Marfan syndrome (FBN1 gene): aorta, eyes, skeleton and inheritance

The NHS describes Marfan syndrome as a disorder of the body's connective tissues, the tissues that maintain structure and support internal organs. Some people are only mildly affected while others develop more serious problems. Typical characteristics include being tall, having unusually long and slender limbs, fingers and toes, heart defects and dislocation of the eye lens.

The NHS Genomics Education Programme groups the features into three main areas. Cardiovascular disease is the most serious: widening of the aortic root can lead to leaking of the aortic valve or to aortic dissection, and rarely sudden cardiac death can be the first presentation. Mitral valve prolapse is also common. Skeletal features include arm span greater than height, long slender fingers, chest wall deformities, scoliosis, flat feet and joint hypermobility. Eye features include lens dislocation (the most specific sign), marked short-sightedness, glaucoma, cataract and retinal detachment.

Other features can include spontaneous collapsed lung, widening of the sac around the spinal cord that can cause back pain, hernias and dental crowding, though the programme says some of these are not specific to Marfan syndrome.

Fibrillin-1 helps build microfibrils, part of the network that gives connective tissue its strength and flexibility, and it interacts with growth factors. The NHS explains that a faulty fibrillin gene leads to reduced fibrillin, so that parts of the body can stretch abnormally under stress, and that it can cause some bones to grow longer than they should, which is why people with Marfan syndrome may be tall.

The NHS Genomics Education Programme adds that a harmful FBN1 variant leads to fragmentation of elastic fibres and excessive signalling of the growth factor TGF-beta, which weakens the wall of the aorta. Most people with Marfan syndrome have a pathogenic or likely pathogenic FBN1 variant, and genomic testing is considered after assessment by a clinical geneticist or a clinician expert in aortic conditions.

Marfan syndrome is autosomal dominant. The NHS says a child can inherit it even if only one parent has the syndrome, with a 1 in 2 chance for the child of an affected parent. It reports that in around 3 in 4 cases Marfan syndrome is inherited from one parent. In the remaining 1 in 4 the fibrillin gene changes for the first time in the egg or sperm, so neither parent has it, though the new change can then be passed on.

The NHS Genomics Education Programme adds two cautions. Penetrance can be incomplete, so not everyone with a variant develops the disease, and severity can vary greatly within a family. If a variant appears new in a child, there is a small possibility of two unaffected parents having a second affected child because of germline mosaicism.

Cascade predictive testing is offered to relatives through clinical genetics or an inherited cardiac conditions service. Because surveillance and treatment options exist, the programme says children should also be referred to discuss predictive testing.

The NHS notes that diagnosis can be difficult because symptoms vary significantly and may not develop in childhood, so it may not be identified until the teenage years. In most cases it rests on a thorough physical examination and detailed medical and family history. The NHS Genomics Education Programme says the revised Ghent criteria are most commonly used, combining family history, examination findings, aortic root measurements and, if appropriate, genomic testing.

The NHS says there is no cure and treatment focuses on managing symptoms and reducing complications, with care from a team of professionals. The NHS Genomics Education Programme says that at diagnosis there should be a baseline eye examination, echocardiogram and CT or MRI of the aorta, with the aorta monitored at regular intervals, usually yearly. Beta blockers and angiotensin receptor blockers have been shown to reduce progression of aortic widening and should be considered in all patients including children. Surgery to replace the aortic root or to support it externally may be considered depending on measurements and other risks.

Lifestyle matters: the programme advises discussing safer physical activities and avoiding activities that significantly increase the risk of aortic dissection, particularly contact sports and isometric exercise, while still encouraging physical activity for fitness and general health. It also advises emergency preparedness, such as seeking medical advice early and carrying documentation of the diagnosis.

The NHS Genomics Education Programme says women with Marfan syndrome should ideally have preconception counselling when considering pregnancy, to be advised about cardiovascular risk, medicines to avoid in pregnancy such as ACE inhibitors, warfarin and angiotensin receptor blockers and their alternatives, and the options of prenatal testing or pre-implantation genetic testing. Pregnancy and the period after birth need close monitoring in a specialist maternal cardiac service, with increased imaging surveillance.