Multiple Endocrine Neoplasia Type 1

Multiple Endocrine Neoplasia Type 1 (MEN) is a medical term used to describe an endocrine neoplastic disorder and genetic mutation of chromosome 11 of MEN Type 1 and chromosome 10 for MEN Type 2a and 2b. MEN can be present in both men and women and is sometimes referred to as Wermer's syndrome or multiple endocrine adenomatosis. An overview of MEN will be provided, however, the focus thereafter will be on MEN Type 1.

What is Multiple Endocrine Neoplasia (MEN)?

Neoplasia is abnormal cell proliferation or growth that may lead to benign, pre-cancerous or cancerous lumps or tumours. Multiple Endocrine Neoplasia (MEN) involves abnormal cell proliferation or growth within the endocrine glandular system, which secretes hormones into the bloodstream where they bind to the receptors of cells within organs, such as the thyroid, adrenals, pancreas, pituitary and pineal glands. The cause of MEN is the genetic mutation of chromosome 10 (RET gene) and chromosome 11. The condition is therefore hereditary.

What are the types of MEN?

There are three different types of Multiple Endocrine Neoplasia (MEN) or abnormal cell growth within the endocrine system. These are:

MEN 1: abnormal long arm genetic mutation of chromosome 11 resulting in irregular melanin production, a protein responsible for slowing down cell division and tumour suppression. When mutated, melanin no longer regulates cell division as it should and this results in excessive cell growth and tumours.
MEN 2a: abnormal RET long arm mutation of chromosome 10 resulting in an overactive receptor, which binds to glial cell-derived neurotrophic factor (GDNF), also triggering unregulated cell division and tumour growth.
MEN 2b: abnormal RET proto-oncogene mutation of chromosome 10; the mutation manifests differently but also results in run-away cell growth and possible tumours.

Each MEN type may present different symptoms and require specific treatment.

Prevalence of MEN 1

As a genetic abnormality MEN 1 may skip a generation but is estimated to be present in one in ten thousand people with equal sex chromosomal distribution. Different medical disorders result from MEN 1 and each disorder carries separate prevalence statistics.

Genetic endocrine disorders resulting from MEN 1

MEN 1 causes different endocrine system disorders and each condition has its own set of symptoms requiring different treatment. These disorders include:

Parathyroid tumours.
Pituitary tumours.
Pancreatic tumours.

Parathyroid tumours

About 80 percent of patients with MEN 1 develop hyperparathyroidism meaning excess secretion of parathyroid hormone (PTH), which increases the level of blood calcium, referred to as hypocalcaemia. In primary hyperparathyroidism only one tumour may be present in one thyroid gland.

However, with hypocalcaemia there is excess cell growth with tumours in all four glands. The symptoms include:

Heightened thirst and the need to drink fluids (polydipsia).
The need for frequent urination (polyuria).
Blocked bowels or constipation.
Fatigue.

These symptoms can progress into further complications, such as muscle weakness, osteoporosis, kidney stones, mental and behavioural changes. Parathyroid tumours are treated through:

Surgery: Subtotal or total parathyroidectomy with or without transplantation of parathyroid tissue.
Lifelong vitamin D replacement for calcium regulation, due to the lack of the parathyroid hormone.

The success of treatment depends on the severity of hypocalcaemia, the type of operation and the overall medical condition of the patient.

Pituitary tumours

Pituitary tumours may be functional or non-functional. Abnormally functioning pituitary tumours present in the anterior pituitary as prolactinomas, adrenocorticotropic hormones or ACTH-secreting and growth hormone secreting. Each type of pituitary tumour triggers different hormonal function and symptoms.

Prolactinomas manifestin 60 percent of MEN 1 cases and the increased prolactin secretion results in:

The over-production of milk even in non-pregnancy (galactorrhoea).
Female absence of milk production (amenorrhoea).
Male infertility and impotence.

Two main treatments for prolactinomas include:

Bromocriptine medication.
Transsphenoidal hypophysectomy surgery.

ACTH-secreting tumours are rarer and over stimulate the adrenal gland, which increases cortisol production. Excessive cortisol secretion leads to:

Cushing's syndrome.
Obesity.
Osteoporosis.
Irregular menstrual cycle in females.
Higher infection rates.
Impeded wound healing and bruising.
Muscle weakness.
Increased blood pressure (hypertension).
Mental and behavioural changes.

Treatments for ACTH-secreting tumours include:

Ketoconazole medication.
Pituitary radiotherapy.
Transsphenoidal surgery.

Growth hormone-secreting tumours affect about 25 percent of people with MEN 1 and causes excessive growth hormone production, resulting in:

Child gigantism and long bones.
Adult acromegaly: excess cartilage and bone growth, heart and organ enlargement, cancer-causing polyps in the colon, hypogonadism and diabetes.

Three types of treatments exist for abnormal growth hormone-section:

Octreotide medication.
Pituitary radiotherapy.
Transsphenoidal surgery.

Pancreatic tumours

About 70 percent of patients with MEN 1 develop abnormal hormone-functioning pancreatic tumours, which include gastrinoma, insulinoma, glucagonoma, PPoma (pancreatic polypeptide) and VIPoma (vasoactive intestinal peptide). Pancreatic endocrine tumours are diagnosed with an endoscopic ultrasound screening. Each tumour type may present with different symptoms and syndromes.

Gastrinomas cause increased levels of gastrin and acidity, manifesting in about 50 percent of cases. Diagnostic screening is carried out with secretin stimulation tests. Symptoms include:

Zollinger-Ellison syndrome (caused by gastrinomas).
Peptic ulcers in the stomach and/or duodenum.
Oesophagitis.
Diarrhoea.

Two main types of treatment for gastrinomas include:

Medication, such as ranitidine or omeprazole, to block acid production.
Surgery to remove the tumours.

Insulinomas occur in about 30 percent of cases and cause abnormal insulin hormone secretion, which reduces blood glucose levels resulting in:

Low blood sugar or hypoglycaemia.
Seizures and potential coma states.
Blurred vision.
Mental confusion and headaches.
Perspiration and palpitations.

Treatments include surgery to eradicate the tumours and chemotherapy for cancerous tumours.

Glucagonomas are not as common and result in abnormal glucagon hormone function, which increases blood glucose levels, causing:

Anaemia and weight loss.
A rash (necrolytic migratory erythema) that itches.

Symptoms can be reduced through the use of octreotide medication and chemotherapy, though surgical removal of the tumour is usually recommended.

PPomas occur frequently in those with MEN 1 and cause excessive secretion of pancreatic polypeptide (PP). The most common effect is increased blood PP levels that may also serve to identify PPomas during diagnostic screening.

VIPomas cause the excessive production and secretion of vasoactive intestinal polypeptide (VIP) and is rarer. Symptoms may include:

Low blood potassium.
Reduced stomach acid production.
Diarrhoea.

Treatment is the same as for glucagonomas.

Diagnostic Screening

Where MEN 1 runs in families as a genetically carried disorder, screening is vital for life expectancy and management of associated medical conditions. Screening may not reduce mortality or prevent MEN 1 transmission, but treatment from diagnosis may prolong survival and allow people to enjoy a quality of life while symptoms are managed.

Management and Prognosis

If identified early MEN1 is treatable and symptoms can be controlled to prevent further medical complications. Although not entirely curable if cancerous, surgical removal of less malignant tumours may extend a patients’ quality of life for fifteen years, as opposed to five when sporadic tumours are present.