WBR0108

Author	[[PageAuthor::William J Gibson (reviewed by Rim Halaby, M.D. [1])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Cardiology
Prompt	[[Prompt::A 32-year-old woman is rushed to the emergency room after being involved in a motor vehicle accident. She complains of a sudden onset of tearing chest pain that radiates between the scapula. Her pulse is 110 beats/min, blood pressure is 90/60 mm Hg, respiratory rate is 20/min. The physician notes that the patient is unusually tall and lean, with very long fingers. Chest X-ray reveals a widened mediastinum. If a genetic defect had predisposed the patient to her current condition, which of the following is the most likely causal gene?]]
Answer A	AnswerA::COLA1
Answer A Explanation	[[AnswerAExp::Mutation in COLA1, the gene coding for collagen type 1 is responsible for osteogenesis imperfecta.]]
Answer B	AnswerB::COLA3
Answer B Explanation	[[AnswerBExp::Mutation of COLA3, the gene coding for collagen type 3 is responsible for the hypermobility subtype of Ehlers-Danlos syndrome.]]
Answer C	AnswerC::TGFBR2
Answer C Explanation	[[AnswerCExp::Mutation in TGFBR2 causes Loeys-Dietz syndrome, which is highly similar to Marfan syndrome but much rarer.]]
Answer D	AnswerD::FBN1
Answer D Explanation	AnswerDExp::Mutation of the FBN1 gene, which codes for the extracellular matrix protein fibrillin is responsible for Marfan syndrome.
Answer E	AnswerE::FGFR3
Answer E Explanation	[[AnswerEExp::Mutation of the FGFR3 gene is responsible for achondroplasia, the most common cause of dwarfism.]]
Right Answer	RightAnswer::D
Explanation	[[Explanation::The patient in this vignette is suffering from a thoracic aortic dissection secondary to Marfan syndrome. Aortic dissection occurs when a tear in the inner wall of the aorta causes blood to flow between the layers of the wall of the aorta, forcing the layers apart. In most cases this is associated with severe "tearing" chest pain that radiates between the scapula. Acute treatment focuses on decreasing blood pressure to a mean arterial pressure of 60 to 70 mm Hg as to decrease the growth of the intimal "false lumen". Definitive treatment may require surgery in certain cases. Marfan syndrome is a genetic disorder primarily affecting connective tissue. The reduced structural integrity of the vasculature in Marfan syndrome predisposes patients to aortic dissection. People with Marfan syndrome tend to be unusually tall, with long limbs and long, thin fingers. Marfan syndrome has a range of expressivity, with clinical symptoms ranging from mild to severe. The most serious complications are typically defects of the heart valves and aorta. Marfan syndrome is a dominant genetic trait, meaning that people who inherit only one copy of the mutated FBN1 gene from either parent will develop Marfan syndrome. The syndrome is carried by the gene FBN1, which encodes the connective protein fibrillin-1. Fibrillin-1 protein is essential for the proper formation of the extracellular matrix, including the biogenesis and maintenance of elastin fibers. In addition to being a connective protein that forms the structural support for tissues outside the cell, the normal fibrillin-1 protein binds to an cytokine called transforming growth factor beta (TGF-β). TGF-β signaling has deleterious effects on vascular smooth muscle development and the integrity of the extracellular matrix. Educational Objective: Marfan syndrome is caused by mutations in the FBN1 gene encoding fibrillin. References: First Aid 2014 page 87]]
Approved	Approved::Yes
Keyword	WBRKeyword::Aorta, WBRKeyword::Aortic dissection, WBRKeyword::Marfan, WBRKeyword::Marfan's syndrome, WBRKeyword::Cardiology, WBRKeyword::Genetics, WBRKeyword::Vascular, WBRKeyword::Artery
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