Alternative names for multiple endocrine neoplasia type 1

Wermer’s syndrome; Wermer syndrome; MEN1; MEN type 1, multiple endrocrine adenomatosis

What is multiple endocrine neoplasia type 1?

Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disease, which is characterised by tumour development in the pituitary gland, parathyroid glands, and the pancreas. The condition can be associated with adrenal nodules, neuroendocrine tumours (of the lungs, thymus or stomach) and benign skin lesions.

What causes multiple endocrine neoplasia type 1?

MEN1 is caused by a defect in a gene called the MEN1 gene. This gene is found on Chromosome 11 and its job is to produce the protein menin. Faults or 'spelling mistakes' (mutations) in this gene have been found in over 90% of patients with MEN1; however, in some patients and their families with the condition, a gene fault still cannot be found. The mutations result in failure to produce the correct menin protein and the loss of the protein allows tumours to develop. Not every patient will have a family history of MEN1 as the mutation can arise anew in an individual.

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

The three endocrine tumours which constitute MEN1 are:

1. Primary hyperparathyroidism – the vast majority of patients with MEN1 will have problems with over activity of the parathyroid glands (hyperparathyroidism) by the age of 50 years. This overproduction of parathyroid hormone results 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, it can result in thinning of bones (osteoporosis) and kidney stones. Very rarely, patients with MEN1 may have a parathyroid cancer. It is important to note that most patients with hyperparathyroidism do not develop all of the above symptoms especially if diagnosed early.

2. Pituitary tumours – about 30–40% of patients with MEN1 develop pituitary tumours. These tumours may produce excess hormones (functional pituitary tumours). The most common functional pituitary tumours diagnosed in patients with MEN1 are prolactinomas (milk hormone producing tumors), occurring in about 20% of patients with MEN1. These tumours produce excess prolactin (milk hormone). In women, prolactinomas may cause breast milk production without pregnancy, lack of periods and may lead to infertility. In men, prolactinomas can cause impotence and infertility (see the article on prolactinoma for more information).

Less commonly, MEN1 patients may develop hormone-producing tumours including those making growth hormone (resulting in acromegaly); and those making adrenocorticotrophic hormone (ACTH) (resulting in Cushing's disease). Pituitary tumours that do not release hormones (non-functioning pituitary tumours) may be picked up incidentally by routine surveillance scans. 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.

• Gastrinomas – these are the most common functioning pancreatic NET in MEN1 and occur in up to 40% of patients. The excess secretion of gastrin by a gastrinoma causes the over-production of acid in the stomach leading to stomach/duodenal ulcers (sometimes known as Zollinger-Ellison syndrome). Patients can present with severe bleeding from these ulcers, and may develop strictures of the upper gastrointestinal tract as well as diarrhoea.
• Insulinomas occur in about 10% of patients with MEN1. They are tumours of the beta cells in the pancreas and by overproducing insulin they cause a low blood sugar level (hypoglycaemia). The symptoms are typically sweating, shakiness, hunger, dizziness and anxiety but can progress to confusion and even loss of consciousness.

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

• glucagonoma – producing glucagon. These can cause skin rashes, weight loss and diabetes mellitus as well as fatigue, shortness of breath and lightheadedness as a consequence of anaemia.
• VIPoma – the over-production of vasoactive intestinal peptide by a VIPoma can cause severe watery diarrhoea and fatigue, muscle weakness and palpitations due to a low blood potassium level.

Some of the pancreatic tumours in MEN1 are non-functioning (non-functioning pancreatic NETs) and are only found by surveillance imaging. Pancreatic NETs in MEN1 are often multiple and can be malignant; they represent the commonest cause of death for patients with MEN1. Non-functioning pancreatic NETs are the most common pancreatic NET in MEN1 and probably carry the greatest risk of malignancy.

MEN1 can also be associated with adrenal nodules (in ~40% of patients; mostly non-functional and benign). Neuroendocrine tumours of the lungs (~2%), thymus (~2%) or stomach (~10%) and benign skin lesions may also occur.

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 many patients with MEN1.

How common is multiple endocrine neoplasia type 1?

MEN 1 is a rare condition. It has been estimated that it affects between 1 in 10,000 to 1 in 30,000 people. The same number of men and women are affected. The age at which people with MEN1 start to develop tumours is variable and is not predictable based on the family history.

Is multiple endocrine neoplasia type 1 inherited?

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

How is multiple endocrine neoplasia type 1 diagnosed?

MEN1 is diagnosed by genetic testing – the MEN1 gene can be screened for mutations. This test is offered to people who have the clinical 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 with appropriate genetic counselling.

The main three types of tumours are diagnosed and monitored in different ways. Tumours have been described in children under the age of 10 and thus assessment is recommended to start as young as 5 years of age.

1. Primary hyperparathyroidism – patients with MEN1 undergo regular measurement of blood calcium and parathyroid hormone levels. The diagnosis of primary hyperparathyroidism is made if the serum calcium is elevated together with the parathyroid hormone being high or inappropriately normal (it should be suppressed if blood calcium is high).

2. Pituitary tumours – surveillance of the pituitary is undertaken by checking blood tests (typically for prolactin and insulin-like growth factor-I levels). Routine 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 then other pituitary hormone investigations can be performed as necessary; for example, specialist tests to investigate for Cushing’s disease.

3. Pancreatic NETs – fasting blood tests are performed in hospital to measure the levels of hormones secreted by the tumours (fasting gut hormones and chromogranin A and B). Patients also undergo regular imaging to look for non-functioning tumours with a variety of techniques including MRI and CT scans, endoscopic ultrasound or nuclear medicine scans (octreotide or Gallium68-PET scan). Endoscopic ultrasound is the most sensitive test to find small pancreatic NETs but is invasive and some patients prefer to have an MRI/CT. A nuclear medicine scan is probably the best investigation to detect tumour spread (metastases) in malignant disease. If an insulinoma is suspected then patients are often admitted to hospital for a 72-hour fast to demonstrate low blood glucose and inappropriately high insulin levels. Patients are closely supervised throughout the test. In addition to all of the investigations described above, sometimes invasive injections and internal venous sampling techniques (involving a thin tube being threaded through the blood vessels) are used to determine where the insulin is being secreted from.

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 usually managed surgically although the timing of intervention remains controversial. Occasionally a medical treatment may be offered for the short or longer term. Usually an operation will involve removal of 3½ or all 4 parathyroid glands and patients will then require life-long supplements of activated vitamin D and possibly calcium to maintain a normal healthy blood calcium level.

2. Pituitary tumours – prolactinomas are usually managed with drugs called dopamine agonists such as cabergoline or bromocriptine. Surgery may occasionally be needed for large tumours that are unresponsive to medical treatment. Patients with acromegaly or Cushing’s disease nearly always 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). Non-functioning pituitary tumours may undergo a period of observation depending upon their size and whether a patient's vision is affected. Surgery and or radiotherapy are treatment options.

3. Pancreatic NETs – gastrinomas are managed initially with medication (proton pump inhibitors), which reduces gastric acid secretion and therefore reduces ulceration. However, some patients have very severe disease and may still require surgery for symptom control. Pancreatic surgery to remove the tumour is the mainstay of treatment for insulinoma. Occasionally, a drug, diazoxide can be used while a patient is awaiting a definitive surgical procedure; long-term drug treatment is not usually used in the management of an insulinoma. In non-functioning pancreatic NETs, currently, the recommendation is to pursue surgery if tumours are larger than 2 cm in size, to consider surgery if tumours are 1-2 cm, and probably to opt for surveillance if tumours are <1 cm. Pancreatic surgery may include enucleation of the lesion only, removing a part of the pancreas, or part of the pancreas, stomach and duodenum (Whipple’s procedure), or in very extreme circumstances the whole pancreas, although this is never undertaken lightly due to the long-term complications for the patient.

Adrenal nodules can often simply be monitored by imaging unless they behave suspiciously; as there is a small increased risk of adrenal cancer in MEN1. Non-pancreatic NETs in MEN1 are often treated surgically although other treatment modalities may be considered. Skin lesions are often treated as per patient preference.

Are there any side-effects to the treatment?

After parathyroid surgery, calcium levels in the blood may drop (hypocalcaemia), which – if severe – can cause tingling in the hands and the face, as well as muscular spasms. This is treated with life-long supplements of activated vitamin D and possibly calcium to maintain a normal healthy blood calcium level.
Some patients will lose normal anterior pituitary hormone function, either as a result of direct compression from the tumour or as a consequence of treatments for the tumour such as surgery or radiotherapy. Consequently, long-term hormone replacement with hormones such as growth hormone, hydrocortisone, thyroxine and oestrogen or testosterone may be required (see the article on hypopituitarism, for more information). Diabetes insipidus may occasionally occur if there is damage to the posterior part of the pituitary gland, resulting in excessive thirst and the need to pass excessive urine. This may be a transient finding following pituitary surgery or it may be permanent; it can be treated using a drug called desmopressin.

Effects after pancreatic surgery depends on how much of the pancreas is 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 lower 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, and tumours can manifest from the first decade of life. Life-long biochemical and radiological screening should be offered to all MEN1 patients on the grounds that detection and treatment of early disease may improve prognosis and life expectancy. Patients should be cared for in a specialist centre under the guidance of an experienced multidisciplinary team.
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. Overall, MEN1 has a reduced life expectancy.

It is important that genetic screening is offered through a specialist service together with genetic counselling so that anyone undergoing the test understands the full implications. Input from patient support groups may be invaluable to patients and their families.

Are there patient support groups for people with multiple endocrine neoplasia type 1?

The Association for Multiple Endocrine Neoplasia Disorders (AMEND) or Pituitary Foundation patient support groups may be able to provide advice and support to patients and their families.