MEN1 Syndrome MCQ — NEET PG Practice Question | NEETPGAI
MEN1 Syndrome
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stethoscope Medicine
A 38-year-old woman presents with recurrent peptic ulcers refractory to high-dose proton pump inhibitors, nephrolithiasis, and recent visual field defects. Laboratory findings show serum calcium 11.6 mg/dL with elevated PTH, fasting gastrin 1200 pg/mL with positive secretin stimulation test, and prolactin 280 ng/mL. Pituitary MRI confirms a macroadenoma. Her father and paternal uncle have hypercalcemia with "stomach ulcers," and her sister has amenorrhea. The pedigree pattern marked **A** in the diagram shows autosomal dominant inheritance with high penetrance across three generations involving parathyroid, pancreatic, and pituitary tumors. Which of the following BEST describes the underlying genetic mechanism in this family?
A. Germline mutation in the RET proto-oncogene causing medullary thyroid carcinoma and pheochromocytoma with autosomal dominant inheritance
B. Germline mutation in the VHL gene causing renal cell carcinoma, hemangioblastomas, and pancreatic cysts with autosomal dominant inheritance
C. Germline mutation in the MEN1 gene (chromosome 11q13) encoding menin, a tumor suppressor, with somatic second-hit inactivation in tumors (Knudson two-hit hypothesis)
D. Germline mutation in the CDKN1A gene causing Li-Fraumeni syndrome with predisposition to multiple malignancies across tissues
Explanation
Why option 1 is correct
The clinical presentation of the triad of hyperparathyroidism (elevated calcium and PTH), gastrinoma (elevated fasting gastrin with positive secretin stimulation), and prolactinoma (elevated prolactin with bitemporal hemianopia and macroadenoma on MRI) in the setting of an autosomal dominant pedigree with high penetrance (father, paternal uncle, and sister all affected) is pathognomonic for Multiple Endocrine Neoplasia Type 1 (MEN1, Wermer syndrome). MEN1 is caused by germline mutations in the MEN1 gene located on chromosome 11q13, which encodes menin, a nuclear protein functioning as a tumor suppressor. The Knudson two-hit hypothesis applies: affected individuals inherit one mutated allele, and tumors develop when a somatic second hit inactivates the remaining wild-type allele. This explains the autosomal dominant inheritance pattern with high penetrance (>50% by age 50) and the development of multiple independent tumors in different endocrine tissues (Harrison's 21e MEN; Thakker 2012 MEN1 Clinical Practice Guidelines).
Why each distractor is wrong
Option 2 (RET mutation): RET mutations cause MEN2A (medullary thyroid cancer + pheochromocytoma ± hyperparathyroidism) and MEN2B (medullary thyroid cancer + pheochromocytoma + mucosal neuromas + marfanoid habitus). This patient has no medullary thyroid cancer, pheochromocytoma, or mucosal features; the pedigree marked A shows parathyroid, pancreatic, and pituitary tumors, not thyroid and adrenal. RET-associated syndromes do not feature gastrinoma or prolactinoma as primary manifestations.
Option 3 (VHL mutation): VHL mutations cause von Hippel-Lindau syndrome, characterized by renal cell carcinoma, hemangioblastomas (CNS and retinal), pancreatic cysts and neuroendocrine tumors, and pheochromocytoma. While VHL can present with pancreatic NETs, it does not typically cause hyperparathyroidism or prolactinoma, and the inheritance pattern and clinical triad do not match MEN1.
Option 4 (CDKN1A/p21 mutation): CDKN1A mutations are extremely rare and associated with Li-Fraumeni-like syndrome with predisposition to diverse malignancies (breast, sarcoma, brain tumors). This does not explain the specific endocrine tumor triad (parathyroid, gastrinoma, prolactinoma) or the autosomal dominant inheritance pattern characteristic of MEN1.
High-YieldNEET PG
MEN1 = Menin (chromosome 11q13 tumor suppressor) + Parathyroid (95%, most common) + Pancreatic/Duodenal NETs (30–80%; gastrinoma most common functional tumor) + Pituitary (15–50%; prolactinoma most common); autosomal dominant with >50% penetrance by age 50; Knudson two-hit mechanism.
Harrison's 21e MEN; Thakker 2012 MEN1 Clinical Practice Guidelines
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