Multiple Endocrine Neoplasia Syndromes

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Multiple endocrine neoplasias are rare inherited diseases in which benign armalignant (cancerous) tumours develop in several endocrine glands.

The tumors of multiple endocrine neoplasias can appear as early as infancy or as late as age 70. The abnormalities caused by multiple endocrine neoplasias result mostly from the excess hormones that the tumors produce.

Multiple endocrine neoplasias occur in three patterns, called types I, IIA, and IIB, although the types occasionally overlap.

Type I Disease

People with multiple endocrine neoplasia type I develop tumors of the parathyroid glands (the small glands located next to the thyroid gland), the pancreas, the pituitary gland, or all three.

Almost all of the people with this disease have tumours of the parathyroid glands; the tumors cause the glands to produce too much parathyroid hormone (a condition called hyperparathyroidism). The excess parathyroid hormone usually raises calcium levels in the blood, sometimes leading to kidney stones.

Most people with type I disease also develop tumours of the islet cells of the pancreas. About 40 percent of these tumors produce high levels of insulin and consequent low blood sugar levels (hypoglycaemia), especially if the person hasn't eaten for several hours. More than half of islet cell tumors produce excessive gastrin, which signals the stomach to overproduce acid. People with these tumours generally develop peptic ulcers that often bleed, perforate and leak stomach contents into the abdomen, or obstruct the stomach. Diarrhoea and fatty, smelly stools (steatorrhoea) are common. The remaining islet cell tumors may produce other hormones, such as vasoactive in-testinal polypeptide, which can cause severe diarrhoea and lead to dehydration.

About one third of the time, the islet cell tumors are cancerous and sometimes spread (metastasize) to other areas of the body. But these cancers tend to grow more slowly than other types of pancreatic cancer.

About two thirds of the people with type I dis-ease develop pituitary gland tumours. About 25 percent of these tumors produce the hormone prolactin, leading to menstrual abnormalities in women and impotence in men. Another 25 per-cent produce growth hormone, leading to acromegaly. A very small percentage of pituitary tumors produce corticotropin, leading to high levels of corticosteroid hormones and Cushing's syndrome. Nearly 25 percent appear to produce no hormones at all. Some pituitary tumors cause headaches, impaired vision, and decreased pituitary gland function.

Some people with type I disease develop thyroid and adrenal gland tumors. A very small percentage develop carcinoid tumors. Some people also develop soft, noncancerous fatty growths just below the skin (lipomas).

Type IIA Disease

Multiple endocrine neoplasia type IIA can in-clude a rare type of thyroid cancer (medullary carcinoma), pheochromocytoma (a type of adrenal gland tumor that is usually not cancerous), and overactive parathyroid glands.

Almost everyone with type IIA disease develops medullary thyroid cancer. About 50 percent develop pheochromocytomas, which usually raise blood pressure because of the epinephrine and other substances they produce. The high blood pressure may be intermittent or constant and is often very severe.

About 25 percent of the people with type IIA disease have overactive parathyroid glands and show symptoms of having increased blood calcium levels, which may lead to kidney stones and sometimes to kidney failure. In another 25 per cent, the parathyroid glands increase in size without producing large amounts of parathyroid hormone, so the people don't have problems related to high calcium levels.

Type IIB Disease

Multiple endocrine neoplasia type IIB can consist of medullary thyroid cancer, pheochromocytoma, and neuromas (growths around the nerves). Some people with type IIB disease have no family history of it.

The medullary thyroid cancer that occurs in type IIB disease tends to develop at an early age and has been reported in infants as young as 3 months of age. The medullary thyroid cancers in type IIB also grow faster and spread more rapidly than those in type IIA disease.

Almost all the people with type IIB disease develop neuromas in their mucous membranes. The neuromas appear as glistening bumps around the lips, tongue, and lining of the mouth. Neuromas may also occur on the eyelids and glistening surfaces of the eyes, including the conjunctiva and cornea. The eyelids and lips may thicken.

Gastrointestinal tract abnormalities cause constipation and diarrhea. Occasionally, the colon develops large, dilated loops (megacolon). These abnormalities probably result from neuromas growing on the intestinal nerves.

People with type IIB disease often develop spinal abnormalities, especially curvature of the spine, as well as bony abnormalities of the feet and thighbones. Many people have long limbs and loose joints (a marfanoid habitus, socalled because the appearance is similar to that of someone with Marfan's syndrome).

Treatment

No cure is known for any of the multiple endocrine neoplasias. Doctors treat each tumor individually, either by removing it or by correcting the hormone imbalance. Because medullary thyroid cancer is ultimately fatal if untreated, a doctor will most likely recommend surgically removing the thyroid gland if a person with type IIA disease has pheochromocytoma or hyperparathyroidism, even if the diagnosis of medullary thyroid cancer can't be established before the surgery. In type IIB disease, medullary thyroid cancer is particularly aggressive. A doctor will recommend removing the thyroid gland as soon as the diagnosis is established. This type of thyroid cancer can't be treated with radioactive iodine.

Screening

Since about half of the children of people with multiple endocrine neoplasia will inherit the disease, screening is important for early diagnosis and treatment. Tests for each type of tumor are currently available. Recently, the abnormal genes responsible for types IIA and IIB disease were identified. Tests for the abnormal gene will even-tually be available, permitting earlier and more effective diagnosis and treatment.

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