Marfan Syndrome

Marfan syndrome is an autosomal dominant connective tissue disorder caused by pathogenic variants in FBN1, encoding fibrillin-1. Prevalence is about 1 in 5,000 to 10,000, with no sex or ethnic predilection. About 25% are de novo mutations. Penetrance is complete, with variable expression.

Pathophysiology

Fibrillin-1 is a major component of extracellular microfibrils that provide structural support and regulate TGF-beta bioavailability. Deficient or dysfunctional fibrillin leads to excess TGF-beta signalling, which drives aortic root dilatation, valve myxomatous degeneration, bone overgrowth, lung and skeletal muscle changes.

Major systems affected

• Cardiovascular (the main determinant of survival): aortic root dilatation (in 80%) at the sinuses of Valsalva, aortic regurgitation, ascending aortic dissection (type A), mitral valve prolapse with regurgitation, pulmonary artery dilatation, and arrhythmia. Untreated life expectancy fell to about 32-40 years before modern surgery, now close to normal with early diagnosis.
• Ocular: ectopia lentis (superotemporal lens subluxation in 60%), severe myopia, retinal detachment, glaucoma, cataract.
• Skeletal: tall stature, long limbs and fingers (dolichostenomelia, arachnodactyly), pectus excavatum or carinatum, scoliosis, flat feet, joint laxity or contracture, high-arched palate, protrusio acetabuli, dural ectasia.
• Pulmonary: spontaneous pneumothorax, bullae, sleep apnoea.
• Skin: striae atrophicae, recurrent hernias.
• Neurological: lumbosacral dural ectasia, causing back pain, headaches.
• Differential diagnoses (conditions with overlapping features): Loeys-Dietz syndrome (TGFBR1/2, SMAD3, TGFB2/3), vascular and hypermobile EDS, Shprintzen-Goldberg syndrome, homocystinuria (ectopia lentis downward, thrombosis, intellectual disability), congenital contractural arachnodactyly (FBN2), Stickler syndrome, familial thoracic aortic aneurysm, bicuspid aortic valve aortopathy, MASS phenotype, Beals syndrome, and Klinefelter syndrome.

• Tall, thin habitus with disproportionately long arms (arm span to height ratio over 1.05), long legs (reduced upper to lower segment ratio below 0.85), long narrow face, dolichocephaly, malar hypoplasia, enophthalmos, retrognathia, and high arched palate with dental crowding.
• Hand signs: thumb sign (Steinberg: thumb tip extends beyond ulnar border of clenched fist), wrist sign (Walker-Murdoch: thumb and fifth finger overlap around wrist).
• Chest: pectus carinatum or excavatum needing surgery in severe cases, scoliosis, kyphosis, flat foot with medial malleolus displacement (pes planus), hindfoot valgus.
• Cardiac: mid-systolic click and late systolic murmur (mitral valve prolapse), early diastolic murmur (aortic regurgitation), and symptoms of dissection (see aortic dissection) such as sudden tearing chest or back pain.
• Eyes: reduced visual acuity from myopia or lens dislocation, monocular diplopia, flashes and floaters (retinal detachment).
• Lungs: sudden pleuritic chest pain and dyspnoea (pneumothorax).
• Back pain and headache, and striae distensae not explained by weight change.
• Revised Ghent nosology (2010): diagnosis based on aortic root dilatation (Z score 2 or more) or dissection plus ectopia lentis, or with FBN1 mutation, or systemic score of 7 or more points (maximum 20):
• Wrist and thumb sign 3 (wrist or thumb alone 1), pectus carinatum 2 (pectus excavatum or chest asymmetry 1), hindfoot deformity 2 (plain pes planus 1), pneumothorax 2, dural ectasia 2, protrusio acetabuli 2, reduced upper to lower segment ratio and increased arm span to height 1, scoliosis or thoracolumbar kyphosis 1, reduced elbow extension 1, facial features 1 (at least 3 of 5), skin striae 1, myopia over 3 dioptres 1, mitral valve prolapse 1.
• Red flags: sudden chest or back pain (dissection), progressive dyspnoea, new regurgitant murmur, pregnancy, and visual loss.

Clinical and genetic

• Systemic score, family history, FBN1 testing (sequencing, deletion/duplication analysis) with multigene aortopathy panel to exclude Loeys-Dietz and other syndromes. Variants must be interpreted in context (pathogenic variants affecting cysteine residues or causing haploinsufficiency).
• Cascade testing of first-degree relatives.

Cardiovascular assessment

• Transthoracic echocardiography at diagnosis: aortic root measurements at sinuses of Valsalva, sinotubular junction, ascending aorta, with Z-scores adjusted for body surface area and age, valvular function, and left ventricle. Repeat 6 months after diagnosis, then annually if stable (every 6 months if root over 4.5 cm or rapid growth over 0.3-0.5 cm/year).
• MR angiography or CT angiography of the entire aorta at diagnosis and every 1-3 years (aortic arch, thoracoabdominal aorta, iliac arteries) after surgery and in follow-up. MRI preferred in young patients. ECG, Holter monitoring.

Other

• Slit lamp ophthalmological examination (lens position, retinal assessment) annually; spine radiographs, MRI lumbosacral spine for dural ectasia (back pain), pelvic radiograph for protrusio, pulmonary function tests, polysomnography, and growth assessment.
• Genetic counselling.

Medical therapy of aortopathy

• Beta blockers: atenolol 50-100 mg daily (or propranolol 40-160 mg twice daily, metoprolol succinate 50-200 mg daily, bisoprolol 2.5-10 mg), titrated to heart rate below 70 beats/minute at rest (or lowest tolerated), reduces haemodynamic stress and aortic growth.
• Angiotensin receptor blockers: losartan 50-100 mg daily (target dose 1.4 mg/kg in children, maximum 100 mg) reduces aortic root growth, equivalent to atenolol in meta-analyses, used in addition to beta blockers or in those who cannot tolerate beta blockers. Irbesartan 150 mg daily is an alternative. Avoid in pregnancy.
• Blood pressure target below 130/80 mmHg (lower if possible), with additional agents (ACE inhibitors, calcium channel blocker amlodipine 5-10 mg) if needed.
• Avoid fluoroquinolones, stimulants (decongestants, amphetamines), and high-dose isometric activity.

Lifestyle and activity

Avoid contact sports, competitive sports, heavy weightlifting, activities with abrupt exertion or Valsalva (isometric, scuba diving), and rapid deceleration. Encourage moderate aerobic exercise (walking, swimming, cycling at light-moderate effort, heart rate under 100-110 beats/minute). Avoid caffeine excess.

Surgery for the aorta

• Prophylactic aortic root replacement when: root diameter 5.0 cm or more (or 4.5 cm with risk factors: family history of dissection, growth over 0.3 cm/year in two consecutive measurements or over 0.5 cm in one year, progressive aortic regurgitation, planned pregnancy, or small body size using Z-score above 3 or aortic size index), or Z-score and absolute thresholds in children.
• Techniques: valve-sparing root replacement (David reimplantation or Yacoub remodelling) preferred when the valve is suitable, avoiding lifelong anticoagulation (reoperation in 5-10% over 10 years). Composite valve graft (Bentall) with mechanical valve and warfarin (INR 2.5-3.5) when the valve is diseased.
• Surgical mortality in elective operations is 1-2% in expert centres, versus 20-30% in emergency dissection.
• Mitral valve repair for severe regurgitation. Descending aortic aneurysm: endovascular repair is relatively avoided, open surgery preferred. Postoperative surveillance imaging.
• Acute type A dissection: emergency surgery. Type B: medical therapy, TEVAR for complications.

Pregnancy

Preconception counselling in a specialist centre. Risk of dissection mainly in third trimester and postpartum, especially with aortic root over 4.0-4.5 cm (high risk, pregnancy discouraged above 4.5 cm without prior repair).

Continue beta blocker (metoprolol, labetalol), stop ARBs and ACE inhibitors, serial echocardiography each trimester (every 4-8 weeks if root over 4.0 cm), and planned vaginal delivery with epidural for root under 4.0 cm or caesarean for dilated root.

50% risk of transmission to offspring, so offer prenatal diagnosis or preimplantation genetic testing.

Other systems

• Eyes: corrective lenses, surgery for lens dislocation (lensectomy with intraocular lens) when impairing vision, retinal detachment repair, glaucoma therapy, annual review.
• Skeletal: bracing for scoliosis (moderate, 25-40 degrees in growing child), spinal fusion for curves over 45-50 degrees, pectus repair for cardiopulmonary compromise or psychological distress (Nuss or Ravitch), orthotics for flat feet, and physiotherapy.
• Pulmonary: pneumothorax management (chest drain, early pleurodesis or video-assisted surgery for recurrence), treat sleep apnoea with CPAP.
• Dural ectasia: analgesia, physiotherapy, rarely surgery.
• Dental: early orthodontic care, endocarditis prophylaxis for prosthetic valves.
• Psychological: counselling for body image, anxiety, and chronic illness. Educational support.
• Children: early diagnosis, medical therapy, growth monitoring, and early surgery planning.
• Anaesthesia and procedures: avoid hypertension, maintain beta blockade, and caution with neck extension and intubation (cervical instability, dural ectasia and epidural difficulty).

Follow-up

Cardiology (echo annually, MRA/CTA every 1-3 years), ophthalmology yearly, orthopaedic review, genetic counselling, and mental health support. Medical alert card for emergency care (suspected dissection), and early imaging in any acute chest or back pain. Prognosis is near-normal with surveillance and timely surgery.