Multiple endocrine neoplasia type 1

Synonym: Wermer's syndrome

Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterised primarily by tumours of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic tract - eg, gastrinomas, insulinomas and carcinoid tumours (30-80% of cases) - and anterior pituitary - eg, prolactinomas (15-90% of cases).^{1 2 3}

Cutaneous tumours are common in MEN1 and include multiple angiofibromas (previously considered pathognomonic for tuberous sclerosis), collagenomas, and lipomas.⁴

Epidemiology

• The prevalence has probably been underestimated because at initial diagnosis most patients only have a single endocrine lesion. MEN1 has a high penetrance and an equal sex distribution.⁵

• The genetic abnormality of MEN1 is on the long arm of chromosome 11 (11q13) and the gene cluster has been mapped precisely.⁶

• Approximately 10% of cases are caused by de novo mutations.⁷

Presentation^{3 8}

• 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.⁹

• 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.

• Tumours may hypersecrete hormone, causing hypercalcaemia and recurrent nephrolithiasis (hyperparathyroidism), Zollinger-Ellison syndrome (hypergastrinaemia), hypoglycaemia (hyperinsulinaemia), amenorrhoea (hyperprolactinaemia) or acromegaly (excess growth hormone).

• Tumours of the pituitary gland may cause symptoms by mass effects.

• 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 MEN1 in about 80% of patients..

• 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

• Pancreatic endocrine tumours 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; however, 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

• Pituitary adenomas may be detected by screening in 30% of patients but are 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.

• 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.

Skin lesions

• These are very common 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. 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^{3 8}

• Diagnosis may result from screening of first- and second-degree relatives of patients with MEN1.

• 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.

• Investigations include hormone hypersecretion blood tests and imaging studies to look for the presence of tumours.

• DNA testing is available and mutation analysis may be used to confirm the clinical diagnosis, provide a genetic diagnosis and screen asymptomatic family members.

• Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in a family is known.⁷

Screening¹⁰¹¹

• The screening of first- and second-degree relatives of patients with MEN1 is aimed at early detection of parathyroid, pancreatic or pituitary lesions in gene carriers, to reduce the associated morbidity.

• 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.

• 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.

• 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. The management will depend on the presenting features of each individual patient.³ Medical therapy may include diazoxide to inhibit release of insulin (especially in tumours that are not amenable to surgery) and high-dose proton pump inhibitors for gastrin-secreting tumours. Hormone replacement may be required after pituitary surgery.

Surgical

• Skin tumours may be removed because of cosmetic concerns, especially larger facial angiofibromas.

• The surgical approach to pancreatic endocrine tumours in 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.

• Pituitary tumours: treatment is the same as for sporadic pituitary tumours. This usually involves a trans-sphenoidal 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.

• The treatment of metastatic disease is the same as in sporadic cases.

Prognosis⁹

• The average age of death in individuals with MEN1 is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.³

• Pancreatic endocrine tumours, particularly gastrinomas, become malignant in about half of patients with MEN1. Untreated, patients may die from peptic ulcer disease, metastatic endocrine pancreatic carcinoma, or foregut carcinoid malignancy.