“Characterization of long bone overgrowth in Marfan syndrome"
$50,000 Funded by TFF
January 2015 - December 2016
Sylvia Smaldone, PhD Assistant Professor
Department of Pharmacology and Systems Therapeutics Icahn School of Medicine of Mount Sinai
New York, NY, United States
Fibrillin-1 (Fbn1) gene is responsible for the expression of an important protein of the connective tissue. The primary function of connective tissue is to hold the body together and provide a framework for growth and development. Marfan syndrome (MFS) is a hereditary genetic disorder in which mutations of Fbn1 gene produce a defective fibrillin-1 protein and promote increase in a small molecule named TGF-β thus causing problems throughout the body. The connective tissue in MFS does not function properly and many organs and tissues functions are affected, including the skeleton, eyes, heart and blood vessels, nervous system, skin, and lungs. A multidisciplinary approach is required to diagnose MFS because signs and symptoms can vary from patient to patient. However, individual with MFS often share similar traits and appear different form their peers: their arms, legs, fingers and toes are disproportionately long compared to the rest of their body; the spine is frequently curved (scoliosis) and overgrowth of the ribs often deform the rib cage resulting in a convex (pectus carinatum) or concave (pectus escavatum) shape. People with MFS have often a long narrow face, a narrow palate with crowded teeth, and joint laxity that is sometimes associated with normal joints or even contractures. These skeletal manifestations, usually appearing during the teenage years, are frequently responsible for significant pain, discomfort, and body deformations that are emotionally difficult to be accepted and they lead to low self-esteem. Moreover, sport restrictions due to the risk of acute aortic dissection (the most frequent cause of morbidity and mortality in MFS), along with the need to wear back braces to support their spine negatively impact the patients’ quality of life and interactions with peers precluding participation to physical activities and leading to intense feeling of isolation and depression. The goal of this project is to understand the causes of bone overgrowth in MFS with the ultimate goal of improving patient’s quality of life. In our laboratory we have generated a new mouse model that replicate MFS bone overgrowth. Our preliminary data suggest that excessive bone lengthening in MFS is the result of structural/functional alterations of ligaments and tendons. By using this mouse model we propose to characterize the onset and progression of bone overgrowth in MFS and also test the efficiency of TGF-β blockade in improving MFS orthopedic problems.