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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson (Reviewed by {{YD}} and {{Rim}})
|QuestionAuthor=William J Gibson (Reviewed by {{YD}} and {{Rim}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Genetics
|MainCategory=Genetics
Line 21: Line 21:
|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Cardiology
|SubCategory=Cardiology
|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. In the ED, her blood pressure is 152/86 mmHg in the left arm and 90/60 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 had predisposed the patient to her current condition, which of the following is the most likely causal gene?
|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?
|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.
|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.


[[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 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.


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.
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.
|AnswerA=COLA1
 
|AnswerAExp=Mutation in COLA1, the gene coding for collagen type 1 is responsible for [[osteogenesis imperfecta]].
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.
|AnswerB=COLA3
|AnswerA=''COL1A1''
|AnswerBExp=Mutation of COLA3, the gene coding for collagen type 3 is responsible for the hypermobility subtype of [[Ehlers-Danlos syndrome]].
|AnswerAExp=Mutation in ''COL1A1'', the gene encoding collagen type I, is responsible for [[osteogenesis imperfecta]].
|AnswerC=TGFBR2
|AnswerB=''COL3A1''
|AnswerCExp=Mutation in TGFBR2 causes [[Loeys-Dietz syndrome]], which is highly similar to Marfan syndrome but much rarer.
|AnswerBExp=Mutation in ''COL3A1'', the gene encoding collagen type III is responsible for the "vascular" subtype of [[Ehlers-Danlos syndrome]].
|AnswerD=FBN1
|AnswerC=''TGFBR2''
|AnswerDExp=Mutation of the FBN1 gene, which codes for the extracellular matrix protein fibrillin is responsible for Marfan syndrome.
|AnswerCExp=Mutation in ''TGFBR2'' causes [[Loeys-Dietz syndrome]], which is a rare genetic disease that is phenotypically similar disease to Marfan syndrome.
|AnswerE=FGFR3
|AnswerD=''FBN1''
|AnswerEExp=Mutation of the FGFR3 gene is responsible for [[achondroplasia]], the most common cause of dwarfism.
|AnswerDExp=Mutation in the ''FBN1'' gene, which codes for the extracellular matrix protein fibrillin, is responsible for [[Marfan syndrome]].
|EducationalObjectives=[[Marfan syndrome]] is caused by mutations in the FBN1 gene encoding fibrillin.
|AnswerE=''FGFR3''
|References=First Aid 2014 page 87
|AnswerEExp=Mutation in the ''FGFR3'' gene is responsible for [[achondroplasia]], the most common cause of dwarfism.
|EducationalObjectives=[[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
|RightAnswer=D
|RightAnswer=D
|WBRKeyword=Aorta, Aortic dissection, Marfan, Marfan's syndrome, Cardiology, Genetics, Vascular, Artery,
|WBRKeyword=Aorta, Aortic dissection, Marfan, Marfan's syndrome, Cardiology, Genetics, Vascular, Artery,
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 23:22, 27 October 2020

 
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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