Marfan syndrome

Marfan syndrome is a multisystem connective tissue disease caused by a defect in the protein fibrillin 1, encoded for by the FBN1 gene. Cardiovascular involvement with aortic root dilatation and dissection is the most feared complication of the disease.

Epidemiology

The estimated prevalence is around 2-6 per 100,000 ^2,5. There is no recognised gender or racial predilection.

Clinical presentation

Patients with Marfan syndrome may have the following symptoms and signs on history and examination:

• general
  • tall stature
  • long arm-span span (often exceeding the height of the patient)
  • joint laxity resulting in recurrent dislocations
• spine/skull
  • high arched palate
  • kyphoscoliosis
  • scaphocephaly
• hands
  • arachnodactyly
  • protrusion of thumb beyond fist when clenched (Steinberg sign)
  • flexion deformity of the 5^th fingerlittle finger
• pelvis / lower limbs
  • ​pes planus
  • hallux valgus
  • clubfoot
• chest wall deformities (present in up to 2/3^rds of⅔ of cases ²)
  • pectus excavatum
  • pectus carinatum
• ocular
  • ectopia lentis
  • myopia
• cardiovascular
  • aortic regurgitation or mitral regurgitation on auscultation

Patients may present with complications of the disease such as, aortic dissection and pneumothorax.

Diagnostic criteria

TheGhent nosology was established in 1995 for the clinical diagnosis of the disease ⁷.

Pathology

The condition is thought to resultresults from an inherited or de novoa mutation in the fibrillin 1 (FBN1) gene located on chromosome 15q21.1 which is responsible for cross-linking collagen. In the majority of cases it is inherited in an autosomal dominant fashion, although in up to one-third of cases the mutation is de novo. The disease has high genetic penetrance but with variable phenotypic expression even amongst affected family members.

Studies show a regulatory relationship between extracellular microfibrils and TGFβ signalling, so an abnormality in either can cause a Marfanoid phenotype ⁹.

Microscopic appearance

Microscopically the arterial walls may show cystic medial necrosis ¹⁰.

Radiographic features

There are no specific radiographic features of Marfan syndrome but the following signs and complications of the disease may be seen in each system on a range of modalities:

Skeletal

• general
  • osteopenia ¹
  • joint dislocation
• spine/skull
  • atlantoaxial subluxation
  • dural ectasia
  • increased interpedicular distance
  • kyphoscoliosis
  • enlarged sacral foramina
  • meningoceles
    • presacral meningocele
    • lateral sacral meningocele
  • vertebral scalloping
  • scaphocephaly
• pelvis / lower limbs
  • progressive protrusio acetabuli
  • slipped upper femoral epiphyses (SUFE)
  • tibial subluxation ⁵
  • patella alta
  • pes planus
  • hallux valgus
  • clubfoot
• hands
  • arachnodactyly
  • protrusion of thumb beyond fist when clenched (Steinberg sign)
  • flexion deformity of the 5^th fingerlittle finger(s)
• chest wall deformities
  • pectus excavatum
  • pectus carinatum

Cardiovascular

• aortic root dilatation and myxomatous degeneration of the mitral valve resulting in mitral valve regurgitation are the most two common cardiac manifestations ⁹
• aortic aneurysm and aortic dissection are the most fearsome consequences - findings suggestive of higher risk of aortic dissection are:
  • family history of aortic dissection
  • dilatation at the aortic sinotubular junction
  • aortic root diameter > 55;55 mm
  • increased aortic stiffness
  • excessive aortic root dilatation (>1.7 mm/year)
• arterial dissection
• aortic valve regurgitation (AR)
• aortic coarctation
• pulmonary arterial dilatation

Pulmonary

• spontaneous pneumothorax
• lung cysts and bullae formation

Treatment and prognosis

Beta blockers are shown to reduce the rate of aortic root dilatation. In patients who can not take beta-blockers, calcium-channel blockers are used. More recently, investigators found that angiotensin receptor blockers which are also TGFβ antagonists significantly reduce cardiovascular and other somatic features ⁹. Cardiovascular complications are the most frequent cause of death ².

Some of the more newer treatment options include.

• personalised external aortic root support (PEARS) procedure

History and etymology

First described in 1896 by Antoine Bernard-Jean Marfan, French paediatrician (1858-1942).

Differential diagnosis

• patientscongenital contractural arachnodactyly​: has significant phenotypic overlap with Marfan syndrome, but is now considered a discrete entity, due to distinct genetics ¹¹
• Loeys-Dietz syndromehave similar: similar features to Marfan syndrome
• patients with homocystinuria: may resemble those with Marfan syndrome in some aspects ⁸;ectopia lentis, however, is downward as opposed to Marfan and intellectual disability is also a common feature
• patients with multiple endocrine neoplasia type IIb may have a Marfan syndrome like body habitus
• patients with Beals syndrome have some features of Marfan syndrome