Multiple endocrine neoplasia

• Multiple endocrine neoplasia (MEN) is a group of inherited cancer syndromes in which tumours arise in two or more endocrine glands. The two main families are MEN1 (the Wermer syndrome) and MEN2 (the Sipple syndrome), and a third, MEN4, looks like MEN1 but is milder and often starts later.
• MEN1 is caused by inactivating mutations of the MEN1 gene on chromosome 11q13, which encodes the nuclear protein menin. Its classic tumours are parathyroid hyperplasia or adenoma, pancreatic and duodenal neuroendocrine tumours, and anterior pituitary adenomas, with parathyroid disease present in 80 to 100% of patients by age 50. ^[3]
• MEN2 is caused by gain-of-function mutations of the RET proto-oncogene on chromosome 10q11.2. It always includes medullary thyroid carcinoma, plus phaeochromocytoma and, in most subtypes, parathyroid hyperplasia. The RET mutation tells you how aggressive the thyroid cancer will be and therefore when the thyroid must be removed.
• MEN4 is caused by mutations in the cyclin-dependent kinase inhibitor gene CDKN1B (p27). It overlaps clinically with MEN1 but has a lower burden of pancreatic neuroendocrine tumours and no mucosal neuromas.
• Because these syndromes are hereditary and autosomal dominant, one affected person means half of first-degree relatives are at risk. Genetic testing and a structured surveillance programme, rather than waiting for symptoms, are what prevent the cancers.
• All topic content here is free to read; there is no sign-in. These notes are educational material and are not a substitute for specialist endocrine or genetics advice.

By the end of this page you should be able to:

1. State the gene and inheritance pattern for MEN1, MEN2 (A and B) and MEN4, and the typical tumour spectrum of each.
2. Tell a MEN1 phenotype from a MEN2 phenotype in a patient, and recognise the mucosal and skeletal clues to MEN2B.
3. Give the three diagnostic criteria for MEN1 and the indications for MEN1 and RET mutational analysis.
4. Plan surveillance for a known MEN1 mutation carrier using the age-based table, and adapt it cautiously for MEN4.
5. Stratify a RET mutation into ATA highest, high or moderate risk and state the recommended age of prophylactic thyroidectomy for each. ^[2]
6. Outline the surgical and medical management of the parathyroid, pancreatic neuroendocrine and pituitary tumours of MEN1 in broad terms.
7. Recognise the MEN1 phenocopies and the tumours that must be excluded before calling a patient "MEN1".
8. Describe safe practice in a low-resource setting, where genetic testing or imaging may not be available.

MEN is one family of several hereditary endocrine tumour syndromes. The others that matter in differential diagnosis are the hereditary paraganglioma and phaeochromocytoma syndromes (mutations in the SDH genes), von Hippel-Lindau disease, Carney complex, and Carney-Stratakis syndrome. They are not the same disease and need not be confused with MEN, but a patient with a phaeochromocytoma or a young paraganglioma should prompt a wider genetic panel, not only a RET test.

MEN is split into two classical families on clinical and genetic grounds.

• MEN1 (Wermer syndrome), about 1 in 30,000 people (estimates range from 1 in 10,000 to 1 in 40,000), is a tumour suppressor syndrome: the MEN1 protein menin is lost and multiple small tumours grow in the parathyroid, duodenum, pancreas and pituitary.
• MEN2 (Sipple syndrome and its variants) is an activating oncogene syndrome: a RET mutation drives medullary thyroid carcinoma in every patient, with phaeochromocytoma and parathyroid disease in many. MEN2 accounts for the inherited fraction of medullary thyroid carcinoma.
• MEN4 is the most recently described member. It is an MEN1-like syndrome caused by mutations in CDKN1B (p27). It is very rare, and most published cohorts describe only a few dozen mutation-positive individuals.

• MEN1 has an estimated prevalence of about 1 in 30,000 individuals (published estimates range from 1 in 10,000 to 1 in 40,000) and no clear gender predominance. The age-related penetrance is roughly 45 to 73% by 30 years, 82% by 50 years and 96% by 70 years. ^[3]
• In a cohort of 924 patients with MEN1, 160 (17%) developed an MEN1-associated tumour before 21 years of age; primary hyperparathyroidism was diagnosed in 75% by age 21, and pituitary adenomas and pancreatic neuroendocrine tumours each in about a third. Lesions have been described in the first 5 years of life, but most appear after age 10. ^[1]
• MEN2A is the commonest variant of MEN2. Published incidence figures are about 1 in 1.97 million (MEN2A) and 1 in 38.8 million (MEN2B), and about 95% of hereditary medullary thyroid cancer belongs to the MEN2 syndromes. ^[2]
• Familial cases account for roughly 25% of MEN2B (the rest are de novo RET mutations), while about 90% of MEN1 passes from an affected parent and 10% arises de novo. ^[1][2]
• MEN4 is extremely rare: its prevalence is estimated at less than one per million, and the largest family reports describe only 13 mutation-positive members. ^[4][5]

The genetic basis is the single most useful thing to know about MEN, because management follows the gene.

• Gene: MEN1, on chromosome 11q13, ten exons, about 9,000 base pairs. ^[1]
• Protein: menin, 610 amino acids, predominantly nuclear, ubiquitously expressed. It has two main nuclear localisation signals (a third accessory one) and no intrinsic enzyme activity; it works by binding more than 50 partner proteins in chromatin and transcription complexes. ^[1]
• Inheritance: autosomal dominant with 90% penetrance by 70 years. Germline heterozygous mutations are found in 70 to 90% of familial cases; the frequency of de novo mutations is much lower in sporadic cases.
• Mutation types: more than 1,200 germline mutations have been described, scattered across the coding region with no hot spots. Roughly two thirds predict truncation of menin (frameshift, nonsense, splice defects and large deletions); most of the rest are missense or in-frame changes. The exact percentages differ between series and classifications. ^[1]
• Two-hit tumour suppression: Knudson's model applies. A patient carries one inactivated allele from birth; a second somatic event in the other allele in an endocrine cell removes the remaining menin and initiates a tumour.
• Those without a mutation: 5 to 25% of patients who look clinically like MEN1 have no detectable MEN1 coding-region mutation. Some of these are whole or partial gene deletions, mutations in the promoter or untranslated regions, or phenocopies involving other genes (see below). ^{[1] [5]}

• Gene: RET (REarranged during Transfection), chromosome 10q11.2, encoding a single-pass transmembrane receptor tyrosine kinase expressed in neural crest-derived and urogenital tissues.
• Inheritance: autosomal dominant with incomplete penetrance of the non-thyroid tumours. Almost all patients with MEN2 carry a germline RET mutation.
• Mechanism: gain of function. The mutation leaves the receptor signalling without ligand, so one altered allele is enough; this is the opposite of the MEN1 tumour-suppressor mechanism. Almost every MEN2 patient therefore has MEN2 on one altered copy of RET.
• Variants: MEN2A (classical MEN2A, cutaneous lichen amyloidosis, and Hirschsprung variants plus the FMTC spectrum) in about 95% of MEN2; MEN2B in about 5%. ^[2]
• Risk classification: ATA highest risk (HST) = MEN2B with RET codon M918T; ATA high risk (H) = RET codon C634 mutations and A883F; ATA moderate risk (MOD) = all other RET mutations associated with MEN2. HST, H and MOD replace the old levels D, C, and A/B and drive the timing of thyroidectomy. ^[2]

• Gene: CDKN1B, which encodes p27Kip1, a cyclin-dependent kinase inhibitor that blocks progression from G1 to S phase of the cell cycle.
• Inheritance: autosomal dominant; penetrance appears high in reported families but cannot be estimated with confidence because of rarity.
• Relationship with menin: menin promotes histone methylation and increases transcription of p27 (and p18), so loss of menin and loss of p27 act on the same brake on cell division. That is why MEN4 looks like MEN1.
• Phenotype: parathyroid adenomas or hyperplasia with primary hyperparathyroidism are the most consistent and often the only tumour. Pituitary adenomas, including prolactinomas less commonly than in MEN1, and gastrointestinal neuroendocrine tumours occur in some cases. Onset is generally later than MEN1 and the disease is milder. ^[4][5]

For MEN1, the pathway is "lose the brake". Menin is a scaffold in chromatin-remodelling complexes; its loss changes the expression of genes that restrain endocrine cell division and also impairs DNA repair. The result is stepwise, multicentric growth: all four parathyroid glands become hyperplastic (asynchronous and of different sizes), the duodenum accumulates micro-gastrinomas, and the pancreatic islets form hundreds of tiny non-functional tumours that can grow for decades before becoming clinically significant. That multicentricity explains why MEN1 surgery is so often not curative in the way sporadic single-tumour surgery can be.

For MEN2, the pathway is "foot on the accelerator". A mutated RET receptor signals constantly, driving C-cell hyperplasia in the thyroid medulla to medullary carcinoma, often requiring only months in the MEN2B phenotype. The same signal transforms adrenal medullary chromaffin cells into phaeochromocytoma and parathyroid chief cells into hyperplasia. The speed of transformation is what makes the age of prophylactic thyroidectomy so time-critical in MEN2B.

For MEN4, the pathway is plausibly the same brake as MEN1 but weaker: p27 deficiency allows cell-cycle progression. Tumours in MEN4 are usually fewer and smaller, and parathyroid disease is more often indolent.

MEN1 usually comes to light in one of three ways: an unexpected calcium, an unexpected pituitary finding, or a family screening.

• Primary hyperparathyroidism is the most common and earliest manifestation and is present in 80 to 100% of patients by 50 years, with onset in the third decade (mean age 20 to 25 years). Unlike sporadic disease, it affects men and women equally, involves multiple glands, recurs after surgery in up to 50% by 12 years, and causes more bone mineral loss, including in the distal radius. Symptoms are those of hypercalcaemia: renal stones, polyuria and polydipsia, constipation, lethargy, depression, sometimes peptic ulcer disease. The degree of calcium elevation is usually mild. ^[1][3]
• Pancreatic and duodenal neuroendocrine tumours occur in 30 to 80% of patients by 40 years, with gastrinoma the most common functioning tumour and Zollinger-Ellison syndrome the first manifestation in up to 40% of patients. Up to 60% of patients with MEN1 have Zollinger-Ellison syndrome or an asymptomatic rise in gastrin. Tumours are small, multiple and diffuse (microadenomatosis), and gastrinomas are predominantly duodenal and metastasise to peripancreatic lymph nodes in one to two thirds of cases at diagnosis. Non-functional pNETs are also common and are now the leading cause of death because of their malignant potential. Insulinoma is the second most common functioning pNET, often diagnosed under 40 years and under 20 years in MEN1. ^[1][3]
• Anterior pituitary tumours develop in roughly 15 to 50% of patients, often as prolactinomas (about 60%), less often as growth-hormone (about 25%) or ACTH (about 5%) secreting tumours, and sometimes as non-functional mass lesions. In MEN1 they tend to be larger and more aggressive than sporadic pituitary adenomas, though in modern series many screen-detected tumours are non-functional microadenomas that remain stable. ^[1][3]
• Other MEN1 tumours: foregut carcinoids (thymic, bronchial) in 5 to 10%, gastric enterochromaffin-like tumours, adrenocortical tumours in up to 40 to 50%, very rare phaeochromocytoma (under 1%), and non-endocrine lesions (lipomas, angiofibromas, collagenomas, meningiomas, ependymomas). Women with MEN1 may have an increased risk of breast cancer. ^[1][3]
• Presentation can be late: MEN1 is often diagnosed only 7 to 12 years after the first symptom, because stones or a prolactinoma do not obviously connect. Genetic testing of family members reduces this lag. ^[3]

Every patient with MEN2 (including those with the FMTC variant of MEN2A) develops medullary thyroid carcinoma if the thyroid is left in place, so the whole clinical picture revolves around the neck and the adrenal.

• MEN2A (classical): medullary thyroid carcinoma, phaeochromocytoma (about 50% penetrance, higher with C634 mutations), hyperparathyroidism (up to 30% with C634, and 2 to 12% with exon 10 mutations), often mild and multiglandular. Parathyroid surveillance can therefore reasonably run alongside phaeochromocytoma surveillance. ^[2]
• MEN2B: medullary thyroid carcinoma in infancy, phaeochromocytoma (about 50%), and a distinctive non-endocrine phenotype: a marfanoid body habitus, narrow long facies, pes cavus, pectus excavatum, scoliosis, thickened everted eyelids, prominent corneal nerves, inability to produce tears in infancy, ganglioneuromatosis of the gastrointestinal tract with bloating, constipation and diarrhoea, mucosal neuromas of the lips and tongue, and a typical facies. Crucially, parathyroid disease is essentially absent (less than 1%). Hyperparathyroidism screening is not required in MEN2B. Last, these patients are not usually tall and marfanoid in the simple sense sometimes taught: the habitus is a skeletal pattern, not true Marfan syndrome. ^[2]
• FMTC: families with two or more generations with medullary thyroid carcinoma and no phaeochromocytoma or hyperparathyroidism. Most investigators now treat FMTC as a variant along the spectrum of MEN2A, not as a separate syndrome. ^[2]

Patients with MEN4 present with primary hyperparathyroidism and pituitary adenomas most often. Gastroenteropancreatic neuroendocrine tumours are less common than in MEN1, with a lower penetrance, and prolactinomas (common in MEN1) were not reported in early MEN4 series and are rare in later ones. Some families also include acromegaly, Cushing disease, bronchial carcinoid, papillary thyroid carcinoma, and meningioma. Primary hyperparathyroidism usually appears later and is milder, often as asymptomatic hypercalcaemia. ^[4][5]

If a young patient has two or more endocrine tumours, do not jump to "MEN1". The following phenocopies and overlaps are all real and change management.

• MEN4 (mutations in CDKN1B) accounts for roughly 1 to 3% of patients who meet clinical criteria for MEN1 but have no MEN1 mutation. ^{[1] [5]}
• Other cyclin-dependent kinase inhibitors (mutations in CDKN1A, CDKN2B, CDKN2C) explain another 1 to 2% of MEN1-like phenocopies. ^[1]
• Familial isolated primary hyperparathyroidism (FIHP): germline MEN1 mutations have been described in these families, with a higher frequency of missense mutations than in classic MEN1. ^[1]
• Hyperparathyroidism-jaw tumour syndrome (CDC73): parathyroid carcinoma risk, ossifying jaw lesions, renal lesions; management differs, including more aggressive parathyroid surgery. ^[1][3]
• Familial hypocalciuric hypercalcaemia (CASR, GNA11, AP2S1): parathyroid surgery does not cure it, so distinguishing it from MEN1 prevents an unnecessary operation. ^[3]
• Familial isolated pituitary adenoma (AIP): think of this when a child or adolescent has a prolactinoma or somatotrophinoma, and work it up before assuming MEN1. ^[1]
• MEN2 and medullary thyroid cancer in a patient also found to have hyperparathyroidism: the diagnosis should rest on germline RET testing, since the neck findings of MEN2 look nothing like MEN1 under the microscope but can co-occur by chance.
• Sporadic clustering of common tumours (for example a prolactinoma in one patient and a parathyroid adenoma in a relative) by chance: commoner than any syndrome.
• Non-MEN hereditary endocrine tumour syndromes with overlapping glands: Carney complex (skin and heart myxomas, pigmentation, PRKAR1A, Cushing, GH-secreting adenoma), von Hippel-Lindau disease, and the paraganglioma or phaeochromocytoma syndromes. ^[3]

By the Endocrine Society 2012 criteria, a clinical diagnosis of MEN1 is made if any of the following is true:

1. Two or more primary MEN1-associated endocrine tumours (parathyroid, enteropancreatic, or anterior pituitary).
2. One such tumour in a first-degree relative of a person with clinical MEN1.
3. A germline MEN1 mutation in an individual who may be completely asymptomatic. ^[1]

Genetic testing should be offered for MEN1 mutational analysis in:

• an index case with two or more MEN1-associated endocrine tumours;
• suspicious or atypical MEN1, including parathyroid adenoma before 30 years, multi-gland disease, gastrinoma or multiple pNETs at any age, or two MEN1-associated tumours not in the classic triad;
• an asymptomatic first-degree relative of a known MEN1 carrier;
• a first-degree relative of a mutation carrier who also expresses familial MEN1. ^[1]

Testing is by PCR of the coding region and splice junctions, with multiplex ligation probe amplification if sequencing is negative, so that large deletions are not missed. It should be performed in an accredited laboratory, after genetic counselling, with pre- and post-test counselling, and as early as possible (before age 5 when asymptomatic). MEN1 mutations are classified among more than 1,200 variants, so variant-of-uncertain-significance results are possible. ^[1]

• RET mutational analysis is the standard: begin with the most commonly mutated cysteine codons in exons 10 and 11 (codons 609, 611, 618, 620, 630 and 634) plus exons 8, 13, 14, 15 and 16. Whole-gene sequencing is reserved for when no mutation is found or the phenotype does not fit, because double and triple mutations occur, particularly involving V804M. ^[2]
• Any case of "sporadic" medullary thyroid carcinoma still needs germline RET testing, because 1 to 7% of apparently sporadic cases carry a germline mutation. ^[2]
• In MEN2B with the M918T phenotype, test exon 16 (codon M918T) first and exon 15 (A883F) second; if both are negative, sequence the whole coding region. ^[2]
• First-degree relatives of a proven mutation carrier, parents of a child with the MEN2B phenotype, patients with cutaneous lichen amyloidosis, and Hirschsprung patients with exon 10 mutations should all be offered counselling and testing. ^[2]
• Where testing is negative but the clinical picture is clearly MEN2A or MEN2B, relatives at risk need conventional biochemical screening repeated at 1 to 3 year intervals. ^[2]

Germline CDKN1B testing should be considered in patients who meet clinical criteria for MEN1 but have no MEN1 mutation, particularly those with hyperparathyroidism and pituitary or pancreatic tumours. There are no established mutation-hotspot panels to prefer, so sequencing of the gene and careful family segregation analysis are used. ^[4][5]

In brief, because management belongs to the tumour-specific MedGrasp topics (phaeochromocytoma, pancreatic neuroendocrine tumours, hyperparathyroidism, pituitary disease, thyroid neoplasms), the investigations below are listed only so a reader knows where to look.

• Parathyroid (MEN1): fasting serum calcium with a simultaneous (or close) parathyroid hormone (PTH) level. Preoperative ultrasound or sestamibi scanning is of limited value because disease is multiglandular, although ectopic gland localisation can help before repeat surgery.
• Gastrinoma: fasting gastrin, ideally with gastric pH; if gastrin is 10 times the upper limit of normal and gastric pH is under 2 the diagnosis is made. Otherwise a secretin or calcium stimulation test, followed by endoscopic ultrasound and MRI for duodenal and pancreatic localisation.
• Insulinoma: the 72-hour fast with serial glucose and insulin (and C-peptide or proinsulin); endoscopic ultrasound is the most sensitive localising test.
• Other pNETs (MEN1): chromogranin A, pancreatic polypeptide, glucagon and vasoactive intestinal peptide, plus MRI, CT or endoscopic ultrasound annually.
• Pituitary: serum prolactin and IGF-1; MRI of the pituitary fossa every 3 years (or sooner if symptomatic).
• Phaeochromocytoma (MEN2): plasma free or urinary fractionated metanephrines, with imaging only after biochemical confirmation; this screen must be done before any thyroid surgery, because operating through an unrecognised phaeochromocytoma is dangerous.
• Medullary thyroid cancer: serum calcitonin, with neck ultrasound; fine-needle cytology when a nodule is present. RET testing is done for all cases.

The three clinical routes to the diagnosis, plus the tumour table, are given above. The penetrance data are worth repeating for bedside recall: parathyroid disease in 80 to 100% by age 50; duodenopancreatic NETs in 30 to 80%; pituitary tumours in 15 to 50%; carcinoids in 5 to 10%; phaeochromocytoma in less than 1%. ^[3]

In all of MEN, treat the syndrome, not the most obvious tumour, and let genetics drive the order of surgery. The following is an outline; each tumour has its own MedGrasp topic with full drug doses, monitoring and surgical detail (search the MedGrasp library for thyroid neoplasms, pancreatic neuroendocrine tumour, phaeochromocytoma and hyperparathyroidism topics).

• Indications for surgery in MEN1 are essentially those for sporadic primary hyperparathyroidism: symptomatic or marked hypercalcaemia or hypercalciuria, nephrolithiasis, or bone disease. Hypercalcaemia also worsens Zollinger-Ellison symptoms, so control of calcium can be required even when the biochemistry looks mild. ^[1]
• The recommended approach is subtotal parathyroidectomy, removing three and a half glands, plus transcervical thymectomy because supernumerary glands sit in the thymus in 6 to 20% of patients. Total parathyroidectomy with heterotopic autotransplantation into the forearm or neck is an alternative when disease is extensive. Removing fewer than three glands leaves persistent disease in a large fraction of patients. ^[1][3]
• Medical options for those unfit or after failed surgery: calcimimetics such as cinacalcet lower calcium, though there is no strong evidence that they protect bone mineral density in MEN1. ^[1]
• Recurrence is common (reported in up to about 50% by 12 years after a subtotal procedure, with lower figures in some series) and each operation risks hypoparathyroidism, which is why some clinicians delay surgery as long as the patient is asymptomatic. ^[1]

This is where most of the morbidity and mortality sits, so the thresholds matter.

• Gastrinoma / Zollinger-Ellison: medical therapy comes first, with proton pump inhibitors or H2 antagonists and, where appropriate, somatostatin analogues. Surgical excision (Thompson's procedure, duodenopancreatectomy, or pancreas-preserving surgery) is considered when non-functional NETs double in size in 6 months or exceed 2 centimetres. Lymph node spread does not automatically imply a poor prognosis in MEN1-related gastrinoma. ^[1]
• Insulinoma: usually resistant to medical treatment, so surgery (enucleation, distal or partial pancreatectomy, often with distal resection plus enucleation of head tumours) is the treatment of choice. Metastatic disease is uncommon. ^[1]
• Other functioning pNETs (glucagonoma, VIPoma, somatostatinoma): managed on lines similar to insulinoma; glucagonomas metastasise in 50 to 80% if not found early. ^[1]
• Non-functional pNETs: the Endocrine Society 2012 guidelines recommend resection when a non-functional tumour exceeds 1 centimetre, or when it is under 1 centimetre but grows significantly (doubling over 3 to 6 months) to over 1 centimetre; many other groups conservatively observe tumours of 2 centimetres or less. No one disputes that ignoring a tumour that reaches 3 centimetres worsens prognosis. ^[1][3]
• Advanced or metastatic pNET: somatostatin analogues, everolimus, tyrosine kinase inhibitors, peptide receptor radionuclide therapy (lutetium-177-labelled somatostatin analogue), chemotherapy, and liver-directed therapies according to burden and growth. ^[1]
• Thymic and bronchial NETs: surgical resection, with prophylactic transcervical thymectomy at the time of parathyroid surgery to reduce the risk (but not eliminate it) of thymic NET. Thymic NETs carry the second highest mortality in MEN1. ^[1]

• Prolactinomas: dopamine agonists first; surgery or radiotherapy only for resistant or invasive disease.
• Growth-hormone- and ACTH-secreting tumours: transsphenoidal surgery first, with medical therapy where needed.
• Non-functional macroadenomas with mass effects or rapid growth: transsphenoidal surgery.
• Asymptomatic non-functional microadenomas detected by screening should usually be observed rather than operated on. ^[1][3]

This is the table that matters most for MEN2 families. Surgery is for prevention, not cure of clinical cancer.

For MEN2B discovered through a new mutation (about 75% of cases), the diagnosis is usually made when a thyroid nodule or phaeochromocytoma is already present. Children recognised because of ganglioneuromatosis, ocular or oral features before a tumour develops are diagnosed far younger and are far more likely to be cured. ^[2]

Where a nodule exists and calcitonin is raised, treatment moves from prevention to removal of established medullary thyroid cancer: total thyroidectomy with central neck dissection, plus lateral dissection where calcitonin is above 200 pg per mL or imaging is positive. ^[2]

• Screen every MEN2A and MEN2B patient before thyroid surgery. Plasma free or urinary fractionated metanephrines, with imaging after biochemical confirmation. ^[2]
• Always remove or treat the phaeochromocytoma before the thyroid. Phaeochromocytomas in MEN2 are usually benign, multicentric and bilateral; when one adrenal tumour appears, the other commonly follows within 10 years. Patients with C634 (high-risk) mutations have the highest penetrance (about 50%), rising with age. ^[2]
• Adrenal surgery, and with it careful peri-operative alpha and beta adrenergic blockade, is guided by symptoms and hormone secretion, in the same way as for sporadic disease. ^[3]

• Primary hyperparathyroidism in MEN2A is usually mild and multiglandular less often than in MEN1; manage as in other primary hyperparathyroidism, preserving normal parathyroid tissue where possible.
• mild disease in MEN2A is usually addressed at the time of thyroidectomy if the glands are clearly abnormal, preserving normal tissue rather than removing it prophylactically. ^[2]
• MEN2B patients essentially do not develop parathyroid disease, so routine calcium screening is unnecessary. ^[2]

There are no dedicated guidelines for MEN4. Given the clinical overlap, management follows MEN1 guidance, with the caveat that disease is generally milder and later. Parathyroid and pituitary tumours are managed surgically as in other familial syndromes, with primary hyperparathyroidism surveillance from about 15 years of age and pituitary screening from adolescence. ^[4][5]

A structured, lifelong programme is the single greatest source of benefit in MEN, and it should be agreed in writing with the family, with roles for the patient, the endocrinologist and genetics.

For MEN2, surveillance is not about a single table. Instead, family members with a known RET mutation need:

• an age-appropriate plan for prophylactic thyroidectomy (see table above);
• biochemical phaeochromocytoma screening before surgery and during follow-up;
• calcium and PTH screening in MEN2A from childhood or alongside phaeochromocytoma screening;
• post-thyroidectomy follow-up with calcitonin and, where indicated, neck ultrasound, under specialist endocrine or oncological direction. ^[2][3]

For MEN4, no consensus surveillance scheme exists. Reasonable practice is to use the MEN1 scheme as a starting template, but start primary hyperparathyroidism screening (calcium, PTH) from about 15 years rather than 8, and pituitary screening from adolescence rather than age 5, reflecting the later onset seen in small published cohorts. Pancreatic and adrenal imaging should still be considered, as occasional pNETs occur. ^[4][5]

• Where a laboratory can measure calcium and PTH, primary hyperparathyroidism can be found and followed cheaply: annual calcium and PTH from the MEN1 ages (8 years) is the highest-yield test in the whole programme.
• In young patients, a family history plus calcium screening beats waiting for renal stones or a pituitary mass. Counselling that the condition is dominantly inherited, and that each child has a 1 in 2 risk, is appropriate even when no test is available.
• Ultrasound of the neck is enough to find parathyroid and thyroid abnormalities in most settings; cross-sectional imaging can be reserved for when biochemistry or examination is abnormal.
• Phaeochromocytoma must be biochemically excluded before any thyroid or adrenal surgery: inexpensive urinary (or plasma, if available) metanephrines do this. Operating without this step is a well-documented cause of death.
• When RET or MEN1 testing is unavailable, clinical criteria lead management: any family member of a person with multiple endocrine tumours, especially a young parathyroid or pituitary tumour, should follow the appropriate screening programme, and a low threshold for referral to a regional endocrine centre is appropriate.
• Education matters: teach the MEN2B phenotype (mucosal neuromas, marfanoid habitus, gut ganglioneuromatosis, inability to cry tears in infancy) to general clinicians and paediatricians, because recognising it even once in a lifetime leads to an early thyroidectomy that cures the patient. ^[2]
• Cinacalcet or a proton pump inhibitor, where available, can control symptoms for years when surgery is not possible or has failed; this is pragmatic management, not a substitute for surgery in appropriate cases.
• Genetic results, if obtained, should be recorded in a way the family can carry with them, because families move and clinics change.

• MEN is a family of inherited endocrine tumour syndromes: MEN1 and MEN4 (tumour-suppressor type) and MEN2 (activating RET).
• MEN1 (about 1 in 30,000; autosomal dominant; menin on 11q13) gives parathyroid hyperplasia, pancreatic and duodenal NETs, and pituitary adenomas, in 80 to 100%, 30 to 80% and 15 to 50% of patients respectively, plus carcinoids and other tumours. Disease is rarely cured surgically because it is multicentric. ^[1][3]
• MEN2 (autosomal dominant; RET on 10q11.2) always produces medullary thyroid cancer and often phaeochromocytoma and, in MEN2A, parathyroid disease. FMTC is now viewed as part of the MEN2A spectrum. ^[2]
• The RET mutation sets the timing of thyroidectomy: highest-risk (M918T, MEN2B) in the first year of life; high-risk (C634, A883F) at or before 5 years; moderate-risk in childhood or young adulthood guided by calcitonin. ^[2]
• MEN2B stands out by its mucosal neuromas, marfanoid habitus, ocular and ganglioneuromatosis features and the absence of parathyroid disease. It is almost always advanced when first found. ^[2]
• MEN4 (autosomal dominant; p27 on 12p13) looks like MEN1 but is rarer, milder and later, with parathyroid and pituitary tumours most common and pancreatic NETs less common. ^[4][5]
• A MEN1 diagnosis rests on clinical, familial and genetic criteria; germline MEN1 testing is positive in 70 to 90% of familial cases and should be offered before age 5 when asymptomatic. ^[1]
• Up to 5% of patients clinically labelled MEN1 have no MEN1 mutation and about half of those are phenocopies (MEN4 and others), which changes screening and counselling. ^[1]
• Surveillance is age-based and lifelong: calcium and PTH from 8, insulinoma and pituitary from 5, pNET imaging under 10, gastrinoma from 20, thymic and bronchial from 15. ^[1][3]
• The greatest preventable deaths in MEN1 come from malignant pancreatic and duodenal NETs and thymic carcinoids; early genetic identification of families reduces both. ^[1][3]

• Thyroid neoplasms (medullary thyroid carcinoma in particular)
• Phaeochromocytoma (biochemical screening, surgical pre-treatment and genetics)
• Pancreatic neuroendocrine tumour topics (gastrinoma, insulinoma, non-functional pNETs) and Zollinger-Ellison syndrome
• Hyperparathyroidism and calcium disorders in MedGrasp
• Pituitary disease topics (prolactinoma, acromegaly, Cushing disease, non-functioning adenoma)
• Carcinoid and neuroendocrine tumour topics (thymic and bronchial NETs)
• Genetics concepts: autosomal dominant inheritance, two-hit tumour suppression, phenocopies
• Paraganglioma and phaeochromocytoma syndromes, von Hippel-Lindau disease, Carney complex
• Cancer genetics counselling and rare disease ethics