Williams Syndrome-associated Cardiovascular Disease

Williams syndrome is a multisystem disorder from a contiguous deletion at 7q11.23 that includes the elastin gene (ELN). Cardiovascular disease is the main cause of morbidity and early death. It features an elastin arteriopathy: supravalvular aortic stenosis, peripheral pulmonary artery stenosis, systemic and renal artery stenosis, coronary ostial narrowing and systemic hypertension.

It affects about 1 in 7500 to 1 in 10,000 live births. Cardiovascular disease is present in about 80% of patients. Supravalvular aortic stenosis occurs in 45 to 75%, pulmonary artery stenosis in 30 to 40%, and hypertension in about half of adults. Other cardiac findings include mitral valve prolapse, bicuspid aortic valve and ventricular septal defect.

Sudden death occurs at 25 to 100 times the rate in the general population. It is often related to anaesthesia or sedation in patients with biventricular outflow obstruction or coronary involvement, and it can occur with exertion.

Non-cardiac features include characteristic facies, a friendly personality, mild to moderate intellectual disability, infantile hypercalcaemia, short stature, hypothyroidism, diabetes and renal anomalies.

Pathophysiology.

Hemizygosity for ELN reduces elastin in the vessel wall. Smooth muscle cells proliferate to compensate, giving a thickened media and narrowed lumen, particularly at the sinotubular junction, in the aorta, coronary ostia, branch pulmonary arteries and renal arteries.

Supravalvular aortic stenosis causes left ventricular hypertrophy and subendocardial ischaemia. Coronary ostial stenosis and diastolic coronary flow reduction add to risk. Fixed obstruction on both outflow tracts leaves the patient dependent on preload and sinus rhythm, so hypotension or tachycardia during sedation can precipitate ventricular failure and fibrillation.

Hypertension is from renal artery stenosis and diffuse stiffening of the arterial tree, with reduced compliance.

Infants may have a murmur, hypercalcaemia (irritability, vomiting, constipation, poor feeding), failure to thrive and colic. Children and adults have a systolic ejection murmur at the right upper sternal edge radiating to the neck, with a thrill and, in aortic stenosis, a blood pressure difference between the arms (right arm higher than left, from the Coanda effect). Exertional dyspnoea, chest pain and syncope signal severe obstruction or coronary disease.

QTc prolongation is common, and many patients have joint laxity, hypotonia and gastrointestinal complaints.

• Genetic confirmation: fluorescence in situ hybridisation or chromosomal microarray for 7q11.23 deletion.
• Cardiovascular assessment at diagnosis and regularly: blood pressure in all four limbs, ECG with QTc, echocardiography (aortic root and ascending aorta, supravalvular gradient, pulmonary arteries, left ventricular hypertrophy and function, mitral valve), and renal artery imaging (ultrasound, MR or CT angiography) when hypertensive.
• CT or MRI angiography of the aorta and branch vessels, and of the coronary ostia when symptoms or risk features are present. Catheter angiography is used before surgery and in high risk patients.
• Calcium, creatinine, thyroid function, glucose, urine calcium to creatinine ratio, and renal ultrasound.
• Stress testing is cautious and done under supervision when ischaemia is suspected.

Differential diagnosis.

• Isolated supravalvular aortic stenosis (ELN point variants) and other genetic arteriopathies (cutis laxa, Alagille syndrome).
• Noonan syndrome and other RASopathies.
• Valvular and subvalvular aortic stenosis and coarctation.
• Renovascular hypertension of other cause.

High risk assessment before any sedation, anaesthesia or procedure. Identify bilateral outflow tract obstruction, coronary ostial stenosis, biventricular hypertrophy, left ventricular dysfunction, and prolonged QTc as high risk markers. Perform non-urgent procedures only in a centre with paediatric cardiac anaesthesia and resuscitation facilities, with a specialist anaesthetist who knows the condition.

Maintain preload and blood pressure, avoid tachycardia and hypotension, avoid drugs that reduce systemic vascular resistance and prolong QTc, and have extracorporeal support available for high risk cases.

Supravalvular aortic stenosis.

• Surgical repair with patch aortoplasty (single patch for discrete lesions, or the inverted-Y three patch technique for diffuse disease) when the peak gradient is over 50 mmHg (mean over 40 mmHg), or earlier for symptoms, left ventricular dysfunction, or coronary involvement. Mortality is about 3 to 7%, higher with coronary or bilateral outflow disease.
• Balloon dilatation is ineffective. Coronary ostial stenosis may require ostial augmentation or bypass grafting.
• Aortic regurgitation develops in a minority, and bicuspid valves may need valve intervention.

Pulmonary artery stenosis. Balloon angioplasty with or without stents, or patch augmentation, when right ventricular systolic pressure is over 50 mmHg, or over half of systemic pressure. Many peripheral lesions improve spontaneously in early childhood.

Hypertension (target under 130/80 mmHg in adults; under the 90th percentile for age and height in children).

• Exclude renal artery stenosis before starting ACE inhibitors or angiotensin receptor blockers.
• Amlodipine 2.5 to 10 mg orally once daily (children 0.1 mg/kg once daily, increased to a maximum of 0.2 mg/kg or 10 mg daily); monitor blood pressure, oedema and heart rate; reduce in severe hepatic impairment. Take care to avoid hypotension in severe outflow obstruction.
• Beta blocker (metoprolol succinate 25 to 100 mg daily; children propranolol 0.5 to 1 mg/kg every 8 hours, maximum 4 mg/kg daily) for left ventricular hypertrophy and tachycardia, with heart rate and blood pressure monitored; use with caution in severe coronary involvement and in asthma.
• Renal artery stenosis: balloon angioplasty or surgical reconstruction.

Hypercalcaemia (infancy). Hydration, reduced calcium and vitamin D intake, and specialist endocrine treatment for severe cases. Check calcium at each early visit.

QT prolongation. Avoid drugs that prolong the QT interval (macrolides, fluoroquinolones, ondansetron at high dose, antipsychotics, methadone) and correct electrolytes (potassium over 4.0 mmol/L, magnesium normal).

Endocarditis prophylaxis. Only for prosthetic material in the first 6 months and after previous endocarditis: amoxicillin 2 g orally (children 50 mg/kg, maximum 2 g) 30 to 60 minutes before dental procedures.

Monitoring. Blood pressure every visit. Echocardiography every 6 to 12 months in infancy and early childhood if there is a gradient, and every 1 to 3 years otherwise; lifelong follow up. ECG with QTc yearly. Renal artery imaging at diagnosis and with new or uncontrolled hypertension. Calcium and thyroid function yearly in early life, and glucose from adolescence.

Referral and escalation. Refer every patient to a congenital cardiology service at diagnosis. Urgent referral for syncope, chest pain, new arrhythmia, severe hypertension or planned anaesthesia.

Special groups.

• Pregnancy: rare. Supravalvular aortic stenosis, hypertension and coronary involvement carry risk of heart failure, arrhythmia and aortic complications; counsel before conception, avoid ACE inhibitors, and deliver in a specialist unit. Transmission to offspring is 50%.
• Children: weight based dosing, with early growth, feeding and developmental support.
• Adults: lifelong follow up of aortic dimension, hypertension, diabetes and renal function.
• Region specific: genetic testing may be limited, so clinical features with cardiac findings should trigger referral rather than waiting for confirmation.