Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 is a rare inherited disease, which can result in tumours in the pituitary and parathyroid glands, and pancreas.

Alternative names for multiple endocrine neoplasia type 1

Wermer’s syndrome; Wermer syndrome; MEN1; MEN type 1

What is multiple endocrine neoplasia type 1?

Multiple endocrine neoplasia type 1 is a rare inherited disease, which can result in tumours in the pituitary and parathyroid glands, and pancreas. It can be associated with adrenal nodules, carcinoid tumours and, very commonly, skin nodules. 

What causes multiple endocrine neoplasia type 1?

Multiple endocrine neoplasia type 1 is caused by a defect in a gene called ‘the menin’ gene. This is found on Chromosome 11. Faults or 'spelling mistakes' have been found in over 90% of patients with multiple endocrine neoplasia type 1; however, in some patients and their families with the condition, a menin gene fault cannot be found. Some patients do not have a family history of multiple endocrine neoplasia type 1 and are the first person in their family in which the diagnosis is made.

What are the signs and symptoms of multiple endocrine neoplasia type 1?

The three endocrine tumours which constitute multiple endocrine neoplasia type 1 (MEN1) are:

  1. Parathyroid hyperplasia/tumours – almost all patients with multiple endocrine neoplasia type 1 will have problems with overgrowth of the parathyroid glands by the age of 50. This causes overproduction of parathyroid hormone (primary hyperparathyroidism) resulting in high calcium levels in the blood and urine. Symptoms include tiredness, depression, stomach ulcers, abdominal pain and non-specific aches and pains, and if left untreated can result in osteoporosis and kidney stones. Rarely, patients with MEN1 may have a parathyroid cancer.
  2. Pituitary tumours – about 30–40% of patients with MEN1 develop pituitary tumours. The commonest are prolactinomas, occurring in about 20% of patients with MEN1. These tumours produces excess secretion of prolactin. In women, prolactinoma may cause breast milk production without pregnancy, lack of periods and may lead to infertility. In men, prolactinoma can cause impotence and infertility (see the article on prolactinoma for more information).

    Other much rarer hormone-producing tumours include those making growth hormone, causing acromegaly; and those making adrenocorticotrophic hormone (ACTH), causing Cushing’s disease. Pituitary tumours may also not make any hormones being picked up during surveillance. Large pituitary tumours may cause problems with vision or headaches.

  3. Pancreatic neuroendocrine tumours (NETs) – these tumours occur in up to 60% of patients with MEN1 and may be i) functioning – making different hormones characterised by different symptoms described below, or ii) non-functioning.
    • Gastrinoma – these are the commonest Pancreatic NET and occur in up to 75% of patients with MEN1. The excess secretion of gastrin by a gastrinoma causes the over-production of acid in the stomach leading to stomach/duodenal ulcers and diarrhoea. This is sometimes known as Zollinger-Ellison syndrome. Patients can present with severe bleeding from these ulcers, and develop severe ulceration and strictures of the upper gastrointestinal tract.
    • Insulinoma occur in about 10% of patients with MEN1. They are tumours of the B cells in the pancreas that overproduce insulin, causing a low blood sugar level (hypoglycaemia). This can cause confusion, sweating and can result in loss of consciousness.

Rarely, other functioning pancreatic NETs can occur in MEN1. These include:

glucagonoma – producing glucagon. This can cause skin rashes, blood clots and diabetes

VIPoma – the over-production of vasoactive intestinal peptide by a VIPoma can causes severe diarrhoea and a low potassium

somatostatinoma – the excessive secretion of somatostatin by a somatostatinoma can cause loose stools, the formation of gallstones and sometimes diabetes mellitus.

Some of the pancreatic tumours in MEN1 are non-functioning (non-functioning pancreatic nets) and are found by surveillance imaging. Whilst most pancreatic NETs are benign, some, in particular gastrinomas, can spread to lymph nodes or the liver and are then described as a neuroendocrine cancer.

Other features described in patients with MEN1 include chest neuroendocrine tumours (2% of patients), adrenal gland nodules (up to 50% of patients), adrenal cancer (<1%), lipomas. Benign tumours of the skin, particularly over the face (collagenomas and angiofibromas) occur in almost all patients with MEN1.

How common is multiple endocrine neoplasia type 1?

Multiple endocrine neoplasia type 1 is a rare condition. It has been estimated that it affects between 1 out of 10,000 to 1 out of 30,000 people. The same number of men and women are affected. The age at which people with multiple endocrine neoplasia type 1 start to develop tumours differs, depending on the individual. Pituitary tumours have been described in patients from the age of 10 and primary hyperparathyroidism and pancreatic NETs have been described in patients in their teens.

Is multiple endocrine neoplasia type 1 inherited?

Multiple endocrine neoplasia type 1 is an inherited condition due to an abnormality or ‘spelling mistake’  in the MENIN gene, which can be passed on from parent to child. It is inherited in an 'autosomal dominant' way, that is, there is a 50% (1 in 2) chance that a child will inherit the abnormal gene, and therefore, MEN 1. About 10% of patients with MEN1 do not have a family history and are the first people to develop a mutation (faulty gene) in their family.

How is multiple endocrine neoplasia type 1 diagnosed?

Genetic testing – there is a genetic test for the faulty MENIN gene. This test is offered to people who have the manifestations of MEN1 (diagnostic testing), or to the relatives of people known to have MEN1 (predictive testing). This should be performed through a Clinical Genetics service so implications for the test can be discussed in advance of testing, and further counselling offered, if necessary, as a positive result has implications for a patient and their family, and can often come as a shock. Patients can then be referred on to an appropriate endocrinology centre as lifelong surveillance is needed for the tumours described.

The three different kinds of tumours are diagnosed and monitored in different ways.

  1. Parathyroid tumours, causing primary hyperparathyroidism – patients with MEN1 undergo regular measurement of calcium and parathyroid hormone. If the calcium is elevated then parathyroid surgery is considered. An US or sesta MIBI scan may be done prior to surgery depending on the preference of the surgeon. Usually 3½ or 4 parathyroid glands are removed and patients may then require 1 alphacalcidol to maintain a normal calcium level.
     
  2. Pituitary tumours – surveillance of the pituitary is undertaken by checking prolactin and insulin-like growth factor-I levels, and performing further hormone tests as necessary. Magnetic resonance imaging (MRI) scans of the pituitary are performed every 3–5 years. If a patient reports any symptoms suggestive of a pituitary tumour at the regular appointment then other investigations can be performed as necessary; for example, specialist tests to investigate for Cushing’s disease.
     
  3. Pancreatic neuroendocrine tumours. Fasting blood tests are done to measure the levels of hormones secreted by the tumours (fasting gut hormones and chromogranin A and B). These have to be transferred to the lab on ice and frozen immediately so have to be performed in the hospital. Patients also undergo regular imaging to look for non-functioning tumours with a variety of techniques including MRI, CT scan and endoscopic ultrasound (EUS). EUS is the most sensitive test to find pancreatic NETs but is invasive and some patients prefer to have MRI/CT. If an insulinoma is suspected then patients are admitted to hospital for a 72-hour fast. This is to demonstrate a low blood glucose and an inappropriately high insulin level. Patients are closely supervised throughout the test. Sometimes pancreatic angiograms are done to detect very small tumours. This procedure involves a thin tube being threaded through the blood vessels to allow the radiologist to inject a special dye and look at the blood supply to the tumours with X-rays. Nuclear medicine scans such as octreotide imaging and Gallium68-PET scans may also be performed to find small functioning pancreatic NETS and also to check if there is any evidence that tumours have spread if surgery is being considered.

How is multiple endocrine neoplasia type 1 treated?

Exact treatment depends on the type of tumours present. If no abnormalities are detected then there is no need for any specific treatment. The three different kinds of tumours are treated in different ways:

  1. Primary hyperparathyroidism is managed surgically. Usually 3½ or 4 parathyroid glands are removed and patients may then require 1 alphacalcidol after to maintain a normal calcium level.
     
  2. Pituitary tumours – prolactinomas are usually managed with drugs called dopamine agonists such as cabergoline or bromocriptine. Surgery may be needed for large tumours if they are affecting a patient’s vision. Other non-functioning pituitary tumours may undergo a period of observation depending on size and whether a patient's vision is affected. Patients with acromegaly or Cushing’s disease usually require pituitary surgery to remove the tumour. Drugs such as somatostatin analogues may be used prior to surgery in acromegaly, or after if a patient is not cured, and radiotherapy may be necessary also if there is residual tumour after surgery (see the articles on acromegaly, Cushing’s disease and prolactinoma, for more information).
  3.  
  4. Pancreatic neuroendocrine tumours – gastrinomas are managed initially with proton pump inhibitors to prevent over-secretion of gastrin and ulceration. However, some patients have severe disease and may require surgery for symptom control. Pancreatic surgery to remove the tumour is the mainstay of treatment for inuslinoma. Occasionally, a drug, diazoxide can be used whilst a patient is awaiting definitive surgical procedure; long-term drug treatment is not usually used in the management of  an insulinoma. Currently, the recommendation is to consider surgery if tumours are larger than 2 cm in size. Pancreatic surgery may include removing a part of the pancreas, or part of the pancreas, stomach and duodenum (Whipples procedure), or in very extreme circumstances the whole pancreas, and is not undertaken lightly. This can be a difficult decision for patients and their doctors to make.

Are there any side-effects to the treatment?

After parathyroid surgery, calcium level in the blood may drop (hypocalcaemia), which causes tingling in the hands and the face, as well as muscular spasms. This is treated with 1 alphacalcidol to restore normal calcium levels, possibly as a lifelong treatment.

Depending on how the pituitary is working, if pituitary surgery is performed, some patients will require long-term replacement with pituitary hormones such as growth hormone, hydrocortisone and thyroxine (see the article on hypopituitarism, for more information). Diabetes insipidus may occasionally occur, causing excessive thirst and the need to pass excessive urine, and, if the condition is permanent, it can be treated using a drug called desmopressin.  

Effects after pancreatic surgery depends on how much of the pancreas in removed. After a total pancreatectomy, patients will have diabetes mellitus, requiring insulin injections, and will require supplements with pancreatic enzymes to help with digestion of food. The risk of these complications is much reduced for smaller operations, but patients should still be observed carefully for these complications, especially in the first few months after surgery. If patients have any concerns about any of these side-effects, they should contact their doctor.

What are the longer-term implications of multiple endocrine neoplasia type 1?

Manifestations of MEN1 can vary greatly, even within families, although virtually all patients will develop primary hyperparathyroidism. Because tumours can manifest from the age of approximately 10 onwards, surveillance is recommended, which should be lifelong, through a specialist endocrinology clinic, with access to appropriate radiology and other specialities needed for the management of the tumours listed above.

Outlook is dependent upon which tumours a patient may develop, and what treatments are recommended. Some pancreatic NETs are malignant, which can be life-limiting.

It is important that genetic screening is offered through a specialist service together with genetic counselling so that anyone undergoing the test understands the implications for them and their families.


Last reviewed: Jan 2015