Orthopaedic Surgery - Marfan Syndrome

Basics

Marfan syndrome is an inherited connective-tissue disorder that primarily affects the cardiovascular, ocular, skeletal, and neurologic systems.

Major manifestations include:

Aortic root dilatation and dissection

Valvular disease

Ectopia lentis

Long, slender extremities and arachnodactyly

Spinal and chest-wall deformities

The disorder results largely from abnormalities in fibrillin-1 and altered regulation of signaling pathways that include TGF-β.

Although the genetic abnormality is present from birth, many important manifestations develop progressively. Aortic enlargement, scoliosis, and pectus deformity may therefore become apparent only later in childhood or adolescence.

Classification and Related Phenotypes

Marfan syndrome belongs to a group of heritable connective-tissue disorders with overlapping features.

Classic Marfan Syndrome

Classic Marfan syndrome results from abnormalities involving fibrillin-1 and is diagnosed using the revised Ghent criteria.

MASS Phenotype

The MASS phenotype includes varying combinations of:

Mitral valve prolapse

Borderline aortic enlargement

Skin abnormalities

Skeletal manifestations

It resembles Marfan syndrome but does not meet full diagnostic criteria.

Congenital Contractural Arachnodactyly

Congenital contractural arachnodactyly, or Beals syndrome, is caused by abnormalities in fibrillin-2.

It is characterized by:

Arachnodactyly, joint contractures, scoliosis, and characteristic external ear abnormalities.

Epidemiology

Marfan syndrome affects males and females approximately equally.

Prevalence

The prevalence is commonly estimated at approximately:

1 in 5,000 individuals.

Risk Factors

Risk is increased by:

A family history of Marfan syndrome

A family history of aortic aneurysm, dissection, or unexplained sudden death

Tall, slender body habitus

Dural ectasia

Protrusio acetabuli

A suggestive phenotype should prompt further cardiovascular and genetic evaluation.

Genetics

Marfan syndrome is inherited in an autosomal dominant pattern with variable expression.

A parent with the disorder has a substantial risk of transmitting the pathogenic variant to offspring.

De Novo Mutations

A significant proportion of patients have a new pathogenic variant without an affected parent.

These cases may present without a family history.

Variable Expressivity

Even within the same family, affected individuals may differ substantially in:

Cardiovascular severity, ocular involvement, skeletal deformity, and age of onset.

Etiology

Marfan syndrome is caused primarily by pathogenic variants in the FBN1 gene on chromosome 15.

FBN1 encodes fibrillin-1, a structural protein important in elastic connective tissues.

Fibrillin-1

Fibrillin-1 is abundant in structures such as:

The suspensory zonules of the lens

The aortic wall

Ligaments

Periosteum and other connective tissues

Abnormal fibrillin leads to both structural weakness and altered cell signaling.

TGF-β Signaling

Fibrillin abnormalities can also alter regulation of transforming growth factor beta signaling, which contributes to several manifestations of the syndrome.

Diagnosis

Diagnosis is based primarily on the revised Ghent criteria, integrating:

Aortic root disease

Ectopia lentis

Systemic skeletal and other features

Family history

FBN1 genetic testing

The exact combination required depends on whether a family history is present.

Signs and Symptoms

Many patients have relatively few subjective symptoms when the diagnosis is first considered.

The disorder is often recognized because of:

Body habitus, skeletal deformity, ocular abnormalities, or family history.

Possible Symptoms

Symptoms may include:

Delayed motor development

Poor coordination

Fatigability

Visual difficulty

Back pain

Chest pain in the setting of aortic disease

Sudden severe chest or back pain raises concern for aortic dissection and requires emergency evaluation.

Skeletal Signs

Common skeletal findings include:

Tall stature

Long extremities relative to the trunk

Arachnodactyly

Scoliosis

Kyphosis

Pectus excavatum or pectus carinatum

Planovalgus feet

Protrusio acetabuli

Joint laxity

Body Proportions

Patients frequently have relatively long arms and legs compared with trunk length.

Useful measurements include:

Upper-to-lower segment ratio

and

Arm-span-to-height ratio.

A reduced upper-to-lower segment ratio supports disproportionate limb lengthening.

Arachnodactyly

The fingers and toes may appear unusually:

Long, slender, and tapered.

Thumb Sign

The thumb sign is positive when the thumb, folded across the palm and enclosed by the fingers, extends beyond the ulnar border of the clenched fist.

Wrist Sign

The wrist sign is positive when the:

Thumb and fifth finger overlap around the opposite wrist.

These signs contribute to the systemic diagnostic score.

Pectus Deformity

Chest-wall abnormalities may include:

Pectus excavatum, in which the sternum is depressed, or

Pectus carinatum, in which the sternum protrudes anteriorly.

Spinal Deformity

Scoliosis and kyphosis may develop progressively during growth.

Curves can become substantial and may be more difficult to control than idiopathic scoliosis because of connective-tissue laxity and altered bone quality.

Foot Deformity

Patients may develop:

Pes planovalgus, long toes, hindfoot valgus, and other deformities.

Joint Laxity

Joint hypermobility may occur but is generally less pronounced than in Ehlers–Danlos syndrome.

Some patients instead develop joint stiffness or contracture.

Ocular Findings

The classic ocular finding is ectopia lentis, caused by weakness of the zonular fibers supporting the lens.

Other complications may include:

Myopia, retinal detachment, glaucoma, and early cataract formation.

Cardiovascular Findings

The most important life-threatening manifestation is aortic root enlargement, which may progress to:

Aneurysm formation and dissection.

Other findings include:

Mitral valve prolapse

Mitral regurgitation

Aortic regurgitation

Physical Examination

Height and Proportions

Measure:

Height

Arm span

Upper and lower body segments

Disproportionate limb length can support the diagnosis.

Spine

Examine for:

Scoliosis, kyphosis, sagittal imbalance, and back pain.

Chest Wall

Look for:

Pectus excavatum or pectus carinatum.

Hands and Wrists

Assess for:

Arachnodactyly, thumb sign, and wrist sign.

Lower Extremities

Evaluate:

Leg-length equality, hindfoot alignment, pes planovalgus, and joint laxity.

Ophthalmologic Examination

A formal slit-lamp examination by an ophthalmologist is important for identifying:

Lens subluxation or dislocation.

Regular ophthalmologic follow-up may also detect retinal and refractive complications.

Laboratory and Genetic Testing

Routine laboratory studies are generally normal.

Genetic testing for FBN1 pathogenic variants can support the diagnosis.

A negative genetic test does not completely exclude Marfan syndrome because not all clinically significant variants are detected by every testing method.

Imaging

Echocardiography

Echocardiography is central to diagnosis and surveillance.

It evaluates:

Aortic root diameter

Ascending aorta

Aortic valve function

Mitral valve structure and regurgitation

A baseline study should be obtained at diagnosis, followed by serial monitoring according to age and aortic dimensions.

CT and MRI of the Aorta

CT angiography or MRI may be used to evaluate the entire aorta, particularly when echocardiography does not adequately visualize distal segments.

MRI has the advantage of avoiding ionizing radiation during repeated surveillance.

Dural Ectasia

MRI of the lumbosacral spine can identify dural ectasia, characterized by enlargement of the dural sac and remodeling of the surrounding vertebral structures.

It most often involves the lower lumbar and sacral region.

Spine Radiographs

Plain radiographs are obtained when scoliosis or kyphosis is suspected.

Standing radiographs allow measurement of:

Curve magnitude and progression.

Pelvis Radiographs

An AP pelvic radiograph may demonstrate protrusio acetabuli, an excessive medial deepening of the acetabulum.

This finding contributes to the systemic manifestations of Marfan syndrome.

Pathological Findings

Aorta

The aortic wall may demonstrate:

Medial degeneration and structural weakness, predisposing to dilatation and dissection.

Dura

Dural ectasia may produce:

Widening of the spinal canal, thinning of the posterior vertebral bodies, and sac-like outpouchings.

Differential Diagnosis

Important differential diagnoses include:

Congenital contractural arachnodactyly

Stickler syndrome

Homocystinuria

Ehlers–Danlos syndrome

MASS phenotype

Familial thoracic aortic aneurysm and dissection syndromes

Loeys–Dietz syndrome

Congenital Contractural Arachnodactyly

This condition is associated with FBN2 variants and can resemble Marfan syndrome.

Contractures and characteristic ear abnormalities help distinguish it.

Stickler Syndrome

Stickler syndrome may include:

Ocular disease, hearing abnormalities, craniofacial features, and early joint degeneration.

Homocystinuria

Homocystinuria may produce a Marfanoid habitus.

Distinguishing findings include:

Developmental or cognitive impairment, thromboembolic disease, and typically inferonasal lens dislocation.

Ehlers–Danlos Syndrome

Ehlers–Danlos syndromes generally produce more pronounced:

Joint hypermobility, skin hyperextensibility, and tissue fragility.

Loeys–Dietz Syndrome

Loeys–Dietz syndrome is another hereditary aortopathy involving abnormalities in the TGF-β signaling pathway.

It may be associated with:

Arterial aneurysms, hypertelorism, bifid uvula, craniosynostosis, and skeletal abnormalities.

Treatment

General Principles

Treatment is aimed at preventing or managing complications rather than correcting the underlying fibrillin defect.

Care should be coordinated among:

Cardiology, genetics, orthopaedics, ophthalmology, and other specialists as needed.

Cardiovascular Medication

Medication is often used to reduce hemodynamic stress on the aorta.

Common options include:

Beta-blockers, such as atenolol, and

Angiotensin-receptor blockers, such as losartan.

The goal is to slow progression of aortic root enlargement.

Genetic Counseling

Genetic counseling should address:

Autosomal dominant inheritance, reproductive implications, family screening, and testing of at-risk relatives.

Cardiology Follow-Up

Periodic cardiovascular imaging is essential.

The frequency depends on:

Patient age, aortic diameter, rate of change, family history, and previous surgery.

Activity

Patients should remain physically active but avoid activities that produce excessive cardiovascular or skeletal stress.

Generally avoided activities include:

High-impact collision sports, heavy isometric exercise, intense weight lifting, and sports involving marked sudden increases in blood pressure.

Activity recommendations should be individualized by the treating cardiologist.

Physical Therapy

Physical therapy may be useful for:

Delayed motor development, muscular deconditioning, back pain, postural problems, and rehabilitation after orthopaedic treatment.

Spinal Bracing

Bracing may be considered for selected growing patients with scoliosis.

Its effectiveness may be less predictable than in idiopathic scoliosis.

Spinal Surgery

Spinal fusion with instrumentation may be required for:

Severe or progressive scoliosis or kyphosis.

Because connective-tissue quality and bone morphology may be abnormal, operative planning can be complex.

Spondylolisthesis

Severe or symptomatic L5–S1 spondylolisthesis may occasionally require spinal fusion.

Hip Surgery

Advanced arthritis related to protrusio acetabuli may rarely require total hip arthroplasty.

Ophthalmologic Treatment

Treatment options are available for:

Significant lens dislocation, refractive error, retinal detachment, and other ocular complications.

Aortic Surgery

Prophylactic aortic root surgery is performed when the risk of dissection becomes sufficiently high.

Decision-making is based on:

Aortic diameter, growth rate, body size, family history, genetic subtype, and associated valve disease.

Procedures

Options may include:

Valve-sparing aortic root replacement

or

Composite graft replacement of the aortic root and valve.

Elective surgery before dissection provides substantially better outcomes than emergency treatment after rupture or acute dissection.

Follow-Up

Referral

When Marfan syndrome is suspected, referral to a:

Cardiologist and clinical geneticist

is appropriate.

Ophthalmology and orthopaedic consultation should be arranged based on associated findings.

Prognosis

Historically, untreated cardiovascular complications substantially shortened life expectancy.

With modern:

Aortic surveillance, medical therapy, and prophylactic surgery, survival has improved dramatically.

Many patients now live well into older adulthood.

Complications

Important complications include:

Aortic aneurysm and dissection

Aortic or mitral valvular insufficiency

Retinal detachment

Spontaneous pneumothorax

Progressive scoliosis or kyphosis

Dural ectasia

Chronic musculoskeletal pain

Aortic Dissection

Aortic dissection is the most feared complication.

Sudden:

Severe chest, back, or abdominal pain, syncope, neurologic symptoms, or signs of shock

require emergency evaluation.

Retinal Detachment

Ocular connective-tissue abnormalities increase the risk of retinal detachment and potential visual loss.

Pneumothorax

Apical pulmonary blebs may predispose to spontaneous pneumothorax.

Sudden pleuritic chest pain or breathlessness requires urgent assessment.

Patient Monitoring

Long-term care should be coordinated by specialists familiar with heritable connective-tissue disorders.

Monitoring typically includes:

Serial echocardiography or aortic imaging

Ophthalmologic examinations

Spinal and skeletal assessment during growth

Evaluation of activity restrictions

Family screening and genetic counseling

Because manifestations evolve with age, children and adolescents at risk require continued surveillance even if early findings are limited.

Key Principle

The major goal in Marfan syndrome is early recognition and prevention of life-threatening cardiovascular complications.

Routine surveillance of the aortic root, timely medical treatment, elective aortic surgery when indicated, and coordinated management of ocular and skeletal problems can markedly improve both survival and quality of life.