Marfan Syndrome

Epidemiology and Genetics

Epidemiology

Incidence: 1 in 5,000 live births
Affects men and women in all ethnic and racial groups

Genetics

Most commonly due to a mutation in the FBN1 gene on chromosome 15
- Affects the connective tissue protein, fibrillin-1
  - Fibrillin-1 is the main component of microfibrils, which form elastic fibers in connective tissue.
  - Mutation in FBN1 gene → impaired fibrillin protein → defective microfibrils → ↓ elasticity in tissues
- Affects connective tissues throughout the body:
  - Organs
  - Blood vessels
  - Eyes
  - Skin
  - Skeletal components
Inheritance pattern: autosomal dominant
- 75% of patients have affected parents.
- 25% of cases are de novo mutations (idiopathic).
Penetrance: complete
Expressivity: variable

Family members with Marfan’s syndrome

Image: “Family members with Marfan’s syndrome” by Birjand Atherosclerosis and Coronary Artery Research Centre, Birjand University of Medical Sciences, Birjand, Iran. License: CC BY 3.0

Clinical Presentation

Musculoskeletal

Tall stature with disproportionately long extremities:
- ↓ upper segment to lower segment ratio (US/LS)
- ↑ arm span to height ratio
Long fingers and toes (arachnodactyly):
- Positive thumb sign (Steinberg’s sign): The distal phalanx of the adducted thumb extends beyond the ulnar border of a clenched fist palm.
- Positive wrist sign (Walker sign): The thumb and 5th finger of the hand overlap with each other when wrapped around the contralateral wrist.
Joint laxity
Elbows may lack full extension mobility.
Vertebral column abnormalities:
- Scoliosis
- Kyphosis
Chest abnormalities:
- Pectus excavatum (funnel chest)
  - Sternum protrudes inward.
  - Looks “caved in”
- Pectus carinatum (pigeon chest or sternal kyphosis): Sternum protrudes outward.
Hindfoot valgus:
- Heel points outward away from midline.
- Associated with pes planus (flat foot)
Protrusio acetabuli (acetabular protrusion)
High-arched palate
Characteristic facial features:
- Dolichocephaly (↓ head width:length ratio)
- Enophthalmos (posterior displacement of the eyeball within the orbit)
- Downslanting palpebral fissures (area between open eyelids)
- Malar hypoplasia (malar or zygomatic bone is small or absent)
- Retrognathia (lower jaw set back further than upper jaw)

Photograph showing arachnodactyly
Image: “Arachnodactyly” by Department of Pedodontics, SRM Dental College, SRM University, Chennai 600078, India. License: CC BY 3.0
Severe pectus excavatum in a man affected by Marfan’s syndrome
Image: “fig2” by Fernando De Maio et al. License: CC BY 4.0
A man affected by Marfan’s syndrome with scoliosis in addition to dorsal skin striae and reduced elbow extension
Image: “fig5” by Fernando De Maio et al. License: CC BY 4.0
A patient with Marfan syndrome with an associated wrist and thumb sign:
(a) The “wrist sign” is positive when the thumb overlaps the fifth finger when grasping the contralateral wrist.
(b) The “thumb sign” is positive when the thumb extends well beyond the ulnar border of the hand when overlapped by the fingers.
Image: “fig1” by Fernando De Maio et al. License: CC BY 4.0
An arm span greater than the patient’s height, and a high-arched palate
Image: “Arm span more than height and high arched palate” by Consultant, Eye and Glaucoma Care, Gariahat, Kolkata-700029, West Bengal, India. License: CC BY 3.0
Hindfoot deformity with a marked valgus heel in a man affected by Marfan’s syndrome
Image: “Hindfoot deformity” by Fernando De Maio et al. License: CC BY 4.0
Radiograph demonstrating protrusio acetabuli: Notice that the femoral head and socket protrude into the pelvis.
Image: “Grade III protrusio acetabuli” by Orthopaedic Research Fellow, Royal Infirmary of Edinburgh, Little France EH16 4SA, UK. License: CC BY 2.0, edited by Lecturio.

Cardiovascular

Aortic disease is the main cause of morbidity and mortality in Marfan syndrome (MFS) patients, and is due to degeneration of the media of the vessel walls.
- Dilation or aneurysm of the aorta
  - Present in 50% of children
  - Dilation may involve thoracic aorta, abdominal aorta, or root of pulmonary artery.
  - Dilation of the aortic root present in 60%–80% of adults with MFS
- Aortic regurgitation
  - Often occurs with aortic dilation
  - Valve leaflets prevented from closing properly
  - Diastolic heart murmur on exam
- Aortic dissection
  - Tear in the intima (innermost layer) of the aorta, allowing blood between the intima and media (middle layer)
  - Life-threatening condition
  - Presents with sudden, severe, chest pain that radiates to the back
  - MFS patients account for 50% of those with aortic dissection under 40 years of age.
  - ↑ risk of dissection during pregnancy and postpartum
Mitral valve prolapse
- Valve leaflets bulge (prolapse) into left atrium during heart systole
- More frequently seen with ↑ age and in women
- Systolic heart murmur and midsystolic click on exam
- Can lead to mitral regurgitation
Dilation of carotid and cranial arteries
- Much less common
- Berry (saccular) aneurysms are typically at the exit of the circle of Willis.
- Rupture of a cranial artery can cause subarachnoid hemorrhage.

Gross pathology specimen of an aortic dissection flap and aortic wall
Image: “Aortic dissection flap and aortic wall” by Department of Obstetrics and Gynaecology, Women’s and Children’s Hospital, Adelaide, SA 5006, Australia. License: CC BY 3.0

Ocular

Dislocation of the lens (ectopia lentis)
- Impaired supporting ciliary zonules fail to keep the lens in place.
- Upward and temporal displacement
- Occurs in 50%–80% of patients
- Iridodonesis can be seen on inspection (vibration of the iris with eye movement).
- Seen on slit lamp examination
Myopia (nearsightedness)
Retinal tears or detachment
- Often bilateral in MFS patients
- Associated with proliferative retinopathy
Glaucoma
Early cataract formation

A and B: symmetrical temporal and upward subluxation of the lens on dilation
C and D: advanced glaucomatous cupping in both eyes
Image: “F2” by Consultant, Eye and Glaucoma Care, Gariahat, Kolkata-700029, West Bengal, India. License: CC BY 3.0

Other manifestations

Skin: striae atrophicae (stretch marks)
- Not associated with weight changes or pregnancy
- Often in uncommon areas:
  - Upper arms
  - Axillary area
  - Mid and lower back
  - Thighs
Pulmonary: emphysematous changes in the lungs
- Lung bullae predominantly in the upper lobes
- ↑ risk for spontaneous pneumothorax
Central nervous system (CNS): lumbosacral dural ectasia
- Dilation of the dural sac surrounding the spinal cord
- Symptoms:
  - Lower back pain
  - Radicular pain
  - Paresthesias
  - Bowel and bladder dysfunction
  - Headaches

Diagnosis

Revised Ghent criteria
- Complex scoring system based on the presence of characteristic Marfan syndrome manifestations
- Requires varying combinations of:
  - Aortic root dilatation
  - Ectopia lentis
  - FBN1 gene mutation
  - Systemic score > 7 (see table below)
- The presence, or absence, of a family history of MFS is factored in.
Genetic testing for the FBN1 mutation is done on a case-by-case basis if it will affect management.
Imaging is used to evaluate for complications of MFS.
- Radiographs → pneumothorax, protrusio acetabuli, scoliosis
- Echocardiography (echo) → valvular and aortic root defects
- Computed tomography (CT) of chest, abdomen, and pelvis with intravenous (IV) contrast → aortic dissection
- Magnetic resonance imaging (MRI) → dural ectasia, aortic dilation

**Table: Systemic score for the revised Ghent criteria (a score ≥ 7 indicates major systemic involvement)**
Wrist and thumb sign	3 points (both) 1 point (1)
Pectus carinatum deformity	2 points
Pectus excavatum or chest asymmetry	1 point
Hindfoot deformity	2 points
Plain pes planus	1 point
Pneumothorax	2 points
Dural ectasia	2 points
Protrusio acetabuli	2 points
↓ US/LS and ↑ arm span/height and no severe scoliosis	1 point
Scoliosis or kyphosis	1 point
↓ elbow extension	1 point
Facial features (at least 3 of 5) Dolichocephaly Enophthalmos Downslanting palpebral fissures Malar hypoplasia Retrognathia	1 point
Skin striae	1 point
Myopia	1 point
Mitral valve prolapse	1 point

This table does not need to be memorized, but provides insight into the important clinical findings and the complexity of the diagnosis.

Transthoracic echocardiography showing an intimal tear in the dilated aortic root above the aortic valve level:
A: Linear intimal tear is seen just above the aortic valve in systole.
B: Linear intimal flap is visible in the dilated aortic root.
Image: “Fig2” by The Department of Interventional Cardiology, John Paul 2nd Hospital, Pradnicka 80, 31 202, Krakow, Poland. License: CC BY 4.0
Magnetic resonance imaging demonstrating dural ectasia: This is ballooning or widening of the dural sac; it may be associated with herniation of the nerve root sleeves through their associated foramina (see arrows).
Image: “CMR” by Manchester Heart Centre, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. License: CC BY 2.0

Management

The management of MFS is based on the clinical manifestations. A multidisciplinary team of cardiologists, ophthalmologists, orthopedists, and cardiovascular surgeons is needed.