WBR0108

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D. and 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 department after being involved in a motor vehicle accident. She complains of a sudden onset of tearing chest pain that radiates between the scapulae and the back. The pain is associated with shortness of breath, cold sweats, and weakness of the lower extremities. In the ED, her blood pressure is 152/86 mmHg in the left arm and 90/60 mmHg in the right arm, heart rate is 110/min, and respiratory rate is 20/min. On physical examination, the physician notes that the patient is unusually tall and lean, with very long fingers and hyperextensible joints. Chest X-ray reveals a widened mediastinum. If a genetic defect has predisposed the patient to her current condition, which of the following is the most likely involved gene?]]
Answer A	AnswerA::''COL1A1''
Answer A Explanation	[[AnswerAExp::Mutation in COL1A1, the gene encoding collagen type I, is responsible for osteogenesis imperfecta.]]
Answer B	AnswerB::''COL3A1''
Answer B Explanation	[[AnswerBExp::Mutation in COL3A1, the gene encoding collagen type III is responsible for the "vascular" subtype of Ehlers-Danlos syndrome.]]
Answer C	AnswerC::''TGFBR2''
Answer C Explanation	[[AnswerCExp::Mutation in TGFBR2 causes Loeys-Dietz syndrome, which is a rare genetic disease that is phenotypically similar disease to Marfan syndrome.]]
Answer D	AnswerD::''FBN1''
Answer D Explanation	[[AnswerDExp::Mutation in 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 in the FGFR3 gene is responsible for achondroplasia, the most common cause of dwarfism.]]
Right Answer	RightAnswer::D
Explanation	[[Explanation::The patient is most likely diagnosed with Marfan syndrome. Marfan syndrome is a clinically variable autosomal dominant genetic disorder that primarily affects connective tissue. It has a wide range of expressivity, with clinical symptoms ranging from mild to severe. Patients with the disease have a unique habitus, characterized by musculoskeletal abnormalities and joint laxity. Patients typically have tall, slender extremities with long, thin fingers. Other abnormalities include scoliosis, pectus excavatum, or pectus carinatum. The most serious complications are typically cardiovascular, such as dilation of the aortic valves at the level of Valsalva sinuses, or mitral valve prolapse with or without regurgitation. Marfan syndrome is caused by a mutation of 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. The patient in this vignette is suffering from a thoracic aortic dissection secondary to Marfan syndrome. Aortic dissection is an acute aortic syndrome that occurs when a stellate or linear tear within the aorta causes blood to flow between the layers of the aortic wall, forcing the layers apart. In most cases, aortic dissection is associated with severe "tearing" or "ripping" chest pain that radiates to the back and between the scapulae. The pain is often associated with dyspnea at rest, weakness, cold sweats, and nausea. In cases of trauma, aortic injury most likely occurs at proximity to the ligamentum arteriosum. While hypertension is the most important risk factor the development of descending aortic dissection (Stanford typ B dissection) in the general population, patients with Marfan syndrome and bicuspid aortic valves comprise 2 specific high-risk populations for dissection of the ascending aorta (Stanford type A dissection). Marfan syndrome is associated with cystic medial degeneration/necrosis of the aorta predisposing patients to aortic dissection even with no or minimal trauma. Other risk factors for aortic dissection include cocaine abuse, vasculitides, pregnancy, and iatrogenic causes such as coronary catheterization and revascularization procedures. Management of aortic dissections includes close monitoring of vital signs, fluid resuscitation, and administration of beta-blockers with a goal of heart rate of 60-80/min, and systolic blood pressure of 100-120 mmHg. While dissection of the descending aorta may be managed conservatively using pharmacologic therapy, treatment for dissections of the descending aorta may require surgery due to the risk of aortic valve involvement. Educational Objective: Marfan syndrome is an autosomal dominant genetic disorder caused by mutations in the FBN1 gene encoding fibrillin. References: Canadas V, Vilacosta I, Bruna I, et al. Marfan syndrome: pathophysiology and diagnosis. Nat Rev Cardiol. 2010;7:256-65 Simon AL, Hipona FA, Slansel HC. Dissecting aortic aneurysm in Marfan's syndrome. 1965;193(2):156-8 Thrumurthy SG, Karthikesalingam A, Patterson BO, et al. The diagnosis and management of aortic dissection. BMJ. 2011;344:d8290 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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