Marfan syndrome

Marfan syndrome is a multisystem connective tissue disease caused by a defect in the protein fibrillin 1, encoded 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:

• general

  • tall stature

  • long arm 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 little finger

• pelvis / lower limbs

  • ​pes planus

  • hallux valgus

  • clubfoot

• chest wall deformities (present in up to two-thirds of cases ²)

  • pectus excavatum

  • pectus carinatum

• ocular

  • ectopia lentis

  • myopia

  • retinal detachment

• cardiovascular

  • aortic regurgitation or mitral regurgitation

  • dolichoectasia¹²

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

Diagnostic criteria

The Ghent Nosology was established in 1995 for the clinical diagnosis of the disease ⁷.

Pathology

Genetics

The condition results from a 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

    • anterior sacral meningocele

    • lateral sacral meningocele

  • vertebral scalloping

  • scaphocephaly

• pelvis and 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 little 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 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

• paraseptal emphysema ¹³

Treatment and prognosis

Pharmacological treatment options include:

• beta blockers: shown to reduce the rate of aortic root dilatation

• angiotensin receptor blockers: these agents are also TGFβ antagonists significantly and reduce cardiovascular and other somatic features ⁹

Aortic root surgery may be required, including aortic root replacement (e.g. Bentall procedure) or investigational procedures such as personalised external aortic root support (PEARS) procedure.

Cardiovascular complications are the most frequent cause of death ².

History and etymology

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

Differential diagnosis

• congenital contractural arachnodactyly​: has significant phenotypic overlap with Marfan syndrome, but is now considered a discrete entity, due to distinct genetics ¹¹

• Loeys-Dietz syndrome: similar features to Marfan syndrome

• 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

• multiple endocrine neoplasia type IIb may have a Marfan syndrome like body habitus