Multiple Endocrine Neoplasias for USMLE Step 3

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Multiple Endocrine Neoplasias for the USMLE Step 3 Exam

Multiple Endocrine Neoplasias (MEN) are inherited syndromes characterized by the development of tumors in multiple endocrine glands. MEN syndromes are divided into MEN1, MEN2A, and MEN2B based on genetic mutations and tumor distribution.
MEN1 (Wermer’s Syndrome): Caused by inactivating mutations in the MEN1 gene (tumor suppressor gene), leading to tumors primarily in the parathyroid, pancreas, and pituitary.
MEN2A and MEN2B: Both result from mutations in the RET proto-oncogene, leading to constitutive activation of the RET tyrosine kinase receptor, causing tumor formation in the thyroid, adrenal medulla, and other tissues.

MEN1

Autosomal dominant inheritance of MEN1 gene mutations. Menin, the protein product of this gene, regulates gene transcription and cell proliferation.

Primary Hyperparathyroidism: The most common manifestation, seen in over 90% of patients. Parathyroid hyperplasia or adenomas cause hypercalcemia, leading to kidney stones, bone pain, and gastrointestinal symptoms.
Pituitary Adenomas:
Prolactinomas: Cause galactorrhea, amenorrhea, or infertility in women, and decreased libido or hypogonadism in men.
GH-Secreting Tumors: Lead to acromegaly.
Pancreatic Neuroendocrine Tumors (NETs):
Gastrinomas: Lead to Zollinger-Ellison syndrome, characterized by peptic ulcers and diarrhea.
Insulinomas: Cause hypoglycemia.

Genetic Testing: MEN1 mutations confirm the diagnosis.
Biochemical Testing: Elevated PTH and calcium levels in hyperparathyroidism. Hormone levels such as prolactin and gastrin guide diagnosis of other tumors.
Imaging: MRI for pituitary adenomas, and CT/MRI for pancreatic NETs.

Parathyroidectomy: Treatment of choice for hyperparathyroidism.
Medical Management: Dopamine agonists for prolactinomas; proton-pump inhibitors for gastrinomas; diazoxide for insulinomas.
Surgery: May be indicated for symptomatic pancreatic NETs.

MEN2A

Autosomal dominant inheritance due to mutations in the RET proto-oncogene.

Medullary Thyroid Carcinoma (MTC): A malignancy of parafollicular C-cells, leading to elevated calcitonin. MTC may cause diarrhea or a neck mass.
Pheochromocytoma: A catecholamine-secreting tumor of the adrenal medulla, presenting with episodic hypertension, palpitations, and headaches.
Primary Hyperparathyroidism: Occurs in about 20-30% of patients, causing hypercalcemia.

Genetic Testing: RET mutation testing confirms the diagnosis.
Biochemical Testing: Elevated calcitonin for MTC, plasma metanephrines for pheochromocytoma, and elevated PTH and calcium for hyperparathyroidism.
Imaging: Thyroid ultrasound, adrenal imaging (CT or MRI), and parathyroid imaging if necessary.

Prophylactic Thyroidectomy: Recommended in early life to prevent medullary thyroid carcinoma in RET mutation carriers.
Adrenalectomy: For pheochromocytoma.
Parathyroidectomy: For hyperparathyroidism.

MEN2B

Also caused by mutations in the RET proto-oncogene, MEN2B presents earlier and more aggressively than MEN2A.

Medullary Thyroid Carcinoma: More aggressive and occurs earlier than in MEN2A.
Pheochromocytoma: Similar to MEN2A.
Mucosal Neuromas: Characteristic benign tumors of the mucous membranes (e.g., lips, tongue).
Marfanoid Habitus: Long limbs, joint hypermobility, and a high-arched palate.

Genetic Testing: RET mutation testing.
Biochemical Testing: Elevated calcitonin and plasma metanephrines.
Physical Examination: Mucosal neuromas and marfanoid features may be present.

Prophylactic Thyroidectomy: Urgent in early childhood to prevent aggressive MTC.
Adrenalectomy: For pheochromocytoma.
Surveillance: Monitoring for tumor recurrence or metastasis.

Key Points

MEN1 is caused by mutations in the MEN1 gene and involves tumors in the parathyroid, pituitary, and pancreas. Hyperparathyroidism is the most common manifestation.
MEN2A and MEN2B are caused by mutations in the RET proto-oncogene and are associated with medullary thyroid carcinoma and pheochromocytoma. MEN2B is more aggressive and includes mucosal neuromas and marfanoid features.
Prophylactic thyroidectomy is critical for RET mutation carriers to prevent the development of medullary thyroid carcinoma.