Multiple Endocrine Neoplasia, Type 1 (MEN 1)

Hyperparathyroidism Primary hyperparathyroidism Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more is present in ≥ 95% of patients. Asymptomatic hypercalcemia Hypercalcemia Hypercalcemia is a total serum calcium concentration > 10.4 mg/dL (> 2.60 mmol/L) or ionized serum calcium > 5.2 mg/dL (> 1.30 mmol/L). Principal causes include hyperparathyroidism... read more is the most common manifestation, but about 25% of patients have evidence of nephrolithiasis Urinary Calculi Urinary calculi are solid particles in the urinary system. They may cause pain, nausea, vomiting, hematuria, and, possibly, chills and fever due to secondary infection. Diagnosis is based on... read more or nephrocalcinosis (1 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). In contrast to sporadic cases of hyperparathyroidism, diffuse hyperplasia, which is often asymmetric, is typical.

Pancreatic islet cell tumors (also known as pancreatic neuroendocrine tumors) occur in 30 to 90% of patients (1 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). They are one type of gastroenteropancreatic neuroendocrine tumor (GEP-NET), which can also develop in parts of the gastrointestinal tract, usually in the stomach and duodenum. Tumors are usually multicentric and sometimes synthesize several hormones. Multiple adenomas or diffuse islet cell hyperplasia commonly occurs; such tumors may arise from the duodenum rather than the pancreas. About 30% of tumors are metastatic at diagnosis. Islet cell tumors due to MEN 1 syndrome often have a less aggressive course than do sporadically occurring islet cell tumors.

The most common functional enteropancreatic tumor in MEN 1 is the gastrinoma Gastrinoma A gastrinoma is a gastrin-producing tumor usually located in the pancreas or the duodenal wall. Gastric acid hypersecretion and aggressive, refractory peptic ulceration result (Zollinger-Ellison... read more , which can arise from the pancreas or the duodenum. Up to 80% of patients with MEN 1 have either multiple peptic ulcers due to gastrin-stimulated increased gastric acid secretion or asymptomatic elevated gastrin levels.

Insulinomas Insulinoma An insulinoma is a rare pancreatic beta-cell tumor that hypersecretes insulin. The main symptom is fasting hypoglycemia. Diagnosis is by a 48- or 72-hour fast with measurement of glucose and... read more are the second most common functional pancreatic tumor and can cause fasting hypoglycemia. The tumors are often small and multiple. Age of onset is often < 40 years.

Nonfunctioning enteropancreatic tumors occur in about one third of MEN 1 patients. Most islet cell tumors, including nonfunctioning tumors, secrete pancreatic polypeptide. Although the clinical significance is unknown, pancreatic polypeptide may be helpful for screening. The size of the nonfunctioning tumor correlates with risk of metastasis and death.

Less commonly, other functional enteropancreatic tumors can occur in MEN 1. A severe secretory diarrhea can develop and cause fluid and electrolyte depletion with non–beta islet cell tumors. This complex, referred to as the watery diarrhea, hypokalemia, and achlorhydria syndrome (WDHA Vipoma A vipoma is a non-beta pancreatic islet cell tumor secreting vasoactive intestinal peptide (VIP), resulting in a syndrome of watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). Diagnosis... read more syndrome, or pancreatic cholera), has been ascribed to vasoactive intestinal polypeptide, although other intestinal hormones or secretagogues (including prostaglandins) may contribute. Hypersecretion of glucagon, somatostatin, chromogranin, or calcitonin, ectopic secretion of ACTH or corticotropin-releasing hormone (causing Cushing syndrome Cushing Syndrome Cushing syndrome is a constellation of clinical abnormalities caused by chronic high blood levels of cortisol or related corticosteroids. Cushing disease is Cushing syndrome that results from... read more ), and hypersecretion of growth hormone–releasing hormone (causing acromegaly Gigantism and Acromegaly Gigantism and acromegaly are syndromes of excessive secretion of growth hormone (hypersomatotropism) that are nearly always due to a pituitary adenoma. Before closure of the epiphyses, the result... read more ) sometimes occur in non–beta islet cell tumors.

Pituitary tumors Pituitary Lesions Patients with hypothalamic-pituitary lesions generally present with some combination of Symptoms and signs of a mass lesion: headaches, altered appetite, thirst, visual field defects—particularly... read more occur in 15 to 42% of patients with MEN 1 (1 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). From 25 to 90% are prolactinomas (1 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). About 25% of pituitary tumors secrete growth hormone or growth hormone and prolactin. Excess prolactin may cause galactorrhea Prolactinoma Prolactinomas are noncancerous tumors made up from lactotrophs in the pituitary gland. The most common symptom of a prolactinoma is galactorrhea. Diagnosis is by measurement of prolactin levels... read more in affected women, and excess growth hormone causes acromegaly Gigantism and Acromegaly Gigantism and acromegaly are syndromes of excessive secretion of growth hormone (hypersomatotropism) that are nearly always due to a pituitary adenoma. Before closure of the epiphyses, the result... read more clinically indistinguishable from sporadically occurring acromegaly. About 3% of tumors secrete ACTH, causing Cushing disease Cushing Syndrome Cushing syndrome is a constellation of clinical abnormalities caused by chronic high blood levels of cortisol or related corticosteroids. Cushing disease is Cushing syndrome that results from... read more . Most of the remainder are nonfunctional.

Local tumor expansion may cause visual disturbance, headache, and hypopituitarism Generalized Hypopituitarism Generalized hypopituitarism refers to endocrine deficiency syndromes due to partial or complete loss of anterior lobe pituitary function. Various clinical features occur depending on the specific... read more .

Pituitary tumors in patients with MEN 1 may be larger and behave more aggressively and may occur at an earlier age than sporadic pituitary tumors; however, a long-term cohort study found MEN 1–associated pituitary tumors were more indolent, similar to sporadic pituitary tumors (2 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

Carcinoid tumors Overview of Carcinoid Tumors Carcinoid tumors develop from neuroendocrine cells in the gastrointestinal tract (90%), pancreas, pulmonary bronchi, and rarely the genitourinary tract. More than 95% of all gastrointestinal... read more , particularly those derived from the embryologic foregut (thymus, lungs, stomach), occur in 5 to 15% of patients with MEN 1 (1 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ). Thymic carcinoids are more common in affected males, and a subset of them may behave quite aggressively. Carcinoid syndrome may occur.

Adrenal adenomas occur in up to 33% of patients and may be bilateral. There is a risk that a benign-appearing adenoma may undergo degeneration into an aggressive adrenocortical carcinoma.

Adenomatous hyperplasia of the thyroid occurs occasionally in patients with MEN 1. Hormone secretion is rarely altered as a result, and the significance of this abnormality is uncertain.

Multiple subcutaneous and visceral lipomas, angiofibromas, meningiomas, ependymomas, and collagenomas may also occur (3 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

In a study in Holland, the United States, Tasmania, and France, the relative risk of breast cancer Breast Cancer Breast cancers are most often epithelial tumors involving the ducts or lobules. Most patients present with an asymptomatic mass discovered during examination or screening mammography. Diagnosis... read more in patients with MEN 1 was 2.3 to 2.8-fold higher and the age at diagnosis was somewhat younger than in participants without MEN 1 (4 Symptoms references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

When an index case is identified, 1st-degree relatives should be given the option of genetic screening. Family members can also be screened biochemically by measurement of calcium and PTH, which is frequently useful because of the high penetrance of hyperparathyroidism in MEN 1.

Although early presymptomatic screening of family members of patients with MEN 1 has not been shown to reduce morbidity or mortality, a large cohort study reported a significant lag time between diagnosis of the index case and diagnosis in the rest of the family. This lag was found to be clinically relevant, because patients diagnosed after a preventable delay were found to have a higher incidence of pancreatic tumors, including metastatic lesions (4, 5 Diagnosis references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).

Preimplantation genetic diagnosis on embryos conceived via assisted reproductive techniques Assisted Reproductive Techniques Assisted reproductive techniques (ARTs) involve manipulation of sperm and ova or embryos in vitro with the goal of producing a pregnancy. For assisted reproductive techniques, oocytes and sperm... read more is also available.

Some clinicians monitor gene carriers by doing pancreatic and pituitary imaging every 3 to 5 years, although such screening has not been shown to improve outcomes.

Screening for breast cancer Breast Cancer Screening and Prevention Breast cancer screening is recommended for all women in the United States, but major medical organizations vary regarding the starting age and frequency of screening (see table ) ( 1, 2). Determining... read more is recommended beginning at age 40 in women with MEN 1 (6 Diagnosis references Multiple endocrine neoplasia, type 1 (MEN 1) is an autosomal dominant syndrome characterized by hyperplasia or adenomas of the parathyroid glands, pancreatic islet cell tumors (also known as... read more ).