Monogenic (Mendelian): ~100%, FBN1 variant (~25% de novo)[1]
Marfan Syndrome
Quick Summary
Definition: A systemic autosomal dominant connective tissue disorder caused by FBN1 variants, with skeletal, ocular and cardiovascular features, notably aortic root dilatation and dissection risk.[1]
- Prevalence: 1 in 5,000 (most common heritable aortopathy)[1]
- Key gene: FBN1 (fibrillin-1), autosomal dominant, ~25% de novo
- Hallmark: Aortic root dilatation (Z≥2) + ectopia lentis + skeletal features (Ghent criteria)
- High-risk markers: Aortic root >45mm, rapid growth (>3mm/year), family history dissection, pregnancy
- First-line Mx: Beta-blockers (target HR 60-70), annual echo, prophylactic surgery >50mm (or >45mm if risk factors)
Aetiology
Genetics
Inheritance: Autosomal dominant; first-degree relatives have a 50% risk of inheriting the pathogenic variant.[1]
Familial vs de novo: Approximately 75% of cases are familial (inherited from an affected parent); approximately 25% arise as de novo FBN1 mutations with no family history of Marfan syndrome.[1]
Gene: FBN1 (fibrillin-1), >90% of cases meeting revised Ghent criteria
Penetrance: ~100%, but expressivity is highly variable, the same mutation can cause mild or severe disease even within the same family
Prevalence
Diagnostic Criteria
Revised Ghent Nosology (2010)
In absence of family history:
- Aortic root dilatation (Z-score ≥2) AND ectopia lentis, OR
- Aortic root dilatation AND FBN1 mutation, OR
- Aortic root dilatation AND systemic score ≥7, OR
- Ectopia lentis AND FBN1 mutation with known aortic disease
With family history:
- Ectopia lentis, OR
- Systemic score ≥7, OR
- Aortic root dilatation (Z ≥2 if age ≥20y, Z ≥3 if <20y)
Diagnosis
Confirming the diagnosis: see the revised Ghent nosology criteria above.[1] Core work-up: echocardiography (aortic root Z-score) and slit-lamp ophthalmology (ectopia lentis) in every suspected case; FBN1 genetic testing is strongly recommended (and is essential for cascade testing of relatives), but the revised Ghent criteria allow a clinical diagnosis in some patients without a detected FBN1 variant, so genetic testing is not an absolute requirement for diagnosis in every case.
Cardinal cardiovascular features:
- Aortic root aneurysm (most important - risk of dissection)
- Aortic regurgitation
- Mitral valve prolapse, mitral regurgitation
- Aortic dissection
Skeletal features: Tall stature, arachnodactyly, pectus deformity, scoliosis, reduced upper:lower segment ratio
Ocular: Ectopia lentis (lens dislocation)
Investigations
Echocardiography: Aortic root dimensions at sinuses of Valsalva (use Z-scores for age/BSA), annually[2]
CT/MR angiography: Full aortic imaging at baseline and follow-up; required if echo suboptimal[2]
Genetic testing: FBN1 sequencing; multi-gene panel (including FBN2, TGFBR1/2) if FBN1-negative[1]
Ophthalmology: Slit-lamp examination for ectopia lentis
Treatments
1. General measures:
- Avoid heavy lifting, isometric exercise, contact sports, competitive sports
- Moderate aerobic activity (low-intensity) generally acceptable
- Genetic counselling and family cascade testing, see the Genetic Testing page
2. Medical therapy:
- Aims to reduce aortic growth rate (ESC 2014 Aortic Guidelines[2])
- Beta-blockers (first-line):
- Atenolol (most evidence in Marfan; the Pediatric Heart Network trial found atenolol and losartan similarly effective at slowing aortic-root dilatation in children and young adults[7]):
- Start 25–50 mg once daily → target 50–100 mg once daily
- Target resting HR <60–70 bpm and blunted exercise HR response
- Dose to maximum tolerated; avoid underdosing
- Bisoprolol (alternative):
- Start 2.5 mg once daily → target 5–10 mg once daily
- Preferred if atenolol not tolerated or renal impairment
- Propranolol (alternative, non-selective):
- Start 20–40 mg twice daily → target 80–160 mg twice daily
- Atenolol (most evidence in Marfan; the Pediatric Heart Network trial found atenolol and losartan similarly effective at slowing aortic-root dilatation in children and young adults[7]):
- Losartan, additive to beta-blocker (ESC Class IIa):
- Start 25–50 mg once daily → target 100 mg once daily (or maximum tolerated)[5]
- COMPARE trial: losartan reduced the aortic-root dilatation rate in adults with Marfan syndrome[8]. The AIMS trial separately found irbesartan slowed aortic-root dilatation in children and young adults[9]. Overall, ARBs and beta-blockers each modestly slow aortic growth, with no clear superiority of one class[3]
- Avoid in pregnancy, switch to beta-blocker monotherapy pre-conception
- Monitor K⁺ and renal function; check BP (target systolic <130 mmHg)
3. Surgery:
- Prophylactic aortic root replacement if diameter ≥50 mm (≥45 mm if family history of dissection, rapid growth >3 mm/year, or concurrent surgery planned)[2][6]
- Valve-sparing root replacement (David/Yacoub procedure) preferred if aortic valve pliable and not regurgitant
4. Advanced heart failure and/or transplant referral:
- Standard advanced-heart-failure pathways apply if severe valve disease leads to LV dysfunction and refractory heart failure
Related Resources
Complications
- Aortic root aneurysm: progressing to dissection or rupture, the principal life-threatening complication[1]
- Aortic and mitral regurgitation: and mitral valve prolapse
- Pregnancy-associated dissection: with risk rising with root size and in the peripartum period
- Multisystem features: ectopia lentis and retinal detachment, spontaneous pneumothorax, dural ectasia and scoliosis
Risk Stratification
Aortic dissection risk increases with: Diameter >50mm, rapid growth (>3mm/year), family history dissection
Life expectancy: Near normal with appropriate management
Pregnancy Management
Pregnancy in Marfan syndrome - individualized risk assessment (2025 ESC pregnancy approach)
Pregnancy risk in Marfan syndrome is not determined by aortic root diameter alone. Risk assessment should incorporate indexed aortic root and ascending aorta measurements, growth rate, any previous dissection, family history of dissection, valve disease (aortic or mitral regurgitation) and, where known, genotype. A larger root or a history of dissection materially raises risk, but there is no single diameter cut-off (e.g. 40 mm or 45 mm) above which pregnancy should be described as universally contraindicated; the decision is individualized.[1][4]
Pre-pregnancy assessment: baseline echocardiography (aortic root and ascending aorta) and, where indicated by prior imaging gaps or dimensions, CT/MR angiography of the whole aorta; review of prior surgery, growth trend and family history; genetic counselling (genetic testing is strongly recommended, but the revised Ghent criteria allow a clinical diagnosis in some patients even without a detected FBN1 variant, so a negative genetic test does not exclude the diagnosis).[1]
During pregnancy: beta-blockers are generally continued; ACE inhibitors and ARBs (including losartan) are stopped before conception as they are teratogenic. Imaging frequency should be individualized to the patient's baseline dimensions and growth rate rather than a fixed monthly schedule for everyone; more frequent surveillance is reasonable for a larger or growing aorta, less frequent for a stable, normal-range aorta.[4]
Delivery: timing and mode (vaginal with an assisted second stage, versus caesarean section) should be decided by the Pregnancy Heart Team based on aortic status at the time, not applied as an automatic rule at a specific diameter.[4]
Postpartum: dissection risk remains elevated for some weeks after delivery, so continued surveillance and patient education about urgent symptoms (chest, back or abdominal pain) are appropriate; the exact schedule should be individualized rather than fixed.
Contraception and future pregnancy: discuss the full range of options, including long-acting reversible contraception and permanent methods, through non-directive counselling; the decision, including whether to consider a future pregnancy, is led by the patient.
Follow-up
Based on the 2024 ESC aortic & peripheral arterial diseases (PAAD) guideline and the revised Ghent nosology[2][1][6].
Advanced / complicated = aortic root ≥45 mm, growth >3 mm/year, prior dissection or repair, significant valve disease, or pregnancy.
Genotype-positive / phenotype-negative (G+/P−) = a confirmed pathogenic-variant carrier with no overt disease expression yet.
| Genotype+ / Phenotype− | Uncomplicated / Stable | Advanced / Complicated | |
|---|---|---|---|
| Frequency | Annual (FBN1+ even if no features) | Annual | Every 6 months (or sooner) |
| Clinical review | Symptoms, BP control, medication | Symptoms, BP control, medication adherence | As above |
| Echocardiography (aortic root) | Annual | Annual if stable and <45 mm | 6-monthly if ≥45 mm or growing |
| CT / MR angiography (whole aorta) | Baseline | Baseline, then every 1–2 years | Annual or sooner |
| Ophthalmology / skeletal | Periodic (ectopia lentis, skeletal) | Periodic (ectopia lentis, scoliosis) | As needed |
| Pregnancy | Pre-conception counselling | Pre-conception aortic assessment & counselling | Aortic imaging during pregnancy, frequency individualised (often each trimester if stable, more frequently for a larger or growing aorta) |
| Family screening | – | Cascade imaging ± genetics | – |
Disclaimer: This table is general guidance based on published guidelines and does not replace clinical judgement. The responsible clinician is accountable for determining the appropriate, individualised follow-up plan for each patient.
Key Points
- Genetic counselling - 50% risk to offspring[1]
- Screen first-degree relatives
- Pregnancy risk rises substantially with a larger or growing aortic root or prior dissection; there is no single universal diameter cut-off, and the decision (including consideration of prophylactic surgery before conception) should be individualized by an aortopathy/Pregnancy Heart Team[1]
- Risk rises as the aortic root enlarges, and mWHO categories are commonly applied in this direction: a root under 40mm is treated as lower risk (though dissection still occurs), 40-45mm as high risk, and around or above 45mm as very high risk falling into mWHO IV in many frameworks. Apply these as a guide to intensity of care and counselling rather than as fixed thresholds, since the classification varies between guidelines and the assessment also depends on growth rate, prior dissection, family history, valve disease and genotype
- Beta-blockers throughout pregnancy unless contraindicated; dose and heart-rate goal individualised[1]
- Delivery at tertiary centre with cardiothoracic surgery on-site
- Lifelong surveillance required - annual imaging[1]
References & Review Date
Last reviewed: July 2026
- Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47(7):476–485. doi:10.1136/jmg.2009.072785
- Erbel R, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases. Eur Heart J. 2014;35(41):2873–2926. doi:10.1093/eurheartj/ehu281
- Milleron O, et al. Marfan Sartan: a randomized, double-blind, placebo-controlled trial. Eur Heart J. 2015;36(32):2160–2166. doi:10.1093/eurheartj/ehv151
- 2025 ESC Guidelines for the management of cardiovascular disease during pregnancy. Eur Heart J. 2025. doi:10.1093/eurheartj/ehaf193
- Joint Formulary Committee. British National Formulary (BNF). bnf.nice.org.uk
- Mazzolai L, Teixido-Tura G, Lanzi S, et al. 2024 ESC Guidelines for the management of peripheral arterial and aortic diseases. Eur Heart J. 2024;45:3538–3700. doi:10.1093/eurheartj/ehae179
- Lacro RV, et al. Atenolol versus losartan in children and young adults with Marfan's syndrome (Pediatric Heart Network). N Engl J Med. 2014;371(22):2061–2071. doi:10.1056/NEJMoa1404731
- Groenink M, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome (COMPARE): a randomized controlled trial. Eur Heart J. 2013;34(45):3491–3500. doi:10.1093/eurheartj/eht334
- Mullen M, et al. Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial. Lancet. 2019;394(10216):2263–2270. doi:10.1016/S0140-6736(19)32518-8