View source for WBR0105

{{WBRQuestion
|QuestionAuthor=William J Gibson (Reviewed by {{YD}})
|ExamType=USMLE Step 1
|MainCategory=Genetics
|SubCategory=Cardiology, Musculoskeletal/Rheumatology, General Principles
|MainCategory=Genetics
|SubCategory=Cardiology, Musculoskeletal/Rheumatology, General Principles
|MainCategory=Genetics
|SubCategory=Cardiology, Musculoskeletal/Rheumatology, General Principles
|MainCategory=Genetics
|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Cardiology, Musculoskeletal/Rheumatology, General Principles
|MainCategory=Genetics
|SubCategory=Cardiology, Musculoskeletal/Rheumatology, General Principles
|MainCategory=Genetics
|SubCategory=Cardiology, Musculoskeletal/Rheumatology, General Principles
|MainCategory=Genetics
|SubCategory=Cardiology, Musculoskeletal/Rheumatology, General Principles
|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Cardiology, Musculoskeletal/Rheumatology, General Principles
|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 that phenotypically resembles that of the patient's condition?
|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. 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. Marfan syndrome has a range of [[expressivity]], with clinical symptoms ranging from mild to severe. 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.

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. It is now believed,  excessive TGF-β accumulation in the lungs, heart valves, and aorta secondary to mutated fibrillin weakens the tissues and causes the features of Marfan syndrome.

Loeys-Dietz Syndrome (LDS) is also an autosomal dominant connective tissue disorder caused by a heterozygous missense mutation of either TGFBR1 or TGFBR2 genes that encode TGF-b receptor. LDS is a recently discovered disease that phenotypically resembles Marfan syndrome and is also characterized by the risk of formation of vascular aneurysms and dissection, along with hypertelorism, cleft palate, or bifid/broad uvula.
|AnswerA=Mutation of ''COLA1''
|AnswerAExp=Mutation of the ''COLA1'' gene, which codes for collagen type I, is responsible for [[osteogenesis imperfecta]].
|AnswerB=Mutation of ''TGFBR2''
|AnswerBExp=Mutations of ''TGFBR1'' and ''TGFBR2'' genes cause [[Loeys-Dietz Syndrome]], a disorder that closely reflects Marfan syndrome.
|AnswerC=Mutation of ''COLA3''
|AnswerCExp=Mutation of ''COLA3'', the gene coding for collagen type III, is responsible for the hypermobility subtype of [[Ehlers Danlos syndrome]].
|AnswerD=Mutation of ''HFE''
|AnswerDExp=Mutation of the ''HFE'' gene is responsible for [[hereditary hemochromatosis]].
|AnswerE=Mutation of ''FGFR3''
|AnswerEExp=Mutation of the ''FGFR3'' gene is responsible for [[achondroplasia]], the most common cause of dwarfism.
|EducationalObjectives=[[Loeys-Dietz syndrome]] (LDS) phenotypically resembles Marfan Syndrome and is caused by defects in the TGF-β receptor encoded by the ''TGFBR1'' or ''TGFBR2'' genes.
|References=
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.

MacCarrick G, Black JH, Bowdin S, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16:576-87.
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.

First Aid 2014 page 87
|RightAnswer=B
|WBRKeyword=Connective tissue, Marfan, Loeys-Dietz, Genetics, Autosomal dominant,
|Approved=Yes
}}