USMLE PRACTICE QUESTION #110

TOPIC: Pathophysiology/Genetics

Dec 19, 2024

In USMLE practice question #110, we’ll assess our ability to recognize the underlying pathophysiology of a highly tested biochemistry/genetics condition.

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A 34-year-old woman presents to a genetics clinic with her 1-year-old son, who was recently diagnosed with a skeletal disorder. The child was born at term via an uncomplicated vaginal delivery after a pregnancy notable only for mild polyhydramnios. Since birth, the mother has noticed that her son has not kept pace with other children in reaching developmental motor milestones, such as crawling or standing. She reports that he has a normal appetite and energy level but has a noticeably large head with a prominent forehead, short arms and legs compared to his torso, and a flattened nasal bridge. He has also developed recurrent middle ear infections. Physical examination reveals a child below the 5th percentile for length with a disproportionately large head and bilateral genu varum. No abnormalities are noted on cardiovascular or respiratory examination. Which of the following best explains the pathophysiology of this condition?

A) Excessive inhibition of chondrocyte proliferation in growth plates
B) Accelerated apoptosis of growth plate chondrocytes
C) Impaired differentiation of hypertrophic chondrocytes
D) Decreased extracellular matrix deposition by chondrocytes
E) Reduced vascular invasion into growth plate cartilage

Detailed Breakdown of Answers + Correct Answer Below ⏬

ANSWER + QUESTION BREAKDOWN

It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our 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 best explains the pathophysiology of this condition?”

Step 2: Is this a first-, second-, or third-order question?
Answer: 2n order. 1st: Diagnose the condition; 2nd: Identify the pathophysiology of this condition.

Step 3: Read the vignette carefully and ask yourself: “What is the underlying pathophysiology of the condition present?”

Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.

GENERAL ANALYSIS

This vignette describes a 1-year-old boy with developmental delay, motor milestone delays (such as crawling and standing), and unique physical features such as a large head with a prominent forehead, short arms and legs compared to his torso, and a flattened nasal bridge. He also has recurrent middle ear infections. The family history reveals that several male relatives on the mother’s side have similar symptoms.

ANSWER CHOICES:

CHOICE A: Excessive inhibition of chondrocyte proliferation in growth plates

Explanation: Achondroplasia is caused by an activating mutation in the FGFR3 gene, which leads to excessive inhibition of chondrocyte proliferation in the growth plates of long bones. This results in impaired endochondral ossification.

CHOICE B: Accelerated apoptosis of growth plate chondrocytes

Explanation: Accelerated apoptosis of chondrocytes could theoretically lead to premature closure of growth plates, but this is not the mechanism underlying achondroplasia.

CHOICE C: Impaired differentiation of hypertrophic chondrocytes

Explanation: Impaired differentiation of hypertrophic chondrocytes could affect bone growth but is not the primary mechanism in achondroplasia.

CHOICE D: Decreased extracellular matrix deposition by chondrocytes

Explanation: Decreased extracellular matrix deposition could affect cartilage structure but does not explain the findings in achondroplasia.

CHOICE E: Reduced vascular invasion into growth plate cartilage

Explanation: Reduced vascular invasion into cartilage can occur in conditions like osteochondrosis but is not relevant to achondroplasia.

FINAL VERDICT…

The most likely diagnosis for this patient is achondroplasia, based on his physical features (short arms and legs, large head with prominent forehead), developmental delays, and family history. Achondroplasia is caused by mutations in the FGFR3 gene, which leads to excessive inhibition of chondrocyte proliferation in the growth plates. This results in impaired bone growth, particularly affecting the long bones, leading to short stature and characteristic skeletal features.

KEY CONCEPTS:

The clinical presentation, including disproportionately short limbs, large head, and prominent forehead, is characteristic of achondroplasia, the most common form of skeletal dysplasia.
Achondroplasia is caused by a mutation in the FGFR3 gene (fibroblast growth factor receptor 3), which plays a key role in regulating bone growth by inhibiting chondrocyte proliferation.
The mutation leads to excessive inhibition of chondrocyte proliferation, particularly in the growth plates of long bones, resulting in shortened limbs and other skeletal abnormalities.

CORRECT ANSWER: A) Excessive inhibition of chondrocyte proliferation in growth plates