Marfan Syndrome

Introduction

Marfan syndrome is a genetic condition that affects the FBN1 gene.¹ Defects in this gene lead to reduced production of fibrillin, resulting in loss of elastic tissue in the musculoskeletal, cardiovascular and ocular systems.

This causes parts of the body to be able to stretch abnormally when placed under stress. The defective fibrillin gene also causes some bones to grow longer than they should.

It is an autosomal dominant syndrome and is one of the most common inherited disorders of connective tissue disorders, with 1 case in every 3000-5000 people. 

Aetiology

Marfan syndrome is an autosomal dominant condition. However, 25% of patients develop the disease due to de novo mutations, where the fibrillin gene mutates for the first time in the parent’s egg or sperm.

This mutation results in defects in the FBN1 gene, which codes for fibrillin-1. Fibrillin is a structural macromolecule that forms microfibril bundles, which are important architectural scaffolds for elastin deposition. Collectively, these scaffolds maintain connective tissue integrity, and the abnormal structure found in these patients is responsible for the symptoms of Marfan syndrome.

Risk factors

As Marfan syndrome is autosomal dominant, having a parent with the condition results in a 50% risk of the child inheriting Marfan syndrome.

Clinical features

History

Marfan syndrome is typically identified during adolescence, with an average age at diagnosis of 19. If detected early in childhood, parents will often note their child is taller than their peers, alongside elongation of limbs, fingers, and facial features.

Typical symptoms of Marfan syndrome include:

• Visual disturbance: due to lens dislocation
• Stretch marks (striae) following growth spurts
• Back pain: due to scoliosis or spondylolisthesis
• Palpitations
• Shortness of breath on exertion
• Hypermobile joints

Other important areas to cover in the history include:

• Parental history of Marfan syndrome: 50% risk of children being affected
• Family history of aortic root dilation/aortic dissection

Clinical examination

Typical clinical features of Marfan syndrome include:

• Facial features: long face, narrow skull, deep-set eyes, small jaw, flat cheekbones
• Lens dislocation (ectopia lentis)
• High-arched palate and crowded teeth: this may be noticed in routine dental examinations
• Tall stature
• Long neck
• Long limbs and wide arm span
• Long fingers and toes (arachnodactyly) 
• Skin striae
• Spine deformities: scoliosis, spondylolisthesis
• Hip and foot deformities
• Hypermobile joints
• Chest deformities: pectus carinatum/excavatum
• Cardiac murmurs: mitral regurgitation producing a pan-systolic murmur or aortic regurgitation producing an early diastolic murmur

Differential diagnosis

Some differential diagnoses for Marfan syndrome are:

• Homocystinuria: an inherited metabolic condition characterised by tall stature, intellectual disability, and downward lens dislocation; however, cardiac complications are uncommon with this condition.
• Ehlers-Danlos syndrome (EDS): a group of hereditary connective tissue disorders manifesting with hyperelasticity and hypermobility. Patients with Marfan syndrome have a normal texture and skin elasticity compared to patients with EDS.
• Klinefelter syndrome: a genetic condition where a male is born with an extra X chromosome. These patients can also present with tall stature and reduced musculature. Patients with Klinefelter syndrome can present with fertility issues, whereas fertility is unaffected in Marfan syndrome.
• Familial Thoracic Aortic Aneurysm and Dissection syndrome (FTAAD): an inherited autosomal dominant condition resulting in enlargement of the aorta. Unlike Marfan syndrome, it primarily affects the aorta with no other syndromic features.

Investigations

In patients with suspected Marfan syndrome, investigations are used to rule out differential diagnoses and confirm genetic mutations. In patients with known Marfan syndrome, imaging is often used to assess for complications of the disease.

Laboratory investigations

• Plasma homocysteine: may be used to rule out homocystinuria if the diagnosis is uncertain

Imaging

• Chest X-Ray: to assess for the presence of pneumothorax
• Echocardiogram: to assess for cardiac complications such as valve disease or ascending aortic dissection
• Abdominal ultrasound: can be useful to visualise the abdominal aorta to assess for aortic dissection or aneurysm
• CT scan: to visualise the aorta in more detail

Other investigations

• Genetic blood screening: to look for a defect in the FBN-1 gene
• Skin biopsy: may be used to rule out EDS if the diagnosis is uncertain

Diagnosis

The diagnostic criteria for diagnosing Marfan syndrome is called the Ghent criteria.²

Management

There is no cure for Marfan syndrome. Multidisciplinary team (MDT) management mainly includes preventing and treating complications. 

Screening

Patients with Marfan syndrome should undergo screening to monitor for complications of the disorder:

• Annual echocardiograms: to screen for dilated aortic roots
• CT thorax: to monitor the thoracic aorta
• MRI: to monitor for scoliosis, dural ectasia and chest deformities
• Regular eye examination via slit lamp: to screen for myopia or astigmatisms

Medical management

Patients may be prescribed medication such as beta-blockers, angiotensin receptor blockers or verapamil, which can delay the progression of dilation of the aorta. 

Physiotherapy, exercise, and NSAIDs can help with joint pain and hypermobility. Spinal braces may be advised for managing scoliosis.

Some people may not be able to participate in contact sports like rugby. Other activities like heavy weight lifting, gymnastics, scuba diving, climbing, and long-distance running should be undertaken with advice from specialists depending on heart and musculoskeletal complications.

Surgical management of complications

Elective cardiac surgery is recommended if the aorta dilates more than 5cm. Procedures can be carried out to replace the aortic root while preserving the aortic leaflets. 

Regular ophthalmology input should be sought, and surgical intervention for complications such as lens subluxation, cataracts, and retinal detachment may be needed.  If patients develop glaucoma, it should be carefully monitored to prevent progression, as it can lead to vision loss.

Orthopaedic input is needed to manage scoliosis, and spinal surgery may be indicated in adolescents depending on the degree of scoliosis or nerve entrapment.

Chest drains may be required to treat spontaneous primary pneumothoraces, which these patients are at increased risk of. 

Genetic counselling

Patients with Marfan syndrome who are considering children should be referred for genetic counselling and offered prenatal testing such as chorionic villus sampling (CVS) or amniocentesis.

Preimplantation genetic diagnosis (PGD) is a technique where eggs and sperm are harvested from the parents so embryos can be created in a laboratory and unaffected embryos are available for implantation in the womb. PGD is only an option after a person with Marfan syndrome has been identified as having a Marfan gene mutation and wants to become a parent.

Complications

• Upwards lens dislocation: present in up to 60% of patients. Visual issues as a result of dislocated lenses are often resolved with glasses, however, surgery may be required later.
• Myopia
• Aortic root aneurysms
• Mitral regurgitation
• Aortic regurgitation
• Mitral valve prolapse
• Aortic dissection and rupture
• Joint subluxation
• Pneumothorax
• Dural ectasia
• Glaucoma
• Retinal tear/detachment
• Inguinal hernias
• Gastro-oesophageal reflux
• Increased cardiac risk during pregnancy

Key points

• Marfan syndrome is a multi-system disease.
• It is progressive, hence identifying early symptoms and signs can prevent progression, complications, and poorer outcomes.
• Diagnosis is usually made clinically. 
• Cardiovascular complications are the most common cause of mortality.
• Early identification of aortic dilation and surgical intervention can prolong life expectancy. 

Reviewer

Dr Geeta Suryanarayan

Community Paediatric Consultant

Airedale Hospital

Editor

Dr Jess Speller

References

1. Sakai, L.Y. et al. (2016) ‘FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders’, Gene, 591(1), pp. 279–291. doi:10.1016/j.gene.2016.07.033. 
2. BMJ Best Practice. Marfan syndrome.Published 2022.  Available from [LINK] 
3. Groth, K.A. et al. (2015) ‘Prevalence, incidence, and age at diagnosis in Marfan syndrome’, Orphanet Journal of Rare Diseases, 10(1). doi:10.1186/s13023-0150369-8. 
4. Patient.info. Marfan’s syndrome. Published 2022. Available from [LINK] 
5. National Organization for Rare Disorders. Marfan syndrome – symptoms, causes, treatment. Published 2021. Available from [LINK]