already written for the anaesthetic. What must happen before she reaches theatre? Model: Stop and screen for phaeochromocytoma first — this is MEN 2A until proven otherwise. Send plasma free metanephrines or 24-hour urine fractionated metanephrines, and offer RET germline testing (codon 634 likely; about 25 percent of MTC is hereditary). If a phaeo is confirmed, alpha-blockade first — phenoxybenzamine 10 mg twice daily titrated over 10 to 14 days with volume expansion, then a beta-blocker for tachycardia, then adrenalectomy, then thyroidectomy. A beta-blocker given first leaves alpha vasoconstriction unopposed and kills. The cardinal rule is alpha before beta; the cardinal sequence is phaeo out before thyroid out.[1][11]

Stem 2 — the bumpy-lipped child with constipation (answer)

A 14-month-old is in clinic for chronic constipation and failure to thrive. On examination he has prominent bumpy lips, mucosal neuromas on the tongue, a marfanoid build, and a firm thyroid nodule. What is the syndrome, the gene, and the operation? Model: This is MEN 2B, recognised at the bedside by inspection. The gene is RET codon 918 (M918T) — the highest ATA-D risk. Send RET testing and a calcitonin and CEA, and arrange prophylactic total thyroidectomy in infancy — within the first months of life — because MTC can already be metastatic at this age. There is no parathyroid disease in MEN 2B. Screen the parents (often a de-novo mutation, but every future child of the proband carries a 50 percent risk). The operation is part of the diagnosis, not a sequel to it.[1][3]

Stem 3 — the young man with ulcers that will not heal (answer)

A 32-year-old man has refractory peptic ulceration and chronic diarrhoea despite a standard PPI. He also passes renal stones and his serum calcium is 2.85 mmol/L. What syndrome, what marker, and what operation will he eventually need? Model: This is MEN 1 gastrinoma (Zollinger-Ellison syndrome) sitting beside primary hyperparathyroidism — two of the three Ps. Confirm with fasting serum gastrin (and a secretin stimulation test), localise the gastrinoma with CT or MRI and endoscopic ultrasound, and test the MEN1 gene. Acid control needs high-dose omeprazole 40 to 80 mg per day; the hyperparathyroidism will need a 3.5-gland parathyroidectomy with thymectomy. Screen for the third P — a prolactinoma — and offer cascade genetic testing of relatives from age 5. He is at risk of dying from a malignant enteropancreatic NET, so surveillance is lifelong.[4][10]

References

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2. [2]Greenberg LA. Multiple Endocrine Neoplasia Type 1, Type 2A, and Type 2B Prim Care, 2024.PMID 39067973
3. [3]Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma Thyroid, 2015.PMID 25810047
4. [4]Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1) J Clin Endocrinol Metab, 2012.PMID 22723327
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6. [6]Brandi ML, Pieterman CRC, English KA, et al. Multiple endocrine neoplasia type 1 (MEN1): recommendations and guidelines for best practice Lancet Diabetes Endocrinol, 2025.PMID 40523372
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8. [8]Ruggeri RM, Benevento E, De Cicco F, et al. Multiple endocrine neoplasia type 4 (MEN4): a thorough update on the latest and least known men syndrome Endocrine, 2023.PMID 37632635
9. [9]Schreinemakers JM, Pieterman CR, Scholten A, et al. The optimal surgical treatment for primary hyperparathyroidism in MEN1 patients: a systematic review World J Surg, 2011.PMID 21713580
10. [10]Rossi RE, Elvevi A, Citterio D, et al. Gastrinoma and Zollinger Ellison syndrome: A roadmap for the management between new and old therapies World J Gastroenterol, 2021.PMID 34629807
11. [11]van der Zee PA, de Boer A. Pheochromocytoma: a review on preoperative treatment with phenoxybenzamine or doxazosin Neth J Med, 2014.PMID 24829175
12. [12]Kuo EJ, Chen L, Wright JD, et al. Phenoxybenzamine is no longer the standard agent used for alpha blockade before adrenalectomy for pheochromocytoma: A national study of 552 patients Surgery, 2023.PMID 36167697
13. [13]Nigam A, Xu B, Spanheimer PM, et al. Tumor Grade Predicts for Calcitonin Doubling Times and Disease-Specific Outcomes After Resection of Medullary Thyroid Carcinoma Thyroid, 2022.PMID 35950622