WBR0110

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 16-year-old male adolescent presents to his pediatrician for the evaluation of scoliosis. During physical examination, the physician notes that in addition to his scoliosis, the patient is tall and has an increased arm span-to-height ratio, with a chest wall deformity (shown below). Also, he has crowded teeth and dental malocclusion. The physician suspects a genetic origin for the patient’s condition. The physician orders a chest x-ray that shows a convex contour of the right superior mediastinum, suggestive of an aortic abnormality. Which of the following medications may potentially be used to reduce the rate of progression of this patient's aortic abnormality? ]]
Answer A	AnswerA::Losartan
Answer A Explanation	[[AnswerAExp::Losartan is shown to be useful among patient’s with Marfan syndrome in reducing the rate of progression of aortic root dilatation.]]
Answer B	AnswerB::Lisinopril
Answer B Explanation	[[AnswerBExp::ACE-inhibitors may be used for hypertension and diabetic nephropathy.]]
Answer C	AnswerC::Hydrochlorothiazide
Answer C Explanation	[[AnswerCExp::Hydrochlorothiazide is a thiazide diuretic which may be used to treat hypertension, hypercalciuria, and nephrogenic diabetes insipidus.]]
Answer D	AnswerD::Spironolactone
Answer D Explanation	[[AnswerDExp::Spironolactone is a potassium-sparing diuretic and a competitive aldosterone receptor antagonist that has been shown to be effective among patients with advanced congestive heart failure.]]
Answer E	AnswerE::Furosemide
Answer E Explanation	[[AnswerEExp::Furosemide is a loop diuretic that may be used for hypertension and congestive heart failure.]]
Right Answer	RightAnswer::A
Explanation	[[Explanation::Marfan syndrome is an autosomal dominant genetic disorder primarily affecting connective tissue with variable expression. Skeletal malformations are the hallmark of Marfan syndrome; patients tend to be unusually tall, with long limbs and long, thin fingers, and hyperextensible joints. Characteristically, patients have lower segments of the body greater than the upper segments and increased arm span-to-height ratio. Additionally, patients may have chest wall abnormalities, such as pectus excavatum (as shown in the patient's image) or carinatum, that may require surgical intervention. Dental abnormalities described among patients with Marfan syndrome usually include crowded teeth and dental malocclusion. Classically, patients with Marfan syndrome also have oular manifestations, most specifically bilateral, symmetrical, and upward ectopia lentis (lens sublaxation) Most patients with Marfan syndrome are diagnosed incidentally during a routine physical examination or at presentation for a Marfan-associated complication. The most serious complications are abnormalities of the cardiovascular system, especially defects of of the heart valves, such as mitral valve prolapse, and of the aorta, such as aortic dissection and root dilatation. 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 the cytokine transforming growth factor beta (TGF-β). TGF-β signaling has deleterious effects on vascular smooth muscle development and the integrity of the extracellular matrix. Fibrillin-1 directly binds a latent form of TGF-β, keeping it sequestered and unable to exert its biological activity. Abnormal or deficient fibrillin-1 protein promotes the release of active TGF-β, leading to the development of aortic medial necrosis and degeneration that ultimately results in aortic dilatation. It is now believed that secondary to mutated fibrillin, excessive TGF-β accumulation in the lungs, heart valves, and aorta weaken the tissues and cause the features of Marfan syndrome. Losartan, an angiotensin-II type 1 (AT1) receptor blocker (ARB) was found to inhibit TGF-β signaling and TGF-β mediated kinases, thereby contributing to the reduced rate of aortic dilatation in mice models and in human trials. Educational Objective: Losartan is an angiotensin-II type 1 (AT1) receptor blocker (ARB) that inhibits TGF-β activity, thereby blocking its effects on aortic cystic medial degeneration among adult patients with Marfan syndrome. References: Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC. Angiotensin II blockade and aortic-root dilation in Marfan's syndrome. N Engl J Med. 2008;358(26):2787-95 Groenink M, den Hartog AW, Franken R, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J. 2013; 34(45):3491-500 Radonic T, de Witte P, Baars MJ, et al. Losartan therapy in adults with Marfan syndrome: study protocol of the multi-center randomized controlled COMPARE trial. Trials. 2010;11:3 First Aid 2014 page 87]]
Approved	Approved::Yes
Keyword	WBRKeyword::Marfan, WBRKeyword::Marfan's syndrome, WBRKeyword::Pharmacology, WBRKeyword::Vascular, WBRKeyword::Connective tissue, WBRKeyword::Autosomal dominant, WBRKeyword::Genetics
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