WBR0105

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Cardiology, SubCategory::Musculoskeletal/Rheumatology, SubCategory::General Principles
Prompt	[[Prompt::A 16-year-old male adolescent presents to his pediatrician for an annual check-up. The patient complains only of pain in his joints and muscles that he has attributed to growing pains. Otherwise, a 14-point review of systems is unrevealing. During physical examination, the physician notices several unusual features. The patient is unusually tall, with long slender limbs, fingers, and toes. On ophthalmic exam, the patient displays a slight superotemporal subluxation of the lens in the right eye. The physician orders molecular genetic testing of the FBN1 gene and confirms the diagnosis. Which of the following molecular defects underlie the syndrome similar to that of the patient's condition?]]
Answer A	AnswerA::Mutation of COLA1
Answer A Explanation	[[AnswerAExp::Mutation of the COLA1 gene, which codes for collagen type 1 is responsible for osteogenesis imperfecta.]]
Answer B	AnswerB::Mutation of TGFBR2
Answer B Explanation	AnswerBExp::Mutation of the TGFBR2 gene causes Loeys-Dietz Syndrome, a disorder that closely reflects Marfan syndrome.
Answer C	AnswerC::Mutation of COLA3
Answer C Explanation	[[AnswerCExp::Mutation of COLA3, the gene coding for collagen type 3 is responsible for the hypermobility subtype of Ehlers-Danlos syndrome.]]
Answer D	AnswerD::Mutation of HFE
Answer D Explanation	[[AnswerDExp::Mutation of the HFE gene is responsible for hereditary hemochromatosis.]]
Answer E	AnswerE::Mutation of FGFR3
Answer E Explanation	[[AnswerEExp::Mutation of the FGFR3 gene is responsible for achondroplasia, the most common cause of dwarfism.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::The patient in this vignette is suffering from Marfan syndrome. Marfan syndrome is a clinically variable genetic disorder that primarily affecting connective tissue. Patients with the disease have a unique habitus, characterized by tall, slender extremities with 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. Fibrillin-1 directly binds a latent form of TGF-β, keeping it sequestered and unable to exert its biological activity. Researchers now believe, secondary to mutated fibrillin, excessive TGF-β accumulation in the lungs, heart valves, and aorta weakens the tissues and causes the features of Marfan syndrome. In support of the TGF-Beta hypothesis, a closely related syndrome, Loeys-Dietz Syndrome is caused by defects in the TGF-Beta Receptor, encoded by the gene TGFBR2. Educational Objective: Loeys-Dietz syndrome is closely related to Marfan Syndrome and is caused by defects in the TGF-Beta receptor encoded by the TGFBR2 gene. References: First Aid 2014 page 87 Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33(3):407-11. Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37(3):275-81.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Connective tissue, WBRKeyword::Marfan, WBRKeyword::Loeys-Dietz, WBRKeyword::Genetics, WBRKeyword::Autosomal dominant
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::