Multiple Endocrine Neoplasia Type 1 (MEN 1)

Synonym: Wermer's syndrome.

The multiple endocrine neoplasia syndromes are genetic neoplastic conditions, these are usually subdivided into two groups: MEN 1 and MEN 2.

The genetic abnormality of multiple endocrine neoplasia type 1 (MEN 1) is on the long arm of chromosome 11 (11q13) and the gene cluster has been mapped precisely.^1,2 Autosomal dominant with a high degree of penetrance.

The prevalence of MEN 1 has been estimated at about 1 in 10,000 with an equal sex distribution. Many MEN 1 cases are sporadic mutations and usually present between the 3rd and 5th decades, but familial cases can be identified earlier through screening.

There is a combination of the following features:

Parathyroid hyperplasia and adenomata

• Hyperparathyroidism is the presenting feature of MEN 1 in about 80% of patients.³.
• Patients present either with asymptomatic hypercalcaemia on biochemical screening or with the features of sporadic hyperparathyroidism.
• All 4 glands are diffusely hyperplastic and there may be nodule formation.

Pancreatic endocrine tumours

• These occur in about 70% of patients with MEN 1 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 MEN 1 syndrome and occur in about 10% of cases. As well as peptic ulcer, gastrinoma produces oesophagitis and diarrhoea.
• VIPoma (vasoactive intestinal peptide) and PPoma (pancreatic polypeptide) 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 MEN 1 associated gastrinomas. They are usually multiple, with up to 15 separate tumours.

Pituitary adenoma

• 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 commonest tumour, and occurs in about 30% of cases. They tend to be more aggressive than sporadic cases.⁴
• 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.⁵ 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.
• Lipomata occur in a significant proportion of patients and act as a marker for affected individuals.

Diagnosis of MEN 1 depends on having a high level of suspicion in patients who present with one of the features such as hyperparathyroidism or increased gastric acid secretion.

Many people may also be diagnosed because of a proband in the family. This is discussed below under 'Screening'.

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

The surgical approach to pancreatic endocrine tumours in MEN 1 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.⁶
• 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; but for insulinomas medical therapy is often unsuccessful and symptoms usually recur after enucleation alone, and more aggressive surgical management may be the best option.
• Treatment is the same as for sporadic pituitary tumours. This usually involves a transphenoidal operation to remove the tumour.
• Parathyroidectomy, subtotal or complete, is practised for MEN 1 but long-term follow-up reveals a high rate of recurrence in MEN 1 despite surgical intervention.⁷
• The treatment of metastatic disease is the same as in sporadic cases.

• The prognosis is generally good if adequate treatment is provided for parathyroid, pancreatic, and pituitary tumours.
• Pancreatic endocrine tumours associated with MEN 1 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.

• The screening of first- and second-degree relatives of patients with MEN 1 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 3 years before imaging studies. As pancreatic tumours are the only life-threatening aspect of the syndrome, such a screening protocol has merit.
• The MEN 1 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 MEN 1 is probably justified, especially in those with gastrinomas or insulinomas.
• There is little evidence to support screening in those with sporadic pituitary tumours.
• MEN 1 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 MEN 1 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 MEN 1 mutation testing of all cases of "classical" MEN 1, familial hyperparathyroidism, and sporadic hyperparathyroidism with one other MEN 1 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%.