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Loeys-Dietz syndrome

Definition
LDS is a heritable disorder of the connective tissue characterized by multisystem involvement, including craniofacial features, skeletal abnormalities, cutaneous findings, and early-onset and aggressive disease of the aorta and its branches.
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Pathophysiology
LDS is linked to mutations in genes encoding components of the transforming growth factor-beta signaling pathway. These mutations lead to an overactivation of the transforming growth factor-beta signaling pathway, which plays a crucial role in the growth and development of connective tissues throughout the body. This overactivation results in the abnormal development of various tissues, particularly those in the heart, blood vessels, and skeletal system.
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Epidemiology
The estimated worldwide prevalence of LDS is estimated at 0.00074 per 100,000 population.
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Disease course
Clinical manifestations include craniofacial features, skeletal abnormalities such as long and slender limbs (arachnodactyly), joint laxity, and chest deformities (pectus excavatum), cutaneous findings, and early-onset and aggressive disease of the aorta and its branches. Vascular complications, such as arterial tortuosity and aneurysms, are common and distinctive features of LDS. These vascular abnormalities can lead to serious events like aortic aneurysm rupture, which can be life-threatening.
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Prognosis and risk of recurrence
The prognosis is variable and is largely dependent on the patient's specific genetic mutations and the management of associated cardiovascular complications.
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Key sources
The following summarized guidelines for the evaluation and management of Loeys-Dietz syndrome are prepared by our editorial team based on guidelines from the Genetic Aortic Disorders Association Canada (GADA 2014) and the Society for Cardiovascular Angiography and Interventions (SCAI/STS/SVM/AATS/SCA/AHA/ACR/ACC/ASA/SIR 2010).
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Guidelines

1.Diagnostic investigations

Aortic imaging: as per AHA 2010 guidelines, obtain complete aortic imaging in patients with LDS or a confirmed genetic mutation known to predispose to aortic aneurysms and aortic dissections such as TGFBR1, TGFBR2,FBN1 , ACTA2, or MYH11, at initial diagnosis and 6 months thereafter to establish if enlargement is occurring.
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  • Duplex arterial screening

  • Cervical spine radiographs

  • DEXA scan

  • Food allergen testing

  • Evaluation for craniosynostosis

2.Medical management

Antihypertensives: as per GADA 2014 guidelines, consider offering BP-lowering medication, such as ARB, ss-blocker, or ACEI.

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  • Bronchodilators

  • Beta-blockers

  • Moisturizing creams

  • Medications to avoid

  • Self-injectable epinephrine

  • Management of rhinitis

  • Management of arrhythmias

  • Management of gastrointestinal disease

  • Management of constipation

3.Nonpharmacologic interventions

Exercise restrictions: advise exercise restrictions, including avoidance of contact or competitive sports, isometric exercises such as sit-ups, push-ups, pull-ups, or weight lifting, exercising to the point of exhaustion, and activities with routine blows to the chest or head.

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  • Physical therapy

  • Foot care/shoe inserts

  • Avoidance of allergens

  • Caloric supplementation

  • Calcium and vitamin D supplementation

  • Psychotherapy

4.Surgical interventions

Aortic repair: as per AHA 2010 guidelines, consider surgical repair of the aorta in all adult patients with LDS or a confirmed TGFBR1 or TGFBR2 mutation and an internal aortic diameter of ≥ 4.2 cm by TEE, or an external diameter of ≥ 4.4 to 4.6 cm by CT and/or MRI.
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  • Orthopedic procedures

  • Hernia repair

  • Pectus repair

5.Specific circumstances

Pregnant patients: as per GADA 2014 guidelines, down titrate ARBs safely prior to pursuing pregnancy, with use of ß-blockade during pregnancy.
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6.Patient education

General counseling: consider preconception genetic counseling regarding autosomal-dominant inheritance, variable expressivity, and genetic testing options including preimplantation or prenatal testing.

7.Preventative measures

Endocarditis prophylaxis: consider subacute bacterial endocarditis prophylaxis in those with artificial valves undergoing dental or other procedures expected to contaminate the blood stream.

8.Follow-up and surveillance

Serial imaging assessment: consider obtaining yearly echocardiography; more frequently depending on severity of aortic disease.

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  • Surveillance vascular MRI

  • Indications for specialist referral