Congenital heart disease - Marfan syndrome
Description
- AD connective tissue disorder of fibrillin-1
- Triad of systems: skeletal + ocular + cardiovascular
- Cardiovascular disease determines survival; everything else determines the diagnosis
The lesions that kill
- Aortic root dilatation -> dissection/rupture (sinuses of Valsalva, effacing the sinotubular junction)
- Aortic regurgitation (annular dilatation)
- Mitral valve prolapse +/- MR (commonest valve lesion)
- Main pulmonary artery dilatation, descending aorta aneurysm
Epidemiology
- 1 in 3,000-5,000; no sex or ethnic predilection
- ~25% de novo mutations (no family history does not exclude)
- Penetrance complete, expression highly variable within a family
- Untreated mean survival ~32 yr; with modern surveillance and surgery approaches normal life expectancy
Aetiopathogenesis
- FBN1 mutation (chr 15q21), >3000 described
- Fibrillin-1 = extracellular matrix glycoprotein, backbone of microfibrils in elastic tissue
- Two mechanisms:
- Structural - defective microfibrils -> weak elastic lamellae in aortic media (cystic medial necrosis)
- Signalling - microfibrils normally sequester latent TGF-beta; defective fibrillin -> inc free TGF-beta -> MMP activation, matrix degradation, aneurysm
- -> the rationale for ARBs (angiotensin II drives TGF-beta signalling)
- Dominant negative > haploinsufficiency
- Dominant negative (esp. cysteine-substitution, exons 24-32) = more severe, earlier aortic events
Related but distinct
| Gene | Discriminator | |
|---|---|---|
| Loeys-Dietz | TGFBR1/2, SMAD3, TGFB2/3 | Arterial tortuosity, hypertelorism, bifid uvula/cleft palate. Dissects at smaller diameters - operate earlier |
| Vascular EDS | COL3A1 | Thin translucent skin, easy bruising, arterial/bowel/uterine rupture. Aorta not usually dilated |
| MASS phenotype | FBN1 | Myopia, MVP, borderline aortic root (non-progressive), skin/skeletal |
| Homocystinuria | CBS | Downward lens dislocation, thrombosis, intellectual disability, dec methionine restriction |
| Congenital contractural arachnodactyly | FBN2 | Crumpled ears, contractures, aorta usually spared |
Diagnosis
Revised Ghent criteria (2010)
Aortic root Z-score and ectopia lentis are the cardinal features
Without family history - any ONE of:
- A. Aortic root Z >=2 + ectopia lentis
- B. Aortic root Z >=2 + a causal FBN1 mutation
- C. Aortic root Z >=2 + systemic score >=7
- D. Ectopia lentis + FBN1 mutation known to be associated with aortic disease
With family history - any ONE of:
- Ectopia lentis, OR
- Systemic score >=7, OR
- Aortic root Z >=2 (age >=20) or Z >=3 (age <20)
Systemic score (>=7 of 20 points)
| Feature | Pts |
|---|---|
| Wrist AND thumb sign | 3 (either alone = 1) |
| Pectus carinatum | 2 (excavatum/asymmetry = 1) |
| Hindfoot deformity | 2 (pes planus = 1) |
| Pneumothorax | 2 |
| Dural ectasia | 2 |
| Protrusio acetabuli | 2 |
| Reduced upper:lower segment AND inc arm span:height, without scoliosis | 1 |
| Scoliosis or thoracolumbar kyphosis | 1 |
| Reduced elbow extension (<170 deg) | 1 |
| 3 of 5 facial features (dolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia) | 1 |
| Skin striae (atypical sites) | 1 |
| Myopia >3 dioptres | 1 |
| MVP | 1 |
Examination
- Tall, arm span > height, reduced upper:lower segment ratio
- Arachnodactyly - Steinberg (thumb) and Walker-Murdoch (wrist) signs
- Joint hypermobility, long narrow face, high-arched palate + dental crowding
- Pectus carinatum/excavatum, thoracolumbar kyphoscoliosis
- Upward (superotemporal) lens dislocation, blue sclerae, myopia, retinal detachment
- Scars from prior spontaneous pneumothorax
- CVS: progressive aortic root dilatation, AR (early diastolic murmur), MVP (mid-systolic click + late systolic murmur), dissection
Investigations
- TTE - aortic root at sinuses of Valsalva, indexed as Z-score; valves
- CT or MR angiography of whole aorta at baseline, then periodic (TTE only images the root)
- Slit-lamp with dilated pupils (lens dislocation missed otherwise)
- MRI lumbosacral spine for dural ectasia
- FBN1 genetic testing + cascade screening of first-degree relatives
- Diagnosis is clinical - a negative FBN1 does not exclude Marfan
Management
A. Surveillance
- Annual TTE; more often if root >45 mm or rapid growth
- Whole-aorta imaging (CT/MRA) at diagnosis and at intervals
- Annual ophthalmology, orthopaedic/scoliosis review
- Strict BP control (target as low as tolerated)
B. Medical - slow aortic growth
- Beta blocker (atenolol) - reduce dP/dt and shear stress
- ARB (losartan) - blocks TGF-beta signalling
- Head-to-head trials show similar effect; meta-analysis supports combination over either alone
- Avoid fluoroquinolones (aortic dissection signal)
C. Surgical thresholds - aortic root/ascending
- Marfan: elective root replacement at 50 mm
- Consider at 45 mm with: family history of dissection, growth >=3 mm/yr, severe AR, or planned pregnancy
- General population threshold is 55 mm (50 mm at experienced centres) - Marfan is lower because dissection occurs at smaller diameters
- Loeys-Dietz: operate earlier still (~42-45 mm)
- Operation:
- Valve-sparing root replacement (David procedure) preferred - no anticoagulation
- Composite valve graft (Bentall) if valve not repairable
- Descending/thoraco-abdominal: >=60 mm threshold retained
- Open repair preferred over TEVAR in connective tissue disease - poor landing zones, endoleak, new dissection
D. Activity
- Avoid: isometric/heavy resistance training, contact and collision sport, competitive/burst sport, scuba diving
- Permit: low-to-moderate aerobic activity at <50% max capacity - walking, cycling, doubles tennis
E. Pregnancy
- Pre-conception counselling + 50% transmission risk
- Root >45 mm: pregnancy contraindicated - offer repair first; 40-45 mm high risk
- Continue beta blocker (ARB is teratogenic - stop pre-conception)
- Echo every 4-8 weeks; delivery in a centre with cardiac surgery
- Highest dissection risk in third trimester and early postpartum
F. Other systems
- Pneumothorax - standard management, low threshold for pleurodesis (high recurrence)
- Scoliosis bracing/surgery; dural ectasia -> epidural may fail or leak
- Endocarditis prophylaxis only if prosthetic valve/material
Associations
- Spontaneous pneumothorax and apical blebs (~5-10%)
- Dural ectasia (>60%) - low back pain, headache
- Protrusio acetabuli, pes planus, recurrent hernia
- Obstructive sleep apnoea (craniofacial)
- Retinal detachment, glaucoma, early cataract
- Striae atrophicae at shoulders/lower back
- Osteopenia
- No intellectual impairment - its presence should prompt reconsideration (homocystinuria)
Natural history & complications
- Aortic dissection/rupture accounts for >90% of deaths
- Risk rises steeply with root diameter and growth rate; family history of dissection is independent
- Modern surveillance + prophylactic surgery -> life expectancy approaching normal
- Re-dissection and distal aortic disease continue after root replacement -> lifelong whole-aorta imaging
- Type B dissection and descending aneurysm become the dominant late problem post-root surgery
- Pregnancy, hypertension, stimulants (cocaine, amphetamine) and weightlifting are the modifiable acute triggers
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