Genetics: Inheritance and expression of Marfan syndrome

Marfan syndrome is a fairly common (1 in 5,000) genetic disorder that is characterized by a myriad of symptoms affecting connective tissues. The predominant genetic defect is in the FBN1 gene, which codes for the glycoprotein fibrillin-1—an important component of the extracellular matrix (ECM). Fibrillin-1 is particularly important for the proper formation of elastic fibers, such as those that constitute the walls of large blood vessels, ligaments, and regions of the eye. 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 leads to the degradation of the ECM.

The most recognizable symptom of Marfan syndrome is the characteristic body morphology: disproportionately long, slender limbs and digits, above average height, stooped shoulders, scoliosis, and either a protruding or sunken appearing chest. In addition, many of these individuals have abnormally flexible joints and early-onset arthritis. These individuals are also predisposed to a number of conditions involving the heart and major blood vessels including poor circulation and various heart murmurs. The most serious of these is a situation known as ‘aortic dissection,’ wherein blood under high pressure forces its way between layers of the wall of the aorta. If untreated, this can lead to massive hemorrhage and death within minutes. Figure 1 shows the incidence of common symptoms of Marfan syndrome among patients with the same mutation.

Figure 1 Relative incidence of common symptoms in Marfan syndrome

A patient has come to see you complaining of arthritis. You find that he has a heart murmur and weak circulation to his extremities. You also notice that he is 6’7” tall with extremely long fingers. You suspect Marfan syndrome and record a thorough family history from the patient. Figure 2 shows the pedigree of this patient’s family with respect to symptoms of Marfan syndrome.

Figure 2 Patient’s family history and pedigree with respect to symptoms of Marfan syndrome

$$‍1 = Your patient
$$‍1a = Son; 6’7” tall; treated for scoliosis from young age
$$‍1b = Normal-appearing daughter; average height
$$‍2,3 = Normal-appearing brother and sister; average heights
$$‍4 = Tall sister; arthritis from age 26
$$‍5 = Father; 6’7” tall; died of aortic dissection
$$‍6 = Aunt; normal limb length; hyper flexible; lost eyesight at age 40
$$‍7 = Normal-appearing uncle; average height
$$‍8 = Uncle with long fingers; average height; circulation issues

$$‍* = Mother’s side of the family all appear normal; average heights