Multiple endocrine neoplasia type 1

Overview

Multiple Endocrine Neoplasia type 1 (MEN1) is a rare, inherited disorder characterized by the development of tumors in multiple endocrine glands. These tumors may be benign or malignant and commonly affect the parathyroid glands, the pancreas (specifically the islet cells), and the anterior pituitary gland. MEN1 is also known as Wermer's syndrome, after the physician who first described it.

The condition is inherited in an autosomal dominant pattern, meaning a single copy of the mutated gene is enough to cause the disorder. It affects both men and women equally and usually manifests in adulthood, though signs can begin as early as childhood. MEN1 requires lifelong monitoring due to the potential for tumor recurrence or transformation into malignancies.

Causes

MEN1 is caused by mutations in the MEN1 gene, located on chromosome 11q13. This gene encodes a tumor suppressor protein called menin, which regulates cell growth and division. Loss-of-function mutations in MEN1 lead to uncontrolled cellular proliferation and the formation of endocrine tumors.

Genetic Features

• Autosomal dominant inheritance: Each child of an affected parent has a 50% chance of inheriting the mutation.

• De novo mutations: About 10% of cases result from new mutations with no family history.

The high penetrance of the gene means that nearly all individuals with a MEN1 mutation will eventually develop some form of endocrine tumor, although the age of onset and type of tumors can vary widely among individuals.

Symptoms

The symptoms of MEN1 depend on the glands affected and the type of tumors that develop. The three most commonly involved glands are the parathyroids, pancreas, and pituitary.

1. Parathyroid Tumors (Primary Hyperparathyroidism)

• Most common feature, occurring in over 90% of patients

• Elevated calcium levels (hypercalcemia)

• Bone pain, kidney stones, fatigue, abdominal pain

• Osteoporosis and neuropsychiatric disturbances

2. Pancreatic and Gastrointestinal Neuroendocrine Tumors (GEP-NETs)

• Gastrinomas (Zollinger–Ellison syndrome): Causes peptic ulcers, diarrhea, abdominal pain

• Insulinomas: Hypoglycemia, confusion, sweating

• Glucagonomas: Diabetes, weight loss, skin rash

• VIPomas and somatostatinomas (rare): Diarrhea, electrolyte imbalance

3. Pituitary Tumors

• Prolactinomas: Galactorrhea, amenorrhea, infertility in women; erectile dysfunction in men

• Growth hormone-secreting tumors: Acromegaly

• ACTH-secreting tumors: Cushing’s disease (rare in MEN1)

Other Possible Manifestations

• Adrenal gland tumors (usually non-functional)

• Facial angiofibromas and collagenomas (cutaneous signs)

• Thymic or bronchial carcinoids (rare but potentially malignant)

Because of its diverse manifestations, symptoms of MEN1 can mimic many other conditions and often require thorough and targeted investigations for accurate diagnosis.

Diagnosis

MEN1 is diagnosed through a combination of clinical evaluation, biochemical testing, imaging studies, and genetic analysis. Early diagnosis, especially in asymptomatic gene carriers, is crucial for proactive management and surveillance.

Clinical Criteria

A diagnosis of MEN1 can be made when a patient has two or more of the following tumors:

• Parathyroid adenomas

• Enteropancreatic neuroendocrine tumors

• Pituitary adenomas

A diagnosis may also be made in individuals with one MEN1-associated tumor and a first-degree relative with confirmed MEN1, or in individuals with a pathogenic MEN1 gene mutation.

Diagnostic Workup

• Blood tests: Serum calcium, PTH, prolactin, insulin, gastrin, glucose, growth hormone, and other hormonal levels

• Imaging: MRI or CT scans of the pituitary and abdomen, parathyroid ultrasound or sestamibi scan

• Endoscopic ultrasound: For detecting small pancreatic tumors

Genetic Testing

• Confirms mutations in the MEN1 gene

• Recommended for individuals with MEN1-associated tumors and their relatives

Once diagnosed, lifelong surveillance for tumor development is recommended, even in asymptomatic carriers.

Treatment

Treatment of MEN1 focuses on managing the individual tumors and associated hormonal imbalances. Management is often complex and requires a multidisciplinary approach involving endocrinologists, surgeons, gastroenterologists, and genetic counselors.

1. Parathyroid Tumors

• Parathyroidectomy: Removal of hyperactive glands, often requiring subtotal or total parathyroidectomy with autotransplantation

• Monitoring: Serum calcium and PTH levels

2. Pancreatic Neuroendocrine Tumors

• Surgical removal: For large or symptomatic tumors

• Medical management: Proton pump inhibitors for gastrinomas, diazoxide for insulinomas

• Targeted therapy: Somatostatin analogs (e.g., octreotide) or everolimus for metastatic tumors

3. Pituitary Tumors

• Prolactinomas: Treated with dopamine agonists (e.g., cabergoline)

• GH-secreting tumors: Surgical removal or medical therapy (e.g., somatostatin analogs)

• Radiation or stereotactic surgery: For refractory or large pituitary tumors

4. Surveillance and Genetic Counseling

• Annual biochemical testing and imaging

• Genetic testing and counseling for first-degree relatives

There is no cure for MEN1, but early detection and management of tumors can significantly reduce complications and improve life expectancy.

Prognosis

The prognosis for individuals with MEN1 depends on the types, number, and severity of tumors present. With proper monitoring and treatment, many individuals live into adulthood with good quality of life. However, malignant transformation, particularly of pancreatic neuroendocrine tumors, is the major cause of morbidity and mortality in MEN1.

Positive Prognostic Factors

• Early diagnosis and intervention

• Regular surveillance and tumor monitoring

• Effective surgical and medical management of hormone-producing tumors

Potential Complications

• Recurrent hyperparathyroidism after surgery

• Metastasis of neuroendocrine tumors

• Functional impairment due to tumor burden or hormone excess

Lifelong follow-up is essential to manage tumor recurrence and detect new tumors early. Family members of affected individuals benefit greatly from genetic counseling and predictive testing to initiate early surveillance if needed.