Multiple Endocrine Neoplasias for ABIM

Multiple Endocrine Neoplasias for the American Board of Internal Medicine Exam

Multiple Endocrine Neoplasias (MEN) are inherited syndromes characterized by the development of tumors in multiple endocrine glands. These syndromes arise from mutations in specific genes that predispose individuals to develop benign or malignant tumors. MEN syndromes are classified into three types: MEN1, MEN2A, and MEN2B.
MEN1 (Wermer's Syndrome): Caused by mutations in the MEN1 gene, which encodes the tumor suppressor protein menin. Menin regulates gene expression and cell growth, and its mutation leads to endocrine tumor development.
MEN2A and MEN2B: Both caused by mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase. These mutations lead to constitutive activation of the RET receptor, promoting cellular proliferation.

MEN1 (Wermer's Syndrome)

Inherited in an autosomal dominant pattern, MEN1 is caused by inactivating mutations in the MEN1 gene on chromosome 11, which encodes menin, a tumor suppressor. Loss of this gene’s function leads to uncontrolled cellular proliferation and tumor formation in endocrine tissues.

Pituitary Adenomas:
Commonly prolactinomas, which cause galactorrhea, amenorrhea, and infertility in women, or hypogonadism in men.
Other types include growth hormone (GH)-secreting tumors (causing acromegaly) and adrenocorticotropic hormone (ACTH)-secreting tumors (causing Cushing's disease).
Parathyroid Hyperplasia:
Primary hyperparathyroidism is the most common manifestation of MEN1. It leads to hypercalcemia, causing symptoms such as kidney stones, osteoporosis, and abdominal pain.
Pancreatic Neuroendocrine Tumors (NETs):
Includes gastrinomas (causing Zollinger-Ellison syndrome with peptic ulcers), insulinomas (causing hypoglycemia), and other less common hormone-secreting tumors like glucagonomas and VIPomas.

Genetic Testing: MEN1 gene mutation testing confirms the diagnosis.
Biochemical Testing:
Elevated calcium and PTH levels in hyperparathyroidism.
Elevated prolactin in prolactinomas.
Gastrin, insulin, or other relevant hormone levels in pancreatic NETs.
Imaging: MRI for pituitary adenomas, sestamibi scan or ultrasound for parathyroid adenomas, and CT or MRI for pancreatic NETs.

Parathyroidectomy: Surgical removal of hyperplastic parathyroid glands to manage hyperparathyroidism.
Medical Management: Dopamine agonists (e.g., cabergoline) for prolactinomas, proton-pump inhibitors for gastrinomas, and insulin therapy or diazoxide for insulinomas.
Surgical Resection: Indicated for symptomatic pancreatic NETs.

MEN2A (Sipple's Syndrome)

MEN2A is inherited in an autosomal dominant pattern and caused by gain-of-function mutations in the RET proto-oncogene. These mutations result in constitutive activation of the RET tyrosine kinase receptor, leading to cellular proliferation and tumor formation, particularly in the thyroid, adrenal glands, and parathyroid glands.

Medullary Thyroid Carcinoma (MTC):
Nearly all patients with MEN2A develop MTC, a tumor of parafollicular C-cells that secretes calcitonin. MTC can lead to diarrhea and flushing.
Pheochromocytoma:
Catecholamine-secreting adrenal medulla tumors that cause episodic hypertension, palpitations, sweating, and headaches.
Primary Hyperparathyroidism:
Less common than in MEN1, but hyperparathyroidism occurs in a subset of MEN2A patients, leading to hypercalcemia.

Genetic Testing: RET proto-oncogene mutation testing confirms the diagnosis.
Biochemical Testing:
Elevated calcitonin levels in medullary thyroid carcinoma.
Elevated plasma free metanephrines and urine catecholamines for pheochromocytoma.
Calcium and PTH levels for hyperparathyroidism.
Imaging: Ultrasound or CT for thyroid evaluation, CT or MRI for adrenal imaging in pheochromocytomas.

Prophylactic Thyroidectomy: Recommended in RET mutation carriers, typically performed in childhood to prevent medullary thyroid carcinoma.
Adrenalectomy: Surgical removal of pheochromocytomas.
Parathyroidectomy: Indicated for primary hyperparathyroidism.

MEN2B

Also caused by RET proto-oncogene mutations, MEN2B is an autosomal dominant syndrome. MEN2B shares some features with MEN2A but also presents with unique non-endocrine findings.
MEN2B is typically more aggressive, with medullary thyroid carcinoma developing at an earlier age and a higher likelihood of metastatic disease.

Medullary Thyroid Carcinoma:
Occurs earlier and is more aggressive than in MEN2A, with nearly all patients developing this malignancy.
Pheochromocytoma:
Similar presentation as in MEN2A, causing episodic hypertension and catecholamine excess.
Mucosal Neuromas:
Benign, painless growths on the tongue, lips, and gastrointestinal tract, often presenting in early childhood and serving as a clinical marker of MEN2B.
Marfanoid Habitus:
Long limbs, a high-arched palate, and joint hypermobility are typical features of MEN2B patients.

Genetic Testing: RET mutation testing confirms the diagnosis.
Biochemical Testing:
Elevated calcitonin levels for medullary thyroid carcinoma.
Elevated plasma metanephrines for pheochromocytoma.
Physical Examination: Detection of mucosal neuromas, marfanoid body habitus.
Imaging: Thyroid ultrasound, adrenal imaging (CT or MRI), and full body imaging for metastases in advanced medullary thyroid carcinoma.

Prophylactic Thyroidectomy: Recommended in infancy or early childhood due to the aggressive nature of medullary thyroid carcinoma.
Adrenalectomy: For pheochromocytoma.
Surveillance: Long-term follow-up is essential for detecting recurrent or metastatic disease.

Key Points

MEN1 is caused by mutations in the MEN1 gene, leading to tumors in the pituitary, parathyroid, and pancreatic endocrine glands. Hyperparathyroidism is the most common manifestation.
MEN2A and MEN2B result from mutations in the RET proto-oncogene. MEN2A features medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism, while MEN2B is characterized by medullary thyroid carcinoma, pheochromocytoma, mucosal neuromas, and marfanoid habitus.
Prophylactic thyroidectomy is recommended for RET mutation carriers to prevent medullary thyroid carcinoma, with earlier intervention in MEN2B due to the more aggressive nature of the disease.
Genetic testing is crucial for early diagnosis and guiding management in affected families.