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MARFAN SYNDROME - Complete NEET PG Notes

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1. DEFINITION

• Skeletal abnormalities (tall stature, arachnodactyly)
• Cardiovascular defects (aortic root dilatation, dissection)
• Ocular changes (ectopia lentis)

OMIM: #154700

• Goldman-Cecil Medicine, p. 2749

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2. ETIOLOGY

Gene & Protein

Epidemiology

• Incidence: 1 in 3,000-5,000 births worldwide
• No ethnic or geographic predilection
• 70-85% are familial cases; 15-30% are de novo mutations (new germ cell mutations)
• Men tend to be more severely affected than women

Related Syndrome

• Marfan Syndrome Type 2 (MFS2): Caused by mutations in the TGF-beta type II receptor (TGFBR2) - clinically similar
• Loeys-Dietz Syndrome: Mutations in TGFBR1 or TGFBR2 - features generalized arterial tortuosity + susceptibility to dissection
• Homocystinuria: Must distinguish - similar Marfanoid features but autosomal recessive, causes mental retardation, hypercoagulability; treatable with Vitamin B6/folate/B12

• Robbins Pathology, p. 110 | Goldman-Cecil, p. 2749

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3. PATHOPHYSIOLOGY

Step 1 - Structural Defect

• Fibrillin-1 is the major structural component of 10-nm microfibrils in the extracellular matrix (ECM)
• Microfibrils are abundantly found in:
  • Aorta (provide tensile strength to vessel wall)
  • Ligaments
  • Ciliary zonules of the eye (support the lens)
• Mutant fibrillin-1 acts as a dominant negative - the abnormal protein incorporates into microfibrils and disrupts them

Step 2 - TGF-beta Dysregulation (KEY CONCEPT for MCQs)

• Normal microfibrils sequester (bind and inactivate) TGF-beta (via Latent TGF-beta Binding Proteins - LTBPs, which are homologous to fibrillin)
• Defective fibrillin → microfibrils cannot sequester TGF-beta → excessive (unregulated) TGF-beta signaling
• This excess TGF-beta signaling causes:
  • Bone overgrowth (skeletal features)
  • Mitral valve prolapse
  • Aortic dilatation
  • Abnormal lung septation (pneumothorax precursor)
  • Muscular hypoplasia

Step 3 - Cardiovascular Pathology (Aorta)

• Elastic fiber fragmentation + increased proteoglycans in tunica media = "Cystic Medial Necrosis" (CMN)
  • CMN is NOT specific to Marfan - also seen in hypertension and aging
• Weakened aortic wall → Aortic root/sinus of Valsalva dilatation → progressive aneurysm
• Aortic dissection usually begins just above the aortic valve (Type A) and can progress to the bifurcation
  • ~10% begin in descending thoracic aorta (Type B)
  • Retrograde dissection → hemopericardium → death

Step 4 - Ocular Pathology

• Ciliary zonule weakness (from deficient microfibrils) → Ectopia lentis (lens subluxation)
• Lens typically displaced superiorly (vs. homocystinuria where it displace inferiorly)

• Robbins Pathology, pp. 110-111 | Goldman-Cecil, p. 2749

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4. SIGNS (Objective Findings)

A. SKELETAL SIGNS (Most Visible)

B. CARDIOVASCULAR SIGNS

• Aortic root dilatation - begins in sinuses of Valsalva (most >80% of adults)
• Aortic regurgitation murmur - early diastolic, high-pitched at left sternal border
• Mitral valve prolapse - midsystolic click + late systolic murmur (~80% of patients)
• Mitral regurgitation murmur
• Wide pulse pressure (if significant AR)

C. OCULAR SIGNS

• Ectopia lentis - bilateral lens subluxation (superior displacement) - seen in 50-80%
• Flat corneas
• Myopia (most common ocular feature, >50%)
• Increased axial length of globe
• Retinal detachment risk

D. OTHER SIGNS

• Dural ectasia - dilatation of lumbosacral thecal sac, occurs in 90% of Marfan patients; major diagnostic criterion; causes widening of neuroforamina, lumbar radiculopathy
• Striae atrophicae (stretch marks) - over shoulders, breasts, lower back
• Spontaneous pneumothorax (~5%)
• Dolichocephaly (long narrow head)
• Enophthalmos, down-slanting palpebral fissures, malar hypoplasia, retrognathia (facial features)
• Sleep apnea
• Simple cysts in liver and kidneys

• Goldman-Cecil, p. 2750 | Firestein & Kelley's Rheumatology, p. 2343

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5. SYMPTOMS (Subjective Complaints)

• Tall stature - noted since childhood
• Visual disturbances - blurring, poor near/distance vision (myopia, astigmatism)
• Back pain - from scoliosis or dural ectasia causing lumbar radiculopathy
• Palpitations / Dyspnea - from mitral valve prolapse, arrhythmias, or progressive heart failure
• Chest pain - acute tearing/ripping chest pain radiating to the back = AORTIC DISSECTION (medical emergency)
• Shortness of breath - pneumothorax (sudden onset pleuritic chest pain + dyspnea)
• Joint pains - from hypermobility and scoliosis-related mechanical problems
• Fatigue - from cardiac dysfunction
• Headache / orthostatic symptoms - CSF leak from ectatic dura causing intracranial hypotension

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6. INVESTIGATIONS

A. Imaging (Most Important)

B. Genetic Testing

• FBN1 sequencing - identifies causative variant
• Used for presymptomatic diagnosis, prenatal diagnosis, and family testing
• Note: >1000 mutations described - testing alone is complex, so clinical diagnosis is primary

C. Revised Ghent Nosology (2010) - Diagnostic Criteria

Scenario 1: No family history of MFS

1. Aortic root Z-score ≥ 2 + Ectopia lentis (= definite Marfan)
2. Aortic root Z-score ≥ 2 + pathogenic FBN1 variant
3. Aortic root Z-score ≥ 2 + Systemic Score ≥ 7
4. Ectopia lentis + pathogenic FBN1 variant

Scenario 2: With family history of MFS

• Ectopia lentis alone
• Systemic score ≥ 7
• Aortic root Z-score ≥ 2 (adults ≥20 yr) or ≥ 3 (<20 yr)

Systemic Score Table (Revised Ghent)

• Firestein & Kelley's Rheumatology, p. 2342-2343 | Tietz Laboratory Medicine, p. 170

D. Other Lab Tests

• Plasma homocysteine - to exclude homocystinuria (key differential)
• Urine amino acids - elevated methionine in homocystinuria
• Echocardiography - essential for follow-up (annually)

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7. TREATMENT

A. Medical Management (Drugs)

1. Beta-Blockers (FIRST-LINE, most important)

• Drug of choice: Propranolol or Atenolol
• Mechanism: Reduce heart rate and dP/dt (force of ventricular contraction) → decrease hemodynamic stress on the aortic wall
• Goal: Prevent/slow aortic root dilatation and reduce risk of dissection
• Dose: Atenolol 25-100 mg/day; Propranolol 20-80 mg 2-4 times daily (titrated to HR and aortic dimensions)
• Route: Oral
• Evidence: Started as soon as diagnosis is established; continued lifelong

2. Angiotensin Receptor Blockers (ARBs) - (Emerging evidence, now used)

• Drug: Losartan (most studied)
• Mechanism: Block TGF-beta signaling via angiotensin receptor type II pathway → slow aortic dilation
• Dose: Losartan 50-100 mg/day orally
• Route: Oral
• Role: Used in patients intolerant to beta-blockers OR in combination with beta-blockers
• Evidence: Several RCTs have shown benefit in slowing aortic root growth, especially in children/adolescents

3. ACE Inhibitors

• Alternative to ARBs, similar TGF-beta pathway attenuation
• Less commonly used as first-choice compared to ARBs

Summary Drug Table

B. Surgical Management (KEY for MCQs)

Indications for Elective Aortic Root Surgery

• Aortic root diameter ≥ 5.0 cm (most guidelines)
• Rate of expansion > 1 cm/year regardless of size
• Moderate-to-severe aortic regurgitation
• Family history of dissection at smaller diameters (some use 4.5 cm threshold)
• Before or during pregnancy if root is enlarging

Surgical Options

1. Bentall Procedure - composite valve-graft replacement (most common) - replaces aortic root + valve
2. Valve-sparing aortic root replacement (David or Yacoub procedure) - preserves native aortic valve; preferred in young patients

Mitral Valve Surgery

• Indicated for severe symptomatic mitral regurgitation
• Repair preferred over replacement when possible

Scoliosis Surgery

• Spinal fusion when curves >40-50 degrees or progressive

C. Activity Restrictions

• Avoid strenuous isometric exercises (weight lifting, heavy resistance training) - increases aortic wall stress
• Avoid contact sports (basketball, football, martial arts)
• Competitive sports are generally contraindicated for patients with significant aortic enlargement
• Moderate aerobic exercise (walking, swimming) is permitted

D. Monitoring Protocol

• Annual echocardiography for aortic root surveillance
• Ophthalmologic exam annually (especially in children)
• Slit-lamp exam for lens assessment
• MRI for dural ectasia if back pain/radiculopathy develops
• Genetic counseling - AD inheritance, 50% chance of passing to offspring

E. Special Situations

Pregnancy

• High-risk situation - aortic dissection risk is significantly elevated during pregnancy
• Aortic root >4.5 cm is a relative contraindication to pregnancy
• Beta-blockers continued throughout pregnancy
• Mode of delivery: Caesarean section preferred if aortic root >4.5 cm or rapidly enlarging
• Avoid Valsalva maneuver (pushing in labor) if aortic root is enlarged

Antibiotic Prophylaxis

• For dental/surgical procedures if prosthetic heart valves are present (follows standard infective endocarditis prophylaxis guidelines)

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8. COMPLICATIONS

• Primary: Aortic dissection/rupture (retrograde → hemopericardium)
• Secondary: Heart failure (from valvular regurgitation)
• Without treatment, many patients die before 30-40 years of age
• With appropriate management, life expectancy approximates that of the general population

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9. IMPORTANT HIGH-YIELD POINTS FOR NEET PG (MCQ TRAPS)

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10. DIFFERENTIAL DIAGNOSIS

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Sources Used:

• Goldman-Cecil Medicine International Edition, Chapter 239 (Marfan Syndrome), pp. 2748-2751
• Robbins & Kumar Basic Pathology, pp. 110-111 (Genetic Disorders chapter)
• Firestein & Kelley's Textbook of Rheumatology, Chapter 107, pp. 2342-2344
• Bradley & Daroff's Neurology in Clinical Practice, Chapter 104
• Tietz Textbook of Laboratory Medicine, 7th Ed., pp. 165-184
• Thompson & Thompson Genetics and Genomics in Medicine, 9th Ed.