Marfan syndrome

Description

AD connective tissue disorder of fibrillin-1 - skeletal, ocular, cardiovascular
The aorta is the only part that kills; everything else is a clue to it

Phenotype

Skeletal - tall, disproportionately long limbs (arm span : height >1.05), arachnodactyly (wrist + thumb signs), pectus excavatum/carinatum, scoliosis, pes planus, joint hypermobility, high-arched palate with crowded teeth, long narrow face, dolichocephaly, enophthalmos, retrognathia, malar hypoplasia, reduced upper:lower segment ratio (<0.85)
Ocular - ectopia lentis (superotemporal displacement, the single most specific feature), myopia, flat cornea, retinal detachment, blue sclerae
Cardiovascular - aortic root dilatation at the sinuses of Valsalva -> AR (wide pulse pressure), dissection; MVP with MR; dilated PA; descending aortic aneurysm
Other - spontaneous pneumothorax, apical blebs, dural ectasia, recurrent herniae, striae atrophicae

FBN1 mutation, chromosome 15q21, AD, near-complete penetrance, highly variable expression
- >3000 mutations; genotype-phenotype correlation weak, except a middle-exon cluster -> neonatal Marfan
Fibrillin-1 = scaffold of elastic microfibrils
- Structural: dec elastic fibre integrity -> cystic medial necrosis
- Signalling: microfibrils sequester latent TGF-beta
  - Deficient fibrillin -> inc free TGF-beta signalling -> matrix degradation, aortic dilatation, myxomatous valves
  - This is the rationale for ARBs - losartan blocks AT1-mediated TGF-beta signalling

Related aortopathies - do not miss

Loeys-Dietz (TGFBR1/2, SMAD3, TGFB2) - hypertelorism, bifid uvula/cleft palate, arterial tortuosity, widespread aneurysms; dissects at smaller diameters - lower surgical threshold
Vascular Ehlers-Danlos (COL3A1) - thin translucent skin, easy bruising, arterial/bowel/uterine rupture; no ectopia lentis
Familial TAAD, bicuspid aortic valve aortopathy
Homocystinuria - marfanoid habitus BUT inferonasal lens dislocation, intellectual disability, thrombosis (not dissection), AR inheritance

Revised Ghent criteria (2010) - aortic root and ectopia lentis dominate

Z score = aortic root diameter corrected for age and BSA.

No family history - any ONE of:

A. Aortic root Z >=2 + ectopia lentis
B. Aortic root Z >=2 + causative FBN1 mutation
C. Aortic root Z >=2 + systemic score >=7
D. Ectopia lentis + FBN1 mutation known to be associated with aortic disease

With a family history of Marfan - any ONE of:

Ectopia lentis, OR systemic score >=7, OR aortic root Z >=2 (age >=20; Z >=3 if <20)

Systemic score (>=7 = positive)

Wrist AND thumb sign = 3 (either alone = 1); pectus carinatum = 2; hindfoot deformity = 2; pneumothorax = 2; dural ectasia = 2; protrusio acetabuli = 2; reduced US:LS + inc arm span:height = 1; scoliosis = 1; reduced elbow extension = 1; 3/5 facial features = 1; striae = 1; myopia >3 D = 1; MVP = 1

Investigations

TTE at diagnosis, repeat at 6 months to establish growth rate, then annually if stable
CT or MR angiography of the whole aorta at baseline - echo does not see beyond the root
Slit-lamp with dilated pupils (ectopia lentis is missed undilated)
Urine/plasma homocysteine to exclude homocystinuria
FBN1 sequencing +/- aortopathy gene panel; cascade testing of first-degree relatives
MRI lumbosacral spine for dural ectasia if score is borderline

A. Slow the aorta

Beta blocker (maximally tolerated) OR ARB - both reduce the rate of root dilatation
- Head-to-head trials show no clear superiority; combination is used in progressive dilatation
Strict BP control
ARB is not a substitute for surgery once the threshold is reached

B. Surveillance

Annual TTE (more often if root >4.5 cm, growth >0.3 cm/yr, or family history of dissection)
Whole-aorta imaging periodically - dissection occurs distal to a replaced root

C. Surgery - elective root replacement before dissection

Aortic root >=5.0 cm -> elective replacement
>=4.5 cm if any of:
- Family history of dissection
- Growth >=0.3 cm/yr
- Planned pregnancy
- Undergoing aortic valve surgery
- Experienced multidisciplinary aortic centre
Valve-sparing root replacement (David procedure) preferred if the leaflets are normal - avoids lifelong anticoagulation
Bentall (composite graft) if the valve is diseased

D. Activity

Avoid: isometric/heavy resistance exercise, contact and collision sport, competitive sport, scuba diving, activity to exhaustion
Encourage low-intensity aerobic exercise
Avoid fluoroquinolones - associated with aortic dissection

E. Pregnancy - high risk

Pre-pregnancy counselling and imaging in every woman
Root >4.5 cm: advise against pregnancy or repair first; highest dissection risk in 3rd trimester and peripartum
Continue beta blocker (ARBs are teratogenic - stop and switch)
Serial echo each trimester; delivery plan in a centre with cardiac surgery; 50% transmission risk

F. Other systems

Annual ophthalmology; lensectomy for significant ectopia lentis; retinal detachment risk - present urgently with flashes/floaters
Scoliosis monitoring during growth; analgesia and neurosurgical review for dural ectasia symptoms
Endocarditis prophylaxis only if prosthetic valve/material or prior IE - no longer indicated for native MVP

Untreated median survival ~40 yr; with surveillance, beta blockade and elective root surgery, approaching normal
>90% of deaths are aortic - dissection or rupture
- The point of the whole management plan is to replace the root electively before it dissects
Type A dissection may occur below the surgical threshold, especially in Loeys-Dietz
Post-root replacement: residual risk of distal dissection - lifelong whole-aorta imaging

Monitor

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