Multiple Endocrine Neoplasias for USMLE Step 2

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Multiple Endocrine Neoplasias for the USMLE Step 2 Exam

Multiple Endocrine Neoplasias (MEN) are a group of inherited disorders that cause tumors in multiple endocrine glands. MEN syndromes are classified into three types: MEN1, MEN2A, and MEN2B.
MEN1: Caused by mutations in the MEN1 gene, which encodes the tumor suppressor protein menin. These mutations lead to uncontrolled growth in endocrine tissues.
MEN2A and MEN2B: Caused by mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase. RET mutations result in constitutive receptor activation, leading to tumor formation in specific endocrine tissues.

MEN1

MEN1 is inherited in an autosomal dominant pattern due to mutations in the MEN1 gene on chromosome 11, which encodes menin.

Primary Hyperparathyroidism: The most common feature of MEN1, caused by parathyroid hyperplasia or adenomas, leading to hypercalcemia. Symptoms include kidney stones, bone pain, and constipation.
Pituitary Adenomas:
Prolactinomas (causing galactorrhea, amenorrhea, or impotence).
Growth hormone (GH)-secreting tumors (causing acromegaly).
ACTH-secreting tumors (causing Cushing’s disease).
Pancreatic Neuroendocrine Tumors (NETs):
Gastrinomas (causing Zollinger-Ellison syndrome), which lead to peptic ulcers.
Insulinomas, causing hypoglycemia.

Genetic Testing: Confirms the presence of MEN1 mutations.
Biochemical Testing: Elevated calcium and PTH for hyperparathyroidism; elevated hormone levels for pituitary and pancreatic NETs.
Imaging: MRI for pituitary adenomas and parathyroid imaging (ultrasound or sestamibi scan).

Parathyroidectomy: For hyperparathyroidism.
Medical Therapy: Dopamine agonists for prolactinomas, proton-pump inhibitors for gastrinomas, and insulin management for insulinomas.
Surgery: For symptomatic pancreatic NETs.

MEN2A

Autosomal dominant inheritance caused by mutations in the RET proto-oncogene.

Medullary Thyroid Carcinoma (MTC): Arises from parafollicular C cells and secretes calcitonin. It may present with neck mass or symptoms such as diarrhea.
Pheochromocytoma: Adrenal medullary tumor secreting catecholamines, causing episodic hypertension, headaches, and palpitations.
Primary Hyperparathyroidism: Occurs in a subset of patients, leading to hypercalcemia and its associated symptoms.

Genetic Testing: Confirms RET mutations.
Biochemical Testing: Elevated calcitonin for MTC, plasma metanephrines for pheochromocytoma, and elevated calcium/PTH for hyperparathyroidism.
Imaging: Thyroid ultrasound, adrenal imaging (CT/MRI), and parathyroid imaging if necessary.

Prophylactic Thyroidectomy: Recommended early in life for RET mutation carriers to prevent MTC.
Adrenalectomy: For pheochromocytoma.
Parathyroidectomy: For hyperparathyroidism if present.

MEN2B

Also caused by RET proto-oncogene mutations, MEN2B has more aggressive characteristics than MEN2A.

Medullary Thyroid Carcinoma: Occurs at a younger age and is more aggressive than in MEN2A.
Pheochromocytoma: Same presentation as in MEN2A.
Mucosal Neuromas: Benign tumors on the lips, tongue, and gastrointestinal tract.
Marfanoid Habitus: Long limbs, joint hypermobility, and a high-arched palate.

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

Prophylactic Thyroidectomy: Urgent, often in infancy or early childhood due to the aggressive nature of MTC.
Adrenalectomy: For pheochromocytoma.
Surveillance: For early detection of recurrences.

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 present with medullary thyroid carcinoma and pheochromocytoma. MEN2B is more aggressive and includes mucosal neuromas and marfanoid habitus.
Prophylactic thyroidectomy is critical for RET mutation carriers to prevent the development of medullary thyroid carcinoma.