A 28-year-old woman is found to carry a germline mutation in the gene located at the locus marked **B** in the diagram. Genetic testing reveals a pathogenic variant affecting codon 634. She is asymptomatic but has a strong family history of early-onset thyroid cancer and hypertension. Which of the following best describes the molecular consequence of this mutation and the most appropriate immediate management?
A. Dominant-negative mutation affecting p53 function; chemotherapy should be initiated to prevent malignant transformation
B. Gain-of-function mutation causing constitutive RET receptor tyrosine kinase signaling; prophylactic total thyroidectomy should be performed after excluding pheochromocytoma
C. Loss-of-function mutation impairing GDNF ligand binding; observation with annual ultrasound screening is sufficient
D. Haploinsufficiency of the RET proto-oncogene; parathyroid imaging and surgery should be prioritized first
Explanation
Why option 1 is correct
The mutation at chromosome 10q11.2 (RET) in MEN2A, particularly at codon 634, is a gain-of-function (activating) mutation that causes ligand-independent receptor dimerization and constitutive downstream signaling through RAS-MAPK and PI3K-AKT pathways (Harrison 21e Ch 384). This leads to medullary thyroid carcinoma (MTC) in essentially 100% of carriers, making prophylactic total thyroidectomy the standard of care. Critically, pheochromocytoma (present in ~50% of MEN2A carriers) must be excluded first via plasma/urine metanephrines to prevent intraoperative hypertensive crisis during thyroid surgery (ATA MTC Guidelines 2015).
Why each distractor is wrong
Option 2: RET mutations in MEN2A are gain-of-function, not loss-of-function. Loss-of-function mutations in RET are associated with Hirschsprung disease, not cancer predisposition. Annual ultrasound is insufficient; prophylactic surgery is the standard.
Option 3: While hyperparathyroidism occurs in ~25% of MEN2A carriers, it is NOT the most lethal or first manifestation. MTC is present in 100% and is the primary driver of morbidity/mortality. Parathyroid surgery should never precede thyroid surgery without pheochromocytoma exclusion.
Option 4: The mutation is in RET (chromosome 10q11.2), not TP53 (chromosome 17p13). TP53 mutations cause Li-Fraumeni syndrome, not MEN2A. Chemotherapy is not indicated for asymptomatic gene carriers.
High-YieldNEET PG
MEN2A = RET gain-of-function (codon 634 most common) → MTC 100% → prophylactic thyroidectomy AFTER pheochromocytoma exclusion to prevent hypertensive crisis.
Harrison 21e Ch 384; ATA MTC Guidelines 2015
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