USMLE PRACTICE QUESTION #89
TOPIC: Genetics/MSK
Today’s question will test your understanding of a commonly tested Genetics/MSK concept.
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A 3-year-old boy is brought to the pediatrician by his parents, who are concerned about his short stature. They report that he is significantly shorter than his peers and has been slow to reach developmental milestones, particularly those involving motor skills. On physical examination, the child has a disproportionately large head, a prominent forehead, and short limbs relative to his trunk. Radiographs reveal shortened long bones with flared metaphyses. Based on the patient's presentation, which of the following molecular mechanisms is most likely responsible for the observed abnormalities in chondrocyte function in this condition?
A) Increased activity of matrix metalloproteinases leading to excessive extracellular matrix degradation
B) Upregulation of Indian hedgehog (IHH) signaling leading to accelerated chondrocyte differentiation
C) Overexpression of parathyroid hormone-related protein (PTHrP) resulting in delayed chondrocyte hypertrophy
D) Downregulation of SOX9 gene expression resulting in impaired chondrocyte differentiation
E) Enhanced activation of STAT proteins leading to overstimulation of chondrocyte proliferation
F) Overactivation of fibroblast growth factor receptor 3 (FGFR3) signaling leading to inhibition of chondrocyte proliferation
G) Reduced production of cartilage oligomeric matrix protein (COMP) compromising the structural integrity of cartilage
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
The MENTAL MODEL used to answer this question comes from our detailed test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following molecular mechanisms is most likely responsible for the observed abnormalities in chondrocyte function in this condition?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Diagnose the problem, and 2nd: Identify the underlying mechanism.
Step 3: Read the vignette carefully and ask yourself: “What’s the underlying cause of this patient’s condition?”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
The 3-year-old boy in the vignette presents with short stature, delayed motor milestones, disproportionately large head, prominent forehead, and short limbs relative to his trunk, which are classic features of achondroplasia. Achondroplasia is a form of skeletal dysplasia caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene.
ANSWER CHOICES:
CHOICE A: Increased activity of matrix metalloproteinases leading to excessive extracellular matrix degradation
Explanation: Matrix metalloproteinases (MMPs) are enzymes that degrade components of the extracellular matrix and are involved in tissue remodeling. Excessive MMP activity is not the primary mechanism in achondroplasia. MMPs are more relevant to conditions involving tissue degradation, such as osteoarthritis or cancer metastasis.
CHOICE B: Upregulation of Indian hedgehog (IHH) signaling leading to accelerated chondrocyte differentiation
Explanation: Indian hedgehog (IHH) signaling plays a role in regulating chondrocyte differentiation and bone growth. Achondroplasia is characterized by impaired chondrocyte proliferation due to FGFR3 overactivation, not accelerated differentiation through IHH signaling.
CHOICE C: Overexpression of parathyroid hormone-related protein (PTHrP) resulting in delayed chondrocyte hypertrophy
Explanation: PTHrP regulates chondrocyte hypertrophy and endochondral ossification during bone development. While PTHrP delays chondrocyte hypertrophy, this is not the mechanism responsible for achondroplasia. The condition is due to FGFR3 overactivation.
CHOICE D: Downregulation of SOX9 gene expression resulting in impaired chondrocyte differentiation
Explanation: SOX9 is a transcription factor critical for chondrogenesis and cartilage formation. SOX9 downregulation would impair chondrocyte differentiation, but achondroplasia is due to overactivation of FGFR3, not SOX9 dysfunction.
CHOICE E: Enhanced activation of STAT proteins leading to overstimulation of chondrocyte proliferation
Explanation: Signal transducer and activator of transcription (STAT) proteins mediate various cellular processes, including proliferation. In achondroplasia, FGFR3 overactivation leads to inhibited chondrocyte proliferation, not overstimulation.
CHOICE F: Overactivation of fibroblast growth factor receptor 3 (FGFR3) signaling leading to inhibition of chondrocyte proliferation
Explanation: Achondroplasia is caused by a gain-of-function mutation in the FGFR3 gene, which leads to constitutive activation of the FGFR3 receptor. FGFR3 negatively regulates bone growth by inhibiting chondrocyte proliferation in the growth plates of long bones. In achondroplasia, overactivation of FGFR3 inhibits normal endochondral ossification, resulting in shortened long bones and disproportionate short stature.
CHOICE G: Reduced production of cartilage oligomeric matrix protein (COMP) compromising the structural integrity of cartilage
Explanation: Mutations in the COMP gene cause pseudoachondroplasia, a different form of skeletal dysplasia characterized by short stature and joint abnormalities. This patient’s presentation is more consistent with achondroplasia, which is caused by FGFR3 mutations, not COMP mutations.
FINAL VERDICT…
The most likely molecular mechanism responsible for this patient's condition is the overactivation of fibroblast growth factor receptor 3 (FGFR3) signaling, which inhibits chondrocyte proliferation and leads to the characteristic skeletal abnormalities seen in achondroplasia.
CORRECT ANSWER: F) Overactivation of fibroblast growth factor receptor 3 (FGFR3) signaling leading to inhibition of chondrocyte proliferation
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That’s it for question 89!
See ya tomorrow 👋