Marfan Syndrome (Main Note)😊

Marfan Syndrome

Q. A 15-year-old boy presented to the Ophthalmology department with an acute reduction in visual acuity in both the eyes. The direct observation of both the eyes is shown here. The ophthalmologist suspected a disorder and ordered for genetic testing, which revealed FBN1 gene mutation. Which of the following is true about the disorder and the protein involved?

• A. The protein reduces TFG-Beta levels

• B. Alpha 2 agonists delay the progression of the disorder

• C. It is an autosomal recessive disorder

• D. The protein involved reduces the elasticity of tissues normally

• Autosomal dominant condition.

• Chromosome affected: 
• Chromosome 15

• Gene affected: 
• FBN1 gene (Fibrillin 1 gene defect)

Fibrillin protein:

• Forms microfibrils in connective tissue.

• Normally reduces TGF beta levels
• TGF β causes necrosis

• With elastin:
• forming scaffolding for elastin
• Increases elasticity
• In Lungs

• Without elastin:
• Increases tensile strength
• In Bone, Tendon, Suspensory Ligament of Linn (Eyes)

Pathophysiology:

• Fibrillin protein ↓↓
• Elasticity, tensile strength ↓↓
• ↑↑ TGF β

• Loss of elasticity:
• Lung gets expanded
• Lung bullae and pneumothorax.
• root of blood vessels.
• Aortic regurgitation and mitral valve prolapse.

• Increased TGF beta levels cause:
• Cystic medial necrosis.
• Dissection of the aorta.

• Loss of tensile strength causes:
• Arachnodactyly
• B/L superotemporal dislocation of the lens.

Clinical Features:

• Mnemonic: MARFANS
• M: Mitral valve prolapse 
• most common cardiac abnormality
• A: Aortic dissection 
• most common cause of death
• R: Retinal detachment
• F: Freely movable joints 
• most common joint: thumb joint
• A: Arachnodactyly 
• (spider-like long fingers, thumb coming out of palm); 
• High arched palate
• N: Nine feet tall (very tall individuals)
• S: Syndrome
• If "disease":
• Dislocation of the lens (Ectopia lentis)
• Direction: Superotemporal (upward and outward)
• Mnemonic: "fan is up, air goes out"
• Differential (opposite dislocation): 
• Homocystinuria (inferonasal)
• If "syndrome":
• Sternal deformity / Pigeon chested individuals

• Cardiovascular:
• Cystic medial necrosis of the aorta
• Aortic root aneurysm, rupture, or dissection
• Most common cause of death
• Mitral valve prolapse

• Lung:
• ↑ Risk of spontaneous pneumothorax

• Overall most common abnormality: 
• Skeletal abnormality 

• Specific Signs:
• Steinberg sign:
• Thumb coming out when folded in fist
• Mnemonic: Stain → Stick ur thumb out and stain it
• Walker sign:
• Little finger and thumb can hold the wrist
• Mnemonic: Walk around the wrist

Revised Gent Criteria: Marfan Gentleman

1. Family history (autosomal dominant)

2. Clinical features 

3. Fibrillin 1 gene mutation

Management:

• Beta blockers or losartan
• reduce TGF beta levels.

Exceptions → Penetrance: 

• The percentage of individuals with a given genotype who express the associated phenotype.
• Example calculation:
• If 70 out of 100 people with the specific genotype are diseased,
• the penetrance is 70%.

Differences Between Homocysteinuria & Marfan's Syndrome

• Fair complexion
• Seen in Homocysteinuria
• Not in Marfans
• (differentiates from Marfan)