Marfan Syndrome is a genetic disorder that impacts the body’s connective tissue, which provides structure and support to many parts of the body. This condition can affect multiple systems, including the heart, blood vessels, bones, and eyes. Individuals are born with the syndrome, though its features may manifest at various ages and with differing severity.
The FBN1 Gene and Its Role
Marfan Syndrome arises from mutations within the FBN1 gene, located on chromosome 15 at position 15q21.1. This gene provides instructions for creating a large protein, fibrillin-1. Fibrillin-1 is secreted from cells into the extracellular matrix, a complex network of proteins and molecules found between cells. Here, fibrillin-1 molecules assemble to form microfibrils, which are thread-like filaments.
These microfibrils are important for the structure and elasticity of connective tissues, enabling skin, ligaments, and blood vessels to stretch while supporting rigid tissues like bones and the lens of the eye. Beyond structural support, microfibrils also regulate growth factors, storing and releasing transforming growth factor-beta (TGF-β). This growth factor influences cell growth, division, and repair processes.
Mutations in the FBN1 gene disrupt this balance, leading to reduced production of functional fibrillin-1 or abnormal, dysfunctional fibrillin-1 protein. One mechanism is haploinsufficiency, where the mutation results in insufficient amounts of normal fibrillin-1. Another mechanism is a dominant-negative effect, where the abnormal fibrillin-1 protein interferes with the assembly and function of normal fibrillin-1. Both mechanisms compromise microfibril formation, leading to a decrease in tissue elasticity and an abnormal activation of TGF-β, contributing to the connective tissue issues seen in Marfan Syndrome.
How Fibrillin-1 Deficiency Impacts the Body
The compromised integrity of connective tissue leads to a variety of features across different body systems. In the cardiovascular system, the most serious concerns involve the aorta, the body’s main artery. Weakened aortic walls can lead to dilation, where the aorta widens, and potentially dissection, a tear in the inner layer of the aortic wall. Mitral valve prolapse, where the heart’s mitral valve does not close properly, is also a common cardiac manifestation.
Skeletal system impacts are also prominent, often leading to a tall, slender build with unusually long arms, legs, fingers, and toes, known as arachnodactyly. Individuals may also experience abnormal spinal curvature, such as scoliosis, and chest wall deformities like pectus excavatum (sunken chest) or pectus carinatum (protruding chest). Joint hypermobility is common.
Ocular manifestations affect many individuals with Marfan Syndrome, with lens dislocation (ectopia lentis) being a distinct feature present in over half of cases. Myopia (nearsightedness) is also very common, and the weakened connective tissue can increase the risk of retinal detachment. Individuals with Marfan Syndrome may develop glaucoma or cataracts at an earlier age. Other less common impacts can include pneumothorax, a collapsed lung, and dural ectasia, a weakening of the dura mater surrounding the spinal cord.
Understanding Inheritance and Diagnosis
Marfan Syndrome is inherited in an autosomal dominant pattern, meaning only one copy of the mutated FBN1 gene is sufficient to cause the disorder. If a parent has Marfan Syndrome, each child has a 50% chance of inheriting the mutated gene. This inheritance pattern applies equally to males and females.
Approximately 25% of Marfan Syndrome cases result from a new (de novo) mutation in the FBN1 gene, occurring in individuals with no family history. In such instances, the mutation arises spontaneously in the egg or sperm cell that formed the affected individual. Genetic testing is important in confirming a diagnosis by identifying the specific FBN1 mutation, particularly when clinical features are not definitive or to differentiate Marfan Syndrome from other connective tissue disorders.
For individuals with a known family history, identifying the familial FBN1 mutation allows for precise genetic testing of at-risk relatives. Genetic counseling is often recommended to help families understand the inheritance risks, interpret genetic test results, and make informed decisions regarding family planning or managing the condition.