A 37-year-old woman comes to the physician for a 6-month history of headaches, anorexia, and vomiting. She has had a 10-kg (22-lb) weight loss during this period. She has type 1 diabetes mellitus for which she takes insulin. The patient's mother and sister have hypothyroidism. Her blood pressure is 80/60 mm Hg. Physical examination shows hyperpigmentation of the lips and oral mucosa. Serum studies show a parathyroid hormone level of 450 pg/mL and antibodies directed against 21-hydroxylase. Which of the following is the most likely diagnosis?

Autoimmune polyendocrine syndrome type 2

Multiple endocrine neoplasia type 2A

Multiple endocrine neoplasia type 2B

Autoimmune polyendocrine syndrome type 1

A 74-year-old retired female teacher is referred to the endocrinology clinic. She is very concerned about a large mass in her neck that has progressively enlarged over the past 2 weeks. She also reports a 15 pound weight loss over the last 3 months. She now has hoarseness and difficulty swallowing her food, giving her a sensation that food gets stuck in her windpipe when she swallows. There is no pain associated with swallowing. Her speech is monotonous. No other gait or language articulation problems are noted. Testing for cranial nerve lesions is unremarkable. On palpation, a large, fixed and non-tender mass in the thyroid is noted. Cervical lymph nodes are palpable bilaterally. The patient is urgently scheduled for an ultrasound-guided fine needle aspiration to guide management. Which of the following is the most likely gene mutation to be found in this mass?

Inactivating mutation of the p53 tumor suppressor gene

Activating mutation of the Ras protooncogene

A 38-year-old female presents to her primary care physician with complaints of several episodes of palpitations accompanied by panic attacks over the last month. She also is concerned about many instances over the past few weeks where food has been getting stuck in her throat and she has had trouble swallowing. She denies any prior medical problems and reports a family history of cancer in her mother and maternal grandfather but cannot recall any details regarding the type of cancer(s) or age of diagnosis. Her vital signs at today's visit are as follows: T 37.6 deg C, HR 106, BP 158/104, RR 16, SpO2 97%. Physical examination is significant for a nodule on the anterior portion of the neck that moves with swallowing, accompanied by mild lymphadenopathy. A preliminary work-up is initiated, which shows hypercalcemia, elevated baseline calcitonin, and an inappropriately elevated PTH level. Diagnostic imaging shows bilateral adrenal lesions on an MRI of the abdomen/pelvis. Which of the following is the most likely diagnosis in this patient?

Multiple endocrine neoplasia (MEN) IIa

Familial medullary thyroid cancer (FMTC)

Multiple endocrine neoplasia (MEN) I

Multiple endocrine neoplasia (MEN) IIb

A 40-year-old man presents with a painless firm mass in the right breast. Examination shows retraction of the nipple and the skin is fixed to the underlying mass. The axillary nodes are palpable. Which of the following statements is FALSE regarding the above condition?

Lobular cancer is the most common breast cancer in males

BRCA2 mutations are associated with increased risk

These are positive for estrogen receptor

Endocrine therapy plays an important role in treatment

Gynecomastia may be caused by certain medications

Multiple endocrine neoplasia syndromes for USMLE Step 1: High-Yield Pathology Lessons

MEN Syndromes - Endocrine Domino Effect

MEN 1 (Wermer's): Pituitary adenoma, Parathyroid hyperplasia, Pancreatic tumors. 📌 (3 P's)
MEN 2A (Sipple's): Parathyroid hyperplasia, Pheochromocytoma, Medullary thyroid carcinoma. 📌 (2 P's, 1 M)
MEN 2B: Pheochromocytoma, Medullary thyroid carcinoma, Mucosal neuromas/Marfanoid habitus. 📌 (1 P, 2 M's)

Organs affected by MEN1 and MEN2 syndromes

⭐ All MEN 2 variants are caused by RET proto-oncogene mutations. Prophylactic thyroidectomy is recommended in childhood for carriers.

MEN 1 - The 3 Ps

Autosomal dominant mutation of the MEN1 (menin) tumor suppressor gene on chromosome 11.
📌 Parathyroid, Pancreatic, Pituitary tumors.

Parathyroid (›90%): Primary hyperparathyroidism is the most common feature. Presents with ↑PTH, ↑Ca²⁺.
Pancreatic endocrine tumors (60%):
- Gastrinoma (Zollinger-Ellison syndrome) is most frequent.
- Insulinoma, VIPoma, glucagonoma.
Pituitary adenoma (40%):
- Prolactinoma is the most common type.

MEN1 and MEN2 Syndromes: Affected Organs

⭐ While the mnemonic is the 3 Ps, remember that angiofibromas, collagenomas, and lipomas are also associated findings.

MEN 2A - The RET Gene Show

Gene: Autosomal dominant gain-of-function mutation in the RET proto-oncogene.
Classic Triad: 📌 Pheo, Parathyroid, Medullary (PPM).
- Pheochromocytoma (50%): Often bilateral, secretes catecholamines (headache, palpitations, sweating).
- Parathyroid Hyperplasia (20%): Leads to primary hyperparathyroidism (↑PTH, ↑Ca).
- Medullary Thyroid Carcinoma (MTC) (100%): Arises from parafollicular C-cells; secretes calcitonin.

⭐ High-Yield: All individuals with a RET mutation require prophylactic thyroidectomy, often by age 5, due to the 100% lifetime risk of MTC.

Multiple Endocrine Neoplasia (MEN) Syndromes Comparison

MEN 2B - Bumpy & Gangly

Autosomal Dominant RET gene mutation.
Clinical Features:
- Medullary Thyroid Carcinoma (MTC): 100% penetrance, presents in infancy. Very aggressive.
- Pheochromocytoma: Bilateral in ~50% of patients.
- Mucosal Neuromas: Bumpy lesions on lips, tongue, conjunctiva.
- Marfanoid Habitus: Tall, lanky frame with long limbs (arachnodactyly).
- Intestinal ganglioneuromas.

📌 Mnemonic: 1 P & 3 Ms - Pheochromocytoma, Medullary cancer, Marfanoid habitus, Mucosal neuromas.

⭐ Unlike MEN 1 and 2A, MEN 2B is NOT associated with primary hyperparathyroidism.

MEN 2B: Mucosal neuromas on tongue and everted eyelids

High‑Yield Points - ⚡ Biggest Takeaways

All MEN syndromes are inherited in an autosomal dominant fashion.

MEN 1 is the 3 P's: Parathyroid hyperplasia, Pancreatic tumors, and Pituitary adenomas. Due to MEN1 gene mutation.

MEN 2A is the 2 P's, 1 M: Parathyroid hyperplasia, Pheochromocytoma, and Medullary thyroid cancer (MTC).

MEN 2B is the 1 P, 2 M's: Pheochromocytoma, Medullary thyroid cancer (MTC), and Mucosal neuromas/Marfanoid habitus.

Both MEN 2A and 2B are caused by activating mutations in the RET proto-oncogene.

Always rule out pheochromocytoma before any surgery in MEN 2 patients.

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