Multiple Endocrine Neoplasias for USMLE Step 1
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Multiple Endocrine Neoplasias for the USMLE Step 1 Exam
- Pathophysiology
- Multiple Endocrine Neoplasias (MEN) are inherited syndromes involving 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. Mutations lead to loss of function and result in tumor formation in multiple endocrine glands.
- MEN2A and MEN2B: Both result from mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase. These mutations lead to constitutive RET activation, driving cell proliferation and tumorigenesis.
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MEN1
- Genetics
- Autosomal dominant inheritance caused by mutations in the MEN1 gene on chromosome 11, which encodes menin.
- Clinical Features
- Primary Hyperparathyroidism: The most common manifestation, caused by parathyroid hyperplasia or adenomas, leading to hypercalcemia and symptoms like kidney stones, bone pain, and fatigue.
- Pituitary Adenomas:
- Prolactinomas are the most common, causing galactorrhea and menstrual irregularities in women or hypogonadism in men.
- Other adenomas include growth hormone (GH)-secreting tumors (acromegaly) or ACTH-secreting tumors (Cushing’s disease).
- Pancreatic Neuroendocrine Tumors (NETs):
- Gastrinomas (Zollinger-Ellison syndrome), which cause peptic ulcers, or insulinomas, leading to hypoglycemia.
- Diagnosis
- Genetic Testing: Identifies MEN1 mutations.
- Biochemical Testing:
- Elevated calcium and parathyroid hormone (PTH) levels for hyperparathyroidism.
- Hormone testing for pituitary adenomas and pancreatic NETs.
- Imaging: Pituitary MRI, parathyroid ultrasound, and pancreatic imaging as needed.
- Management
- Parathyroidectomy for hyperparathyroidism.
- Medical management (dopamine agonists for prolactinomas, proton-pump inhibitors for gastrinomas).
- Surgical removal of pancreatic NETs if symptomatic.
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MEN2A
- Genetics
- Autosomal dominant inheritance caused by mutations in the RET proto-oncogene.
- Clinical Features
- Medullary Thyroid Carcinoma (MTC): Arises from parafollicular C cells, secretes calcitonin, and can cause diarrhea and flushing.
- Pheochromocytoma: Catecholamine-secreting adrenal medullary tumor causing episodic hypertension, headaches, sweating, and palpitations.
- Primary Hyperparathyroidism: Occurs in a subset of patients, leading to hypercalcemia.
- Diagnosis
- Genetic Testing: Confirms RET mutations.
- Biochemical Testing:
- Elevated calcitonin for MTC.
- Plasma metanephrines and urine catecholamines for pheochromocytoma.
- Imaging: Thyroid ultrasound and adrenal CT/MRI.
- Management
- Prophylactic Thyroidectomy in childhood to prevent MTC.
- Adrenalectomy for pheochromocytoma.
- Parathyroidectomy if hyperparathyroidism is present.
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MEN2B
- Genetics
- Also caused by RET proto-oncogene mutations, MEN2B shares similarities with MEN2A but has additional non-endocrine manifestations.
- Clinical Features
- Medullary Thyroid Carcinoma: More aggressive and occurs earlier than in MEN2A.
- Pheochromocytoma: Same as in MEN2A.
- Mucosal Neuromas: Painless growths on the tongue, lips, and gastrointestinal tract, often appearing in early childhood.
- Marfanoid Habitus: Features include long limbs, joint hypermobility, and a high-arched palate.
- Diagnosis
- Genetic Testing: Identifies RET mutations.
- Biochemical Testing: Elevated calcitonin and plasma metanephrines.
- Physical Examination: Presence of mucosal neuromas and marfanoid features.
- Management
- Prophylactic Thyroidectomy at an early age due to the aggressive nature of MTC.
- Adrenalectomy for pheochromocytoma.
- Regular surveillance for tumor recurrence or metastasis.
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Key Points
- MEN1 involves tumors in the parathyroid glands, pituitary, and pancreas, with hyperparathyroidism being the most common manifestation. It is caused by mutations in the MEN1 gene.
- 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 also presents with mucosal neuromas and marfanoid features.
- Prophylactic thyroidectomy is critical in MEN2 to prevent the aggressive development of medullary thyroid carcinoma.