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# A family history of Marfan syndrome

## Problem

Marfan syndrome is a genetic disorder of the connective tissue in which mutations on the FBN1 gene cause the protein it codes for to misfold. This protein is fibrillin-1, a large glycoprotein essential in creating the extracellular matrix (ECM). Fibrillin-1 helps provide structural support in elastin fibers, which are involved in helping tissues regain their shape after stretching. It also sequesters transforming growth factor beta (TGF-β), a growth factor responsible for cell proliferation and differentiation. Low fibrillin-1 levels can lead to elevated TGF-β, which actually leads to the degradation of the ECM.
In particular, Marfan syndrome affects the ocular, skeletal, and cardiovascular systems. Elastin fibers are key components of the ligaments responsible for suspending the lens of the eye, as well as aortic root. Patients with Marfan syndrome can have serious heart valve and aortic defects. They are often very tall and thin, and can suffer from arachnodactyly (long, thin fingers). Many patients have some form of myopia, and have an increased risk of retinal detachment.
Sandy and Danny have come to a clinic because they are considering having another child but are worried by the history of Marfan syndrome in Sandy’s family. After questioning Sandy further, the geneticist learns that both of her brothers are very tall and each has had lens dislocations. Her niece has mitral valve prolapse, a heart murmur due to a thicker heart valve. Sandy’s mother was tall and had long fingers, though she had no cardiovascular or ocular issues. Sandy’s maternal grandfather passed away due to an aortic aneurysm – an enlargement of the aorta to more than 150, percent its normal size. However, Sandy’s sister has never shown any sign of the disease and has a perfectly healthy son.
Figure 1 Pedigree of Sandy’s family
In Figure 1, who is Sandy?