Fibrillin-1 is a large (350 kDa) cysteine-rich glycoprotein that is the principal component of extracellular microfibrils — the 10–12 nm diameter fibres found in virtually every connective tissue in the body.

Functions of fibrillin-1:

1. Structural scaffolding — microfibrils serve as a scaffold upon which tropoelastin is deposited to form mature elastic fibres (think of microfibrils as the "rebar" in reinforced concrete, and elastin as the "concrete")
2. TGF-β sequestration and regulation — fibrillin-1 binds latent TGF-β binding proteins (LTBPs) in the matrix, keeping TGF-β in an inactive state. When fibrillin-1 is deficient, TGF-β is released and over-activated → this drives many of the pathological features ^[1][2]
3. Tissue homeostasis — maintains the structural integrity and elastic recoil of tissues in the aorta, heart valves, suspensory ligament of the lens (zonules), dura mater, skin, and lung

• FBN1 gene is located on chromosome 15q21.1 ^[1][2]
• It is a large gene (65 exons, ~235 kb of genomic DNA)
• Encodes the fibrillin-1 protein

Types of FBN1 mutations: ^[2]

• Missense point mutations (substitutions) — the majority (often involve cysteine residues in calcium-binding EGF-like domains)
• Insertions/deletions
• Splice site mutations

There are over 3,000 different FBN1 mutations reported to date — this extreme allelic heterogeneity means that almost every family has its own "private" mutation, making genotype-phenotype correlation difficult.

• Almost exclusively autosomal dominant (AD) ^[1][2]
• High penetrance — if you carry the mutation, you will almost always show some manifestation
• Variable expressivity — the severity and which organ systems are involved can differ enormously, even within the same family (interfamilial and intrafamilial variation) ^[2]

The current pathogenic model has moved beyond simply "defective scaffolding":

1. Deficient/abnormal fibrillin-1 → failure to sequester latent TGF-β in the ECM
2. Excessive free TGF-β signalling → downstream activation of SMAD2/3 and non-canonical (ERK1/2) pathways
3. This drives:
   • Aortic smooth muscle cell apoptosis and matrix metalloproteinase (MMP) activation → cystic medial degeneration
   • Excessive bone growth (TGF-β stimulates periosteal growth)
   • Myxomatous valve degeneration (MVP)
   • Dural ectasia (meningeal connective tissue weakness)

This TGF-β mechanism is why losartan (an angiotensin II receptor blocker that also reduces TGF-β signalling) has been studied as a disease-modifying therapy in MFS — more on this in management ^[1].

TGFBR1 and TGFBR2 mutations cause Loeys-Dietz syndrome (LDS) — a related but distinct aortopathy with more aggressive vascular disease (arterial tortuosity, aneurysms throughout the arterial tree, bifid uvula, hypertelorism) ^[1][2].

• MFS affects all ethnic groups including Hong Kong Chinese
• The Hong Kong Paediatric Cardiology service at Queen Mary Hospital and Prince of Wales Hospital actively screens for and follows paediatric MFS patients
• Genetic testing is available through the Clinical Genetic Service (CGS) at the Department of Health
• In HK, awareness may be lower than in Western countries — late diagnosis is still a problem, particularly if the family has no prior diagnosis
• Neonatal screening is NOT routinely performed; diagnosis relies on clinical suspicion

This is the most life-threatening aspect. Understanding the pathophysiology here is crucial.

Normal aortic wall structure:

• The aortic media contains concentric layers (lamellae) of elastic fibres, smooth muscle cells, and collagen, held together by microfibrils (fibrillin-1)
• This gives the aorta its characteristic Windkessel function — elastic recoil that smooths pulsatile flow

In MFS:

1. Deficient fibrillin-1 → disrupted microfibrillar scaffold → cystic medial degeneration (previously called "cystic medial necrosis")
   • Loss of elastic lamellae
   • Smooth muscle cell death (via excessive TGF-β → apoptosis)
   • Accumulation of mucoid ground substance ("cystic" spaces) ^[4]
2. The aortic root (sinuses of Valsalva) is the most commonly and earliest affected site
   • Why the root? Because this is where wall stress is highest (highest pressure, greatest curvature)
3. Aortic root dilatation → progressive → if unmonitored/untreated → aortic dissection (typically Stanford Type A) or aortic rupture
4. Dilatation of the aortic root → aortic regurgitation (AR) (annular dilatation pulls valve leaflets apart)

Mitral valve:

• Fibrillin-1 deficiency in valve leaflets → myxomatous degeneration → leaflet prolapse
• Mitral valve prolapse (MVP) occurs in ~75% of MFS patients (higher rate than general population)
• Can progress to mitral regurgitation (MR)
• In severe neonatal MFS, MR can be severe enough to cause congestive heart failure in infancy

Cardiac manifestations of Marfan syndrome: ^[3]

• Aortic root dilatation → which may lead to aortic regurgitation
• Mitral valve prolapse

The most clinically apparent features, and usually what prompts the initial clinical suspicion.

• Ectopia lentis (lens dislocation/subluxation) — occurs in ~60% of MFS patients ^[1]
  • Usually upward and temporal (superotemporal) — this is a distinguishing feature from homocystinuria where lens dislocation is typically downward and medial (inferonasal)
  • Mechanism: fibrillin-1 is a major component of the zonular fibres (suspensory ligament of the lens) → deficient zonules → lens displacement
• Severe myopia — due to increased axial length of the globe (connective tissue laxity → globe elongation) ^[1]
• Flat cornea — reduced corneal curvature ^[1]
• Hypoplastic iris — underdeveloped dilator pupillae due to connective tissue deficiency ^[1]
• Later complications: retinal detachment, cataract, glaucoma ^[1]

• Dural ectasia — expansion/ballooning of the dural sac, typically in the lumbosacral (L-S) region ^[1]
  • Mechanism: fibrillin-1 deficiency in dural connective tissue → dural sac yields to CSF pressure → outpouching
  • Detected on MRI spine
  • Can cause low back pain, radicular symptoms, or headache (from CSF leak)
  • Present in ~60–90% of MFS patients (very sensitive but not specific)

• Spontaneous pneumothorax — due to rupture of apical blebs (weakened alveolar connective tissue)
• Mechanism: fibrillin-1 deficiency in alveolar walls → loss of structural integrity → bleb formation → rupture under normal ventilatory pressures
• Occurs in ~5–10% of MFS patients

• Striae atrophicae / striae distensae (stretch marks) — occur in unusual locations (shoulders, lower back, thighs) without corresponding weight gain or pregnancy ^[1]
  • Mechanism: dermal elastic fibre deficiency → skin cannot withstand normal stretching forces
• Recurrent or incisional hernias (weakened fascia)

MFS exists on a clinical spectrum:

(Will be elaborated fully in Part 2 — Diagnostics, but briefly introduced here for context)

The 2010 revised Ghent nosology shifted emphasis to two cardinal features:

1. Aortic root dilatation/dissection (the primary cause of morbidity/mortality)
2. Ectopia lentis (the most specific clinical finding)

Plus a systemic scoring system (covering musculoskeletal, dural, skin, and pulmonary features) and FBN1 mutation testing.

Symptoms:

• Parents may report the child is "always the tallest in class" and has "unusually long fingers"
• Joint pain or recurrent joint dislocations (due to hypermobility)
• Back pain (scoliosis, dural ectasia)
• Foot pain (pes planus → altered biomechanics)
• Pectus deformity may cause cosmetic concern or, in severe pectus excavatum, cardiopulmonary compression (reduced exercise tolerance, dyspnoea)

Signs:

• Tall stature — plot on growth charts; typically > 97th percentile for age. Use paediatric growth charts appropriate for local population (Hong Kong Chinese growth charts differ from WHO/CDC)
• Increased arm span to height ratio (arm span exceeds height by > 5 cm) ^[1]
• Reduced upper segment to lower segment ratio (< 0.85 in adults; age-dependent normal values in children) ^[1]
• Positive Steinberg (thumb) sign ^[1]
• Positive Walker-Murdoch (wrist) sign ^[1]
• Pectus excavatum or pectus carinatum (excavatum more common) ^[1]
• Scoliosis — measure Cobb angle (> 20° is significant for systemic score)
• Joint hypermobility — assess with Beighton score (≥ 5/9 is hypermobile; count in systemic score)
• Pes planus — medial arch collapse, assess with weight-bearing
• Hindfoot valgus — often accompanies pes planus
• Protrusio acetabuli — usually asymptomatic in childhood; detected on X-ray pelvis ^[1]

Symptoms (in children):

• Often asymptomatic until significant valve disease or aortic dilatation develops
• Exercise intolerance (if significant MR or AR develops)
• Palpitations (MVP-related arrhythmia, or if AF develops — rare in children)
• Chest pain (atypical, non-anginal — associated with MVP)
• Syncope (rare — if severe AR or arrhythmia)
• Dyspnoea on exertion (heart failure from severe MR — especially in neonatal MFS)

Signs:

• Mid-systolic click ± late systolic murmur at the apex — MVP ^[5]
  • The click occurs because the prolapsing mitral leaflet suddenly tenses against the chordae
  • Murmur is exacerbated with patient standing (reduced preload → earlier prolapse → earlier and longer murmur) ^[5]
• Early diastolic decrescendo murmur at the left sternal border — AR (when aortic root dilates sufficiently)
  • This murmur is best heard with the patient sitting up, leaning forward, in end-expiration
• Pan-systolic murmur at the apex radiating to the axilla — MR (if MVP progresses to regurgitation)
• Wide pulse pressure, collapsing (waterhammer) pulse — if significant AR
• Signs of heart failure (in severe cases): tachycardia, gallop rhythm, hepatomegaly, peripheral oedema

In paediatric practice, a routine echocardiogram is the definitive investigation to detect aortic root dilatation and valve disease — clinical auscultation alone is insufficient for screening.

Symptoms:

• Blurred vision or progressive myopia (often severe, requiring strong corrective lenses)
• Monocular diplopia or visual distortion (if lens subluxation → part of the pupil sees through the lens and part doesn't)
• Sudden visual loss (retinal detachment — emergency)

Signs:

• Ectopia lentis — visible on slit-lamp examination as decentred lens; iridodonesis (quivering iris) may be seen if zonules are significantly weakened ^[1]
  • ~60%, usually superotemporal displacement ^[1]
• Myopia — often progressive and severe ^[1]
• Flat cornea — reduced keratometry readings ^[1]
• Hypoplastic iris — underdeveloped, may show transillumination defects ^[1]
• Increased axial globe length — measurable on ocular biometry
• Later: cataract (may occur earlier than age-expected), glaucoma (from angle abnormalities or lens-related angle closure) ^[1]

Symptoms:

• Low back pain (dural ectasia)
• Radicular leg pain, numbness, weakness (nerve root compression from ectatic dura)
• Positional headache (if CSF leak from dural ectasia)
• Hypotonia in infancy — often the earliest neurological sign ^[1]

Signs:

• Dural ectasia — detected on MRI of the lumbosacral spine ^[1]
• Hypotonia (infants/young children)
• Learning difficulties are NOT a feature of MFS — intelligence is normal

Symptoms:

• Sudden pleuritic chest pain + dyspnoea (spontaneous pneumothorax)
• Recurrent pneumothorax

Signs:

• Spontaneous pneumothorax — reduced breath sounds, hyperresonance on percussion
• Apical bullae on CT chest

Symptoms:

• Stretch marks appearing without weight gain or pregnancy (in adolescents)
• Recurrent hernias (inguinal, umbilical)

Signs:

• Striae atrophicae — especially over shoulders, lower back, thighs ^[1]
  • Mechanism: elastic fibre deficiency → dermal tearing under normal mechanical stress

These share the FBN1 gene mutation but do NOT meet full criteria for Marfan syndrome. They are part of the fibrillinopathy spectrum ^[2][7].

Connective tissue diseases associated with inherited cardiac conditions: ^[3]

• Marfan syndrome — AD
• Ehlers-Danlos syndrome — AD (hypermobile, classical, vascular) / AR (kyphoscoliotic)
• Loeys-Dietz syndrome — AD
• Familial thoracic aortic aneurysm and dissection — AD
• Bicuspid aortic valvulopathy — AD with incomplete penetrance and variable expressivity

In the ABSENCE of family history of MFS, Marfan syndrome is diagnosed if ANY ONE of the following combinations is present: ^[1][7]

The logic: Without a family history, you need two independent lines of evidence — either two cardinal features together, or one cardinal feature plus genetic confirmation, or one cardinal feature plus a high systemic score.

In the PRESENCE of family history of MFS (i.e., a first-degree relative independently confirmed to have MFS), diagnosis is made if ANY ONE of the following is present: ^[7]

The logic: With a confirmed affected relative, you already have one very strong prior — you just need one clinical feature or a sufficient systemic score to clinch the diagnosis. The threshold is lower because the pre-test probability is much higher.

The "aortic criterion" is satisfied by ANY of:

The systemic score is a points-based tally of features across organ systems. A score ≥ 7 is required to contribute to the diagnosis ^[1][7].

How to remember which features score the highest (2–3 points): The features with the highest scores are either (a) very specific for MFS (wrist + thumb sign together = 3, protrusio acetabuli = 2, hindfoot valgus = 2) or (b) strongly associated with serious underlying pathology (dural ectasia = 2, pneumothorax = 2, pectus carinatum = 2).

In paediatric practice, this is very common at initial presentation. The Revised Ghent Nosology provides guidance:

• If systemic score < 7 and aortic Z-score is borderline (2–3 in a child): diagnose as "potential MFS" and arrange longitudinal follow-up
• If FBN1 mutation is found but clinical criteria not met: may be classified as MASS phenotype, Ectopia lentis syndrome, or MVP syndrome depending on what features are present
• Re-evaluate periodically — especially at puberty when growth accelerates and features may emerge

Step 1 — Clinical Suspicion (Who Gets Worked Up?)

• Any child referred for: unexplained tall stature + Marfanoid features, ectopia lentis, aortic root dilatation, MVP in a young child, family history of MFS/sudden death/aortic dissection, spontaneous pneumothorax in a teenager

Step 2 — History and Examination

• Detailed 3-generation family history (sudden cardiac death, aortic dissection, tall stature, lens problems, skeletal problems)
• Full systemic examination with measurement of: height, weight, arm span, upper:lower segment ratio
• Calculate systemic score at the bedside
• Assess thumb sign, wrist sign, Beighton score, pectus, scoliosis, pes planus, hindfoot valgus, facial features, palate, uvula, striae

Step 3 — Obligatory Investigations (for every suspected case)

• Slit-lamp ophthalmological examination (after full pupil dilatation) — ectopia lentis
• Echocardiography — aortic root Z-score, MVP, MR, AR

Step 4 — Adjunctive Investigations (guided by findings)

• Genetic testing: FBN1 sequencing ± TGFBR1/2 panel
• MRI lumbosacral spine: dural ectasia
• Pelvic X-ray: protrusio acetabuli
• CT chest (if pneumothorax suspected)
• Plasma homocysteine (if ectopia lentis present — to exclude homocystinuria)

Step 5 — Apply Revised Ghent Nosology

• Determine whether aortic criterion, ectopia lentis, systemic score, and FBN1 status allow a definitive diagnosis
• If not → classify as potential MFS or alternative fibrillinopathy → longitudinal follow-up

Why is echo the most important investigation? Because the leading cause of morbidity and mortality in MFS is aortic root disease, and echocardiography is the primary tool for measuring aortic root diameter and calculating Z-scores in children.

Frequency of echocardiographic surveillance in paediatric MFS:

• At diagnosis: baseline echo
• If aortic root Z-score is stable and < 3: repeat annually
• If Z-score is increasing or 3–4: repeat every 6 months
• If Z-score > 4 or rapidly increasing: consider surgical referral + more frequent imaging (3–6 monthly)
• At puberty: increase frequency (growth spurt → accelerated aortic dilatation)

Z-score nomograms: The most commonly used are the Boston Children's Hospital nomograms (Colan/Sluysmans) and the Detroit/Lopez nomograms. They require accurate measurement of BSA (calculated from height and weight using paediatric formulae such as Haycock or Mosteller).

When to order genetic testing in paediatrics:

• When clinical diagnosis is uncertain (systemic score borderline, equivocal echo findings)
• To confirm the diagnosis and allow cascade screening of family members
• When the phenotype raises concern for an alternative diagnosis (e.g., Loeys-Dietz)
• Genetic counselling must be provided before and after testing (in Hong Kong, via the Clinical Genetic Service, Department of Health) ^[3]

In Hong Kong, FBN1 testing is available through the CGS. Turnaround time is typically several weeks to months. Do NOT delay clinical management (echo surveillance, beta-blocker consideration) while awaiting genetic results.

There is no blood test that diagnoses MFS. Fibrillin-1 levels are not routinely measured clinically. The diagnosis is clinical + genetic.

In children, the Revised Ghent criteria may be difficult to apply definitively at a single time point:

• Aortic root Z-score may be < 3 in early childhood and only cross the threshold during the pubertal growth spurt
• Ectopia lentis may be subtle initially (minimal subluxation detectable only on careful slit-lamp after full dilatation) and become more apparent with age as zonules progressively weaken
• Systemic score may increase over time as skeletal features evolve with growth (e.g., pectus deformity worsens during adolescence, scoliosis progresses)
• Dural ectasia — usually not imaged unless symptomatic, so may be missed early on

Implication: A child who does not meet criteria at age 5 should NOT be "cleared." They should be labelled as "potential MFS" and re-evaluated annually (or more frequently if features are evolving).

Neonatal MFS is a distinct, severe phenotype that presents at birth or in the first months of life:

• Usually due to mutations in exons 24–32 of FBN1 (the "neonatal region")
• Features: severe AV valve regurgitation (especially MR and TR), congestive heart failure, joint contractures (not hypermobility), loose redundant skin, diaphragmatic hernia, pulmonary emphysema
• Prognosis is poor — many die in infancy from intractable heart failure
• The Revised Ghent criteria were NOT designed for neonatal MFS — diagnosis is primarily clinical + genetic

Once MFS is diagnosed in a child (the proband):

1. Genetic testing of the proband to identify the specific FBN1 mutation
2. Genetic counselling for the family (AD inheritance → 50% risk to each offspring) ^[3]
3. Cascade genetic testing of all first-degree relatives
4. Any relative carrying the mutation → echocardiography + ophthalmology assessment regardless of symptoms
5. Relatives NOT carrying the mutation can be reassured (but only if the proband's mutation is definitively identified as causal)

This is one of the most impactful conversations you will have with a paediatric MFS patient and their family.

Why restrict activity?

• Isometric exercise (e.g., weight lifting, sit-ups, push-ups) increases systemic blood pressure acutely → increased wall stress on an already weakened aorta → increased risk of dissection ^[1]
• Contact sports risk direct chest/thoracic trauma → risk of traumatic aortic injury
• Diving (SCUBA) increases risk of pneumothorax (already elevated in MFS due to apical blebs) and involves Valsalva-like manoeuvres that acutely raise intrathoracic pressure ^[1]
• Competitive high-intensity sports trigger sustained catecholamine surges → tachycardia + hypertension → increased dp/dt (rate of rise of aortic pressure) → increased aortic wall stress

Activities to avoid: ^[1]

• Contact sports (rugby, football, martial arts, boxing)
• Isometric/static exercise (weightlifting, sit-ups, push-ups, heavy resistance training)
• Diving (SCUBA) — risk of pneumothorax
• High-intensity competitive sports (sprinting, competitive swimming at elite level)
• Activities with risk of sudden deceleration (e.g., roller coasters — debated but generally advised against in severe aortopathy)

Activities generally permitted:

• Low-to-moderate intensity dynamic (aerobic) exercise: walking, cycling at moderate pace, recreational swimming (non-competitive), golf
• The goal is to maintain cardiovascular fitness without pushing the aorta to dangerous haemodynamic stress
• Heart rate during exercise should ideally stay below the submaximal threshold set by the cardiologist

MFS management is inherently multidisciplinary. In a paediatric setting, the core team includes:

• Current guidelines (AHA/ESC 2023) do NOT recommend routine antibiotic prophylaxis for MVP alone
• Prophylaxis IS indicated if the patient has had prior prosthetic valve replacement or previous infective endocarditis
• Patients with MFS should maintain good dental hygiene to reduce bacteraemia risk

Beta-blockers have traditionally been considered the standard of care in patients with MFS and aortic aneurysm ^[2][12].

Mechanism of action (first principles):

• β₁-adrenergic receptor blockade → negative chronotropy (↓heart rate) + negative inotropy (↓contractility)
• This reduces dp/dt — the rate of rise of aortic pressure during systole
• dp/dt is the primary haemodynamic determinant of aortic wall stress. Lower dp/dt = less force hammering the weakened aortic wall with each heartbeat
• Additionally, lower HR → longer diastole → reduced total number of aortic pulsations per minute → cumulative reduction in mechanical stress

Dose is typically titrated to achieve a resting HR < 100 bpm during submaximal exercise ^[12]. In practice for children:

• Atenolol is most commonly used in paediatric MFS (β₁-selective, long half-life allows once-daily dosing, good paediatric data)
  • Starting dose: 0.5 mg/kg/day PO once daily
  • Titrate to 1–2 mg/kg/day (max ~100 mg/day in adolescents)
  • Target resting HR: typically < 70–80 bpm at rest in children; < 100 bpm during submaximal exercise
• Propranolol (non-selective) is an alternative, but requires multiple daily doses (TDS) and has more side effects (bronchospasm in asthmatic children)
  • Dose: 0.5–1 mg/kg/day PO in 2–3 divided doses, titrate to 2–4 mg/kg/day
• Metoprolol is another option (β₁-selective)

Paediatric formulation note: Atenolol is available as tablets (25 mg, 50 mg, 100 mg). For younger children who cannot swallow tablets, an oral suspension can be compounded by pharmacy (typically 2 mg/mL). Propranolol is available as oral solution (5 mg/5 mL or 10 mg/5 mL).

Contraindications / Cautions in children:

• Asthma (β₂-blockade → bronchospasm; use β₁-selective agents with caution, avoid propranolol)
• Bradycardia, AV block
• Decompensated heart failure (negative inotropy → worsening failure)
• Hypoglycaemia-prone children (β-blockers mask hypoglycaemic symptoms)
• Depression (less relevant in young children but important in adolescents)

Side effects to monitor:

• Fatigue, exercise intolerance (important in children — impacts PE at school)
• Cold extremities
• Sleep disturbance, nightmares (especially propranolol — crosses blood-brain barrier)
• Bradycardia — monitor HR at each visit

ARBs (losartan) are recommended as addition to beta-blockers in patients with MFS and aortic aneurysm ^[1][12].

Mechanism of action (first principles):

• Losartan blocks the angiotensin II type 1 receptor (AT1R)
• This has a dual benefit in MFS:
  1. Haemodynamic: reduces blood pressure → reduces aortic wall stress
  2. Anti-TGF-β effect: Extensive evidence links angiotensin II signalling to TGF-β activation and signalling ^[12]. Blocking AT1R reduces TGF-β-mediated matrix degradation, smooth muscle apoptosis, and MMP activation in the aortic wall — this is the disease-modifying rationale

Losartan has been shown to slow the rate of progression of aortic root dilatation ^[12] — this was first demonstrated in the landmark mouse model by Habashi et al. (2006) and subsequently in clinical trials (COMPARE trial, Pediatric Heart Network trial).

Paediatric dosing:

• Losartan: 0.4–0.8 mg/kg/day PO once daily (max 50 mg/day initially, can increase to 1.4 mg/kg/day or max 100 mg/day)
• Available as tablets (25 mg, 50 mg, 100 mg). Can be compounded into oral suspension for younger children (2.5 mg/mL)

Practical approach in paediatrics:

• Many centres now use beta-blocker + ARB combination as standard
• Some centres use losartan as monotherapy if beta-blocker is contraindicated or not tolerated

Contraindications:

• Pregnancy (teratogenic — relevant for adolescent females; ensure contraceptive counselling)
• Bilateral renal artery stenosis (rare in children but worth knowing)
• Hyperkalaemia
• Severe aortic stenosis (caution with afterload reduction)

Monitoring:

• Blood pressure (avoid symptomatic hypotension)
• Renal function and potassium (at baseline, 1–2 weeks after starting, then periodically)

ACEI have also been mentioned as having a role in reducing the rate of aortic dilatation ^[1]. However:

• The evidence for ACEi is less robust than for ARBs in MFS specifically
• The TGF-β pathway is most directly influenced by AT1R blockade (ARBs) rather than ACE inhibition
• In practice, if an ARB is not tolerated, an ACEi (e.g., enalapril, ramipril) can be substituted
• Enalapril paediatric dose: 0.08–0.1 mg/kg/day PO once or twice daily, titrate to 0.5 mg/kg/day (max 40 mg/day)

This is the most critical surgical intervention in MFS and has transformed the prognosis (life expectancy has increased from ~32 years in the 1970s to > 70 years with modern management).

Indications for aortic surgery in MFS: ^[1][12]

Paediatric nuance: In children, absolute diameter thresholds (5 cm) are less useful — a 5 cm aortic root in a 6-year-old is vastly different from a 5 cm root in a 16-year-old. Many paediatric centres use a combination of Z-score trajectory (rate of Z-score increase over time) and absolute diameter indexed to body surface area to guide surgical timing. There is no universal consensus on the exact Z-score threshold for surgery in children, but Z-score > 4–5 or rapid increase is generally considered an indication for surgical consultation.

Elective aortic repair is associated with reduced mortality when compared with urgent or emergency repair ^[12]. This underscores the importance of surveillance and timely referral.

Preservation of the native aortic valve at time of repair is desirable to avoid the need for lifelong anticoagulation ^[12].

Mitral valve repair or replacement is advised for severe MR with associated symptoms or progressive LV dilatation or dysfunction ^[12].

• Repair is preferred over replacement when feasible (avoids anticoagulation, preserves subvalvular apparatus)
• Indications are similar to non-MFS MR:
  • Severe symptomatic MR
  • Severe asymptomatic MR with LV dysfunction (LVEF < 60%) or LV dilatation (LVESD > 40 mm — adult values; paediatric values are indexed)
  • New-onset atrial fibrillation or pulmonary hypertension

Paediatric note: In neonatal MFS, severe MR may require early surgical intervention — but the operative mortality is high and the prognosis remains poor.

If a child or adolescent with MFS presents with acute aortic dissection:

Principles of management: ^[13][14]

1. Haemodynamic stabilisation — control BP to SBP 100–120 mmHg ^[13][14]
2. Definitive treatment — surgical resection and graft ^[13]

Step-by-step:

For Type B dissection in Marfan syndrome specifically: surgical intervention is indicated ^[13] — this is because the connective tissue is inherently unstable and medical management alone has a higher failure rate than in non-MFS patients.

Paediatric dosing for acute dissection:

• Labetalol IV: 0.2–1 mg/kg/dose bolus (max 20 mg), then infusion 0.25–3 mg/kg/hour. Titrate to target SBP and HR
• Esmolol IV (alternative short-acting β-blocker): Loading 500 µg/kg over 1 min, then 50–200 µg/kg/min infusion
• Sodium nitroprusside IV: 0.3–5 µg/kg/min infusion (cyanide toxicity risk with prolonged use — monitor thiocyanate levels)

Complications of Type A aortic dissection: ^[14][16]

Complications of Type B aortic dissection: ^[14][16]

Further focal neurological deficits from dissection: ^[14][16]

• Horner syndrome — dissection compressing superior cervical ganglion (miosis, ptosis, anhidrosis)
• Hoarseness — dissection compressing left recurrent laryngeal nerve

• In neonates/infants with severe MFS: severe MR/TR → congestive heart failure in the first months of life → often refractory to medical therapy → high mortality
• In older children/adolescents/adults: progressive AR or MR → chronic volume overload → LV dilatation → eventual LV systolic dysfunction → heart failure
• Heart failure in MFS is a late complication of unmanaged valve disease — this is precisely why surveillance and timely surgery are so important

• MVP-related arrhythmias: premature ventricular complexes (PVCs), supraventricular tachycardia
• Severe MR → LA dilatation → atrial fibrillation (uncommon in paediatric age but can occur in adolescents/young adults)
• Sudden cardiac death from arrhythmia is rare in MFS (unlike HCM) but can occur in the context of acute dissection or severe valve disease

• Abnormal valves (MVP, AR) are at risk of infective endocarditis
• Current guidelines do NOT recommend routine antibiotic prophylaxis for MVP alone — only for prior prosthetic valve or prior IE
• Good dental hygiene should be maintained