Marfan Syndrome
Summary
Marfan Syndrome (MFS) is the most common heritable disorder of connective tissue, caused by mutations in the FBN1 gene (encoding Fibrillin-1). It is a multisystem disorder primarily affecting the skeletal, ocular, and cardiovascular systems. The major cause of premature mortality is Aortic Root Dilation leading to Type A Dissection. Early diagnosis (using the Revised Ghent Criteria) and prophylactic aortic root surgery have transformed life expectancy from 40 years to near-normal. [1,2]
Clinical Pearls
The "Thumb Sign" (Steinberg): Ask the patient to fold their thumb into their palm and close their fingers over it to make a fist. The sign is positive if the entire distal phalanx of the thumb protrudes beyond the ulnar border of the hand.
The "Wrist Sign" (Walker-Murdoch): Ask the patient to grip their own wrist with the opposite hand (thumb and little finger). The sign is positive if the thumb and little finger overlap by at least the length of a fingernail.
Ectopia Lentis Direction: In Marfan, the lens dislocates UP and OUT (Superotemporal). In Homocystinuria (the main differential), it dislocates DOWN and IN (Inferonasal).
Demographics
- Prevalence: 1 in 5,000 (0.02%).
- Inheritance: Autosomal Dominant (75%).
- De Novo: 25% of cases are spontaneous mutations (associated with advanced paternal age).
- Penetrance: Complete (everyone with the gene has the disease), but Expressivity is variable (severity differs even within families).
Mechanism
- Structural: Fibrillin-1 is the main component of microfibrils, which form the scaffold for elastin. Defective fibrillin leads to weak elastic tissue (Aorta, Ligaments, Zonules of eye).
- Signalling (Crucial): Normal fibrillin sequesters (hides) the growth factor TGF-beta. Mutated fibrillin cannot hold TGF-beta, leading to excessive signaling. Excess TGF-beta causes:
- Overgrowth of long bones (Tall stature).
- Myxomatous valve degeneration.
- Apoptosis of smooth muscle cells in the aortic media.
Diagnosis is no longer just "counting features". It places huge weight on Aortic/Lens findings.
In the absence of family history:
- Aortic Root Dilatation (Z > 2) AND Ectopia Lentis = Marfan.
- Aortic Root Dilatation AND FBN1 Mutation = Marfan.
- Aortic Root Dilatation AND Systemic Score ≥ 7 = Marfan.
The Systemic Score (Max 20 points)
- Wrist AND Thumb sign (3)
- Wrist OR Thumb sign (1)
- Pectus Carinatum (2)
- Pectus Excavatum or Asymmetry (1)
- Hindfoot deformity (2)
- Pneumothorax (2)
- Dural Ectasia (MRI) (2)
- Protrusio Acetabuli (X-ray) (2)
- Reduced Upper/Lower Segment Ratio (1)
- Scoliosis (1)
- Facial Features (1)
- Striae (1)
- Myopia (1)
- Mitral Valve Prolapse (1)
Skeletal
Ocular
Cardiovascular
Pulmonary
Skin
Essential
- Echocardiogram: Measure Aortic Root at the Sinus of Valsalva. Calculate Z-score.
- Slit Lamp Examination: By Ophthalmologist (check for subluxed lens).
- Genetic Testing: FBN1 sequencing (90-95% sensitivity).
Optional
- MRI Spine: Check for Dural Ectasia (widening of dural sac).
- Pelvic X-Ray: Protrusio acetabuli.
Management Algorithm
MARFAN DIAGNOSIS
↓
BASELINE ECHO + GENETICS
↓
CARDIOVASCULAR PROTECTION
• **Beta-Blockers** (Atenolol)
- Titrate to HR less than 60 bpm
- Reduces shear stress dP/dt
• **ARBs** (Losartan)
- Blocks TGF-beta signalling
- Add if intolerant to BB or
progressive dilation
↓
ANNUAL SURVEILLANCE
(Echo / MRI Aorta)
↓
SURGICAL THRESHOLD REACHED?
• Aorta ≥ 5.0 cm (Adult)
• Aorta ≥ 4.5 cm (Family hx dissection)
• Rapid growth > 3mm/year
┌─────────┴─────────┐
NO YES
↓ ↓
CONTINUE MEDS SURGERY
- Valve Sparing Root
Replacement (David)
- Composite Graft
(Bentall)
Lifestyle Modifications
- Avoid: Isometric (static) exercise (Weightlifting, push-ups) -> spikes BP.
- Avoid: Contact sports (Rugby/Boxing) -> Risk of aortic rupture or eye injury.
- Allowed: Aerobic exercise (Swimming, cycling, jogging).
- Aortic Dissection (Type A): Fatal if untreated. Tear in intimal layer.
- Endocarditis: Risk in those with MVP/Regurgitation.
- Blindness: Lens dislocation/glaucoma.
- Untreated: 50% mortality by age 40 (Dissection).
- Treated: Life expectancy approaches general population.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Aortic Diseases | ESC (2014) | Diagnosis and thresholds for surgery. |
| Marfan Syndrome | ACC/AHA | Monitoring protocols. |
Landmark Evidence
1. Loeys et al (J Med Genet 2010)
- Established the Revised Ghent Nosology, simplifying diagnosis by focusing on Aorta+Lens.
2. Lacro et al (NEJM 2014)
- Comparison of Atenolol vs Losartan in children. Showed no significant difference in aortic root growth between the two. Both are acceptable. (Debunked the idea that Losartan was miraculously superior, but established it as a valid alternative).
What is Marfan Syndrome?
It is a genetic condition affecting the body's connective tissue. Think of connective tissue as the "glue" or "scaffold" that holds the body together. In Marfan's, the glue is a bit stretchier than normal.
How does it affect the body?
- Bones: Because the tissues don't hold them back, bones grow extra long. Patients are tall, thin, with long fingers.
- Eyes: The tiny strings holding the lens in place can stretch, causing the lens to slip (dislocate).
- Heart: The main pipe leaving the heart (The Aorta) is made of elastic tissue. In Marfan's, it can stretch like a balloon over time.
Why do I need medicine?
The danger is that the Aorta stretches too much and tears. We give you medicine (Beta-blockers) to lower the pressure inside the pipe and stop it stretching. If it gets too big, we perform a planned operation to replace usage weak section with a strong tube, so you can live a normal life.
Primary Sources
- Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010.
- Lacro RV, et al. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014.
- Erbel R, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases. Eur Heart J. 2014.
Common Exam Questions
- Diagnosis: "Tall man, sudden chest pain?"
- Answer: Aortic Dissection.
- Sign: "Wrist Sign?"
- Answer: Walker-Murdoch Sign.
- Genetics: "Inheritance pattern?"
- Answer: Autosomal Dominant.
- Differential: "Tall, Intellectual Disability, Downward lens dislocation?"
- Answer: Homocystinuria.
Viva Points
- Fibrillin-1 & TGF-beta: Understanding the dual mechanism (structural weakness + signalling overactivity) is key to high marks.
- Pregnancy: A huge risk period. Blood volume increases by 50%. Dissection risk peaks in 3rd trimester/post-partum. Needs monthly Echo monitoring.
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.