Loeys-Dietz Syndrome

Loeys-Dietz syndrome is an autosomal dominant connective tissue disorder with aggressive aortic root aneurysm, arterial tortuosity and dissection at smaller aortic diameters than in Marfan syndrome. Early recognition and timed surgery prevent sudden death.

Pathophysiology. Loss-of-function variants in genes of the transforming growth factor beta signalling system (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3, SMAD2) paradoxically increase downstream signalling in the vessel wall. The result is medial degeneration and weakening of the aorta and of medium sized arteries.

Many cases arise de novo. Severity differs by gene: TGFBR1 and TGFBR2 disease is often the most aggressive, while SMAD3 disease adds early onset osteoarthritis.

Dissection can occur in childhood and in pregnancy, and at aortic diameters that would be low risk in other conditions.

• Wide set eyes (hypertelorism), bifid or broad uvula, cleft palate
• Arterial tortuosity, especially in the head and neck vessels
• Aortic root aneurysm and dissection, and aneurysms in other arteries
• Translucent skin with easy bruising and widened atrophic scars
• Craniosynostosis, pectus deformity, scoliosis, talipes equinovarus, joint laxity with contractures
• Food allergy, eczema, asthma and eosinophilic gastrointestinal disease
• Spontaneous rupture of the spleen, bowel or uterus in some
• SMAD3 variants: early osteoarthritis with osteochondritis dissecans

• Genetic testing: a panel covering TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3 with deletion and duplication analysis, plus FBN1 when Marfan syndrome is in the differential.
• Baseline vascular imaging: echocardiography for the aortic root and ascending aorta, with z-scores in children, and CT or MR angiography of the head, neck, chest, abdomen and pelvis to define aneurysms and tortuosity.
• Eye examination: slit lamp and refraction for myopia, strabismus and retinal detachment risk.
• Skeletal and craniofacial assessment: spine and cervical spine films, and a head scan for craniosynostosis and Chiari malformation.
• Family cascade: targeted testing of parents, siblings and children.

Differential diagnosis.

• Marfan syndrome
• Vascular Ehlers-Danlos syndrome
• Shprintzen-Goldberg syndrome
• Arterial tortuosity syndrome
• Familial thoracic aortic aneurysm and dissection
• Turner syndrome and bicuspid aortic valve aortopathy

• Medical therapy: start a beta blocker or losartan at diagnosis to lower wall stress.
  • Losartan 25 mg orally daily, titrated over weeks to 50 to 100 mg daily (children 0.4 to 1.4 mg/kg daily, maximum 100 mg). Check blood pressure, potassium and creatinine at 1 to 2 weeks after each step.
  • Atenolol 25 to 100 mg orally daily, or propranolol 40 mg twice daily titrated to heart rate and blood pressure (children propranolol 1 to 4 mg/kg daily in divided doses). Combination of both agents is common in specialist units.
• Prophylactic aortic root surgery: in adults, consider valve sparing root replacement when the root reaches 4.0 cm in TGFBR1 or TGFBR2 disease, earlier with a family history of dissection, severe extra-aortic features or fast growth (over 0.5 cm in a year), and at 4.5 cm in lower risk genotypes. In children the threshold is a z-score of about 3 or fast growth.
• Other arteries: repair aneurysms in head and neck, thoracic or abdominal vessels by size and growth, with endovascular options chosen carefully because of fragile wall.
• Activity advice: avoid contact sports, heavy isometric lifting and straining, and stimulants. Low to moderate dynamic exercise is acceptable.
• Drugs to avoid: fluoroquinolones, and decongestants or stimulants that raise blood pressure.
• Allergy and gastrointestinal disease: treat eczema, asthma and food allergy in the usual way.
• Orthopaedic care: spinal bracing and fusion for progressive scoliosis, and cervical spine stabilisation for instability.

Special groups.

• Pregnancy carries a high risk of dissection and uterine rupture. Preconception counselling is needed, losartan is stopped before conception, and a beta blocker continues. Delivery is planned in a cardiac centre, often by caesarean section for a dilated root.

Monitoring. Echocardiography every 6 months until stable, then every 12 months. Whole body angiography at baseline, after any surgery, then every 1 to 2 years depending on findings. Annual eye examination and spine review.

Referral and escalation. Refer to clinical genetics, cardiology and vascular surgery. Emergency for sudden chest, back or abdominal pain, syncope, or neurological deficit, since dissection is possible even at small diameters.