BASICS

DESCRIPTION

Autosomal dominant connective tissue disorder of the fibrillin gene that affects the cardiovascular, musculoskeletal, and ophthalmic systems.

EPIDEMIOLOGY

Prevalence

• 4–6 in 10,000 individuals

• Affects both genders equally

• 25% sporadic mutation

RISK FACTORS

• Family history

• 50% risk in each pregnancy

Genetics

• Autosomal dominant 65–75% of cases

• Defect of fibrillin, on 15q21 (FBNI)

• Tissue growth factor-β receptor 2 on 3p24.2–25

• High penetrance with variable manifestations

PATHOPHYSIOLOGY

• Fibrillin is essential component of microfibril assembly in extracellular matrix

• Structural function in tissues

• Fibrillin found in ciliary zonule, lens capsule, endothelium of Schlemm’s canal, sclera, choroid, Bruch’s membrane, lamina cribrosa, and corneal epithelium

• May explain ectopia lentis, axial myopia, glaucoma, corneal ectasia, and retinal complications

• Most common cause of nontraumatic ectopia lentis (1)[B]

ETIOLOGY

Defect in fibrillin or TFGβR2 or spontaneous mutation.

COMMONLY ASSOCIATED CONDITIONS

• Cardiac manifestations (80%)

– Aortic root dilatation, dissecting aneurysm, mitral valve prolapse

• Musculoskeletal manifestations

– Tall stature, scoliosis or kyphoscoliosis, chest deformities (pectus excavatum), generalized joint hypermobility

• Pulmonary manifestations

– Spontaneous pneumothorax, apical blebs

• Neurosurgical manifestations

– Dural ectasia

DIAGNOSIS

HISTORY

• Family history

• Focused history on cardiac, musculoskeletal, pulmonary, integumentary symptoms

PHYSICAL EXAM

• Ghent diagnostic criteria (1996)

– Major criteria in 1 organ system and minor criteria of another with positive family history or positive genetic testing

– With no family history, major criteria in 2 organ systems with minor in third required (2)

• Ocular examination

– Corneal ectasia, often flat cornea

– Ectopia lentis classically superotemporal, however, all meridians have been reported. Seen in 50–80% of patients.

– Poorly dilating pupils due to hypoplastic iris or ciliary muscle

– Earlier onset nuclear sclerosis (10–20 years earlier)

– Central/posterior vitreous liquefaction

– Axial myopia

– Retinal detachment common (8–25.6%), often in younger age (mean 22 years). Common in conjunction with ectopia lentis secondary to traction of unstable lens. Also common after lens extraction, although improved detachment rate with pars plana lensectomy versus anterior approach.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Although mutation in FBN1 is known, molecular testing is neither sensitive nor specific (3)

• Clinical and radiologic diagnosis according to Ghent criteria

Imaging

• Echocardiography

• MRI or CT

• B-scan if poorly dilated pupils with suspected retinal detachment

DIFFERENTIAL DIAGNOSIS

• Ectopia Lentis

• Trauma

• Buphthalmos

• Aniridia

• Ectopia lentis et pupillae

• Familial ectopia lentis

• Syphilis

• Weill-Marchesani syndrome

• Sulfite oxidase deficiency

• Xanthine oxidase deficiency

• Molybdenum cofactor deficiency

• Hyperlysinemia

• Methylenetetrahydrofolate reductase deficiency

TREATMENT

MEDICATION

First Line

• β-blockers (3)

• Has been shown to decrease event rates, but no effect on mortality

Second Line

• ACE inhibitors or ARB

• Currently experimental

ADDITIONAL TREATMENT

Issues for Referral

Cardiology, Pulmonary, Neurosurgery, Dermatology, and Ophthalmology/Retinal Surgery.

SURGERY/OTHER PROCEDURES

• Cataract-Pars plana lensectomy with vitrectomy preferred

• Retinal detachment

– May need pupil stretching techniques

– Scleral buckle-consider with minimal lens displacement with well-dilated pupil

– Pars plana vitrectomy-consider with severe lens displacement. Additional encircling band may decrease risk of redetachment

– Must examine fellow eye, as risk of bilateral detachment is high

– Reported success rates for retinal reattachment is 71–89% (2)[C].

Pregnancy Considerations

Maternal risk

• Increased risk of aortic dissection, with higher risk of maternal and fetal mortality

• Progressive aortic dilatation

• Most common complications in second and third trimester

• Overall complication rate in pregnancy is low, and relatively safe in women with aortic root diameter <4.0 cm

• Consider prophylactic surgery if aortic dilatation exceeds 4.7 cm (<4.0 cm carries 10% risk of dissection).

• Consider prophylactic β-blocker with overall favorable side effect profile on the fetus.

• Vaginal delivery safe in patients with minimal aortic dilatation (<4.0 cm), but consider C-section in higher risk mothers (>4.0 cm) as hemodynamic instability during labor/delivery increases risk of dissection. Cardiac surgery can follow, or concurrent with C-section.

Fetal risk

• Variable penetrance-mildly affected mother may have severely affected fetus.

• Development of aortic dissection carries substantial risk.

• Higher rate of obstetric complications (40%) (4)[B]

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Regular monitoring of valvular function and aortic diameter with echocardiography

• Elective repair of moderately regurgitant mitral valve or moderately dilated aortic root

• Low dynamic activity with avoidance of bodily collisions during exercise

• Regular ophthalmic exams

Patient Monitoring

Echocardiography

PATIENT EDUCATION

• Exercise

• Pregnancy

• Genetic counseling

• Retinal detachment warning symptoms (flashing lights, floaters, curtain over vision)

PROGNOSIS

• With modern cardiothoracic surgical techniques, average life expectancy 70 years (3)

• Visual prognosis varied and is dependent on degree of involvement in regards to amblyopia, ectopia lentis, retinal detachment

COMPLICATIONS

Visual loss

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