Epidemiology

• The frequency of multiple endocrine neoplasia type 1 (MEN1) is estimated to be 1 case in 30,000 persons.^[2]
• The genetic abnormality of MEN1 is on the long arm of chromosome 11 (11q13) and the gene cluster has been mapped precisely.^[3]
• MEN1 syndrome is inherited in an autosomal dominant manner. Approximately 10% of cases are caused by de novo mutations.^[4]

Presentation

• The age of onset of endocrine tumours is usually in the teenage years, but symptoms from these tumours may not appear for several years, and the diagnosis is frequently delayed until the fourth decade of life. Cutaneous tumours may develop prior to the manifestation of overt clinical symptoms resulting from endocrine tumours. The earliest cutaneous tumours appear in the teenage years.^[2]
• Tumours may hypersecrete hormone, causing hypercalcaemia and recurrent nephrolithiasis (hyperparathyroidism), Zollinger-Ellison syndrome (hypergastrinaemia), hypoglycaemia (hyperinsulinaemia), amenorrhoea (hyperprolactinaemia) or acromegaly (excess growth hormone).^[2]
• Tumours of the pituitary gland may cause symptoms by mass effects.^[2]
• Angiofibromas, collagenomas, and lipomas do not typically cause symptoms, and they are mostly of cosmetic concern.

Parathyroid hyperplasia and adenomas

• Hyperparathyroidism is the presenting feature of multiple endocrine neoplasia type 1 (MEN1) in about 80% of patients.^[5].
• Patients present either with asymptomatic hypercalcaemia on biochemical screening or with the features of sporadic hyperparathyroidism.
• All four glands are diffusely hyperplastic and there may be nodule formation.

Pancreatic endocrine tumours

• These occur in about 70% of patients with MEN1 and usually present between the ages of 15 and 50 if not identified by screening.
• Over 60% of tumours are gastrinomas and produce the Zollinger-Ellison syndrome and about 30% are insulinomas.
• Peptic ulcers account for most of the morbidity and mortality of the MEN1 syndrome and occur in about 10% of cases. As well as peptic ulcer, gastrinoma produces oesophagitis and diarrhoea.
• VIPoma (= vasoactive intestinal peptide and pancreatic polypeptide-secreting tumour) have rarely been described and there are only isolated reports of glucagonoma, but non-functioning tumours may occur frequently.
• Diffuse hyperplasia of the pancreas is usually seen and is similar to the parathyroid. In the majority of cases there are multiple adenomata, most of which are less than 1 cm in diameter.
• Duodenal microgastrinoma is very common and probably accounts for almost half of all MEN1-associated gastrinomas. They are usually multiple, with up to 15 separate tumours.

Pituitary adenomas

• This may be detected by screening in 30% of patients, but is found at post-mortem in 50%.
• Unlike the pancreas and parathyroid, there does not appear to be diffuse pituitary hyperplasia.
• Prolactinoma producing hyperprolactinaemia is the most common tumour, and occurs in about 30% of cases. They tend to be more aggressive than sporadic cases.^[6]
• Acromegaly, due to excessive production of human growth hormone (hGH) occurs in about 30%.
• Adrenocorticotrophic hormone (ACTH) may produce Cushing's syndrome but other functioning tumours are rare.

The clinical presentation of pituitary tumours is described in the article on the subject.

Skin lesions

• These are common and occur in nearly 90% of patients, but they can be easily overlooked because of their subtle appearance.
• Benign tumours include multiple angiofibromas that were previously considered pathognomonic for tuberous sclerosis, collagenomas, and lipomas.^[7] They should be sought because they can act as markers for this syndrome.

Other lesions

• Lesions in other tissues have been reported, but their relationship to the syndrome remains controversial.
• Carcinoid tumours of the foregut, midgut, and thymus occur in about 10%, and are often found in the pancreas, but they are rarely symptomatic.

Diagnosis

• Many people may also be diagnosed because of screening of first- and second-degree relatives of patients with multiple endocrine neoplasia type 1 (MEN1) - see below.
• Diagnosis of MEN1 depends on having a high level of suspicion in patients who present with multiple facial angiofibromas, collagenomas, and lipomas, or other features such as hyperparathyroidism or increased gastric acid secretion.^[2]
• Investigations include hormone hypersecretion blood tests and imaging studies to look for the presence of tumours.
• DNA testing is available and identifies a mutation in about 80% of patients with familial MEN1. Mutation analysis may be used to confirm the clinical diagnosis, provide a genetic diagnosis and screen asymptomatic family members.^[2]
• Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in a family is known.^[4]

Screening

• The screening of first- and second-degree relatives of patients with multiple endocrine neoplasia type 1 (MEN1) is aimed at early detection of parathyroid, pancreatic or pituitary lesions in gene carriers, to reduce the associated morbidity.
• There is no evidence that screening reduces mortality, although the identification of affected individuals in 'malignant kindred' with aggressive pancreatic disease may allow curative surgery which would be expected to prolong survival.
• Screening lowers the age of detection of the syndrome by about 20 years.
• The most useful screening investigations are serum calcium, fasting gastrin, and prolactin, although in practice a full gut hormone screen is usually performed. It has been suggested that the most sensitive markers of pancreatic disease are basal and test-meal stimulated pancreatic polypeptide and gastrin, and basal insulin and proinsulin, identifying lesions at least three years before imaging studies. As pancreatic tumours are the only life-threatening aspect of the syndrome, such a screening protocol has merit.
• The MEN1 syndrome rarely develops before the age of 5 or after the age of 70, and so screening should be performed annually from 5 to 65, and at longer intervals thereafter. 80% of affected individuals will have been identified by the 5th decade. Screening of patients with apparently sporadic pancreatic endocrine tumours for evidence of MEN1 is probably justified, especially in those with gastrinomas or insulinomas.
• There is little evidence to support screening in those with sporadic pituitary tumours.
• MEN1 is present in 15% of all patients with hyperparathyroidism, but hypercalcaemia per se may be associated with elevated fasting gastrin and pancreatic polypeptide. In those at risk of MEN1 this would be highly significant, but in those with sporadic hyperparathyroidism, this very rarely indicates pancreatic disease. Hence, screening of all patients with hypercalcaemia is not warranted.
• Routine germline MEN1 mutation testing of all cases of 'classical' MEN1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN1-related condition is justified by national testing services, and testing should be considered for patients under 30 years old with sporadic hyperparathyroidism and multigland hyperplasia.^[8]
• Genetic linkage analysis has greater than 95% predictive accuracy, and in most families a haplotype associated with the mutant allele can be found. If three markers can be identified, the accuracy improves to greater than 99%.

Management

If the condition is confirmed, then genetic counselling is required.

Pharmacological

• Diazoxide can be used to inhibit release of insulin, especially in tumours that are beyond surgery.
• High-dose proton pump inhibitors are required for gastrin-secreting tumours.
• After surgery to the pituitary, hormone replacement may be required.

Surgical

• Skin tumours may be removed because of cosmetic concerns, especially larger facial angiofibromas.
• The surgical approach to pancreatic endocrine tumours in multiple endocrine neoplasia type 1 (MEN1) is controversial:
  • Surgical cure is best achieved by removing the pancreas and duodenum with adjacent lymph nodes. There is still a high rate of recurrence but the overall mortality remains low.^[9]
  • An alternative, potentially curative approach is to perform a subtotal pancreatectomy with enucleation of palpable tumours in the head and careful exploration for duodenal lesions, which should also be resected.
  • A more conservative strategy is to enucleate gross lesions to reduce the risk of developing metastatic disease and then control hormonal syndromes with appropriate medical therapy. The latter approach is probably appropriate for gastrinomas, because proton pump inhibitors are such an effective treatment. However, medical therapy is often unsuccessful for insulinomas and symptoms usually recur after enucleation alone; therefore, more aggressive surgical management may be the best option.
• Pituitary tumours: treatment is the same as for sporadic pituitary tumours. This usually involves a transsphenoidal operation to remove the tumour.
• Parathyroidectomy, subtotal or complete, is practised for MEN1 but long-term follow-up reveals a high rate of recurrence in MEN1 despite surgical intervention.^[10]
• The treatment of metastatic disease is the same as in sporadic cases.

Prognosis

• The average age of death in individuals with multiple endocrine neoplasia type 1 (MEN1) is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.^[1]
• Pancreatic endocrine tumours, particularly gastrinomas, become malignant in about 50% of patients with MEN1. Untreated, patients may die from peptic ulcer disease, metastatic endocrine pancreatic carcinoma, or foregut carcinoid malignancy.^[2]
• Pancreatic endocrine tumours associated with MEN1 are less malignant than sporadic tumours and carry a better prognosis, with a median survival of 15 years compared to 5 years for patients with sporadic tumours. This may reflect more indolent disease or earlier diagnosis.