Williams Syndrome

Introduction

• The prevalence of WS ranges between 1:8000 and 1:10000.¹
• WS is associated with a greatly increased risk of perioperative morbidity and mortality.^2-4
• Perioperative cardiac arrest has been reported in up to 11.1% of anesthetics, which represents a ~100x increase in risk compared to the general pediatric population.²
• Coronary artery disease is a frequent and often unappreciated feature of WS.

WS

Pathophysiology

• WS is a sporadic autosomal dominant syndrome caused by a microdeletion on the long arm of chromosome 7q11.23, which includes the elastin and LIMK1 genes.
• Familial cases exist, but are much less prevalent.

Cardiac Manifestations¹

• Cardiovascular anomalies are present in 80% of patients with WS.
• Normal elastin deposition allows for reversible vascular distention. Reduced elastin production seen in WS leads to a diffuse arteriopathy characterized by medial and neointimal hypertrophy, vascular stenoses, and increased arterial stiffness.
• Supravalvar aortic stenosis (SVAS; Figure 1) is the most common cardiovascular anomaly seen with WS, occurring in 45-75% of patients with WS. It may manifest as a discrete hourglass narrowing at the sinotubular junction, or less commonly, as a more diffuse, long-segment narrowing of the ascending aorta.
• SVAS may be progressive in a subset of patients with moderate-severe stenosis.
• Aortic valve abnormalities are sometimes seen in conjunction with SVAS.
• Other associated lesions include supravalvar pulmonary stenosis (~12%), multi-level pulmonary artery stenosis (~40%; Figure 1), aortic arch abnormalities, and coronary artery anomalies (Figure 1).

• About 45% of patients with SVAS have coronary artery involvement. This may manifest as discrete ostial stenosis, mechanical obstruction by the aortic valve leaflets and/or the sinotubular ridge (Figure 2), or diffuse coronary artery stenosis or dilation.

• WS may also involve the thoracic aorta leading to middle aortic syndrome and renal artery stenosis with early-onset hypertension.
• QTc prolongation is present in 13% of patients with WS and may contribute to the risk of sudden cardiac death.⁵

Noncardiac Manifestations

• LIMK1 protein is highly active in the brain, and a reduction in LIMK1 protein may underlie some of the neurocognitive characteristics associated with WS.
• Mild intellectual disability is common. Patients with WS have strong verbal and language skills, but severe visuospatial weakness. There may be an intense affinity to music.
• “Cocktail personality” is often used to describe the outgoing, friendly, and empathetic disposition seen in WS. Despite this, there is a very high incidence of anxiety that may coexist with attention deficit hyperactivity disorder or phobias.
• Patients with WS often have poor weight gain and reduced linear growth.
• Connective tissue abnormalities lead to low muscle tone and joint laxity early in life as well as the development of contractures with age.
• Facial dysmorphism: Characteristic facies features stellate irises, a broad forehead, periorbital fullness, high, rounded cheeks, a pointed chin, and a flattened nasal bridge (Figure 3). Dental malocclusion is common.
• WS is associated with several endocrine abnormalities, including hypercalcemia (usually symptomatic in the first 2 years and associated with dehydration), hypothyroidism, impaired glucose tolerance, and an increased risk of diabetes in adolescents and adults.

Management¹

Diagnosis and Follow-Up

• Given the high incidence of cardiovascular abnormalities in WS, all patients should undergo a detailed evaluation by a pediatric cardiologist, including a complete history and physical examination, four extremity blood pressure measurements, electrocardiogram, and echocardiography.
• Advanced cardiac imaging or cardiac catheterization may be indicated based on the findings of this evaluation.
• Twenty-four-hour ambulatory electrocardiographic monitoring should be performed at 1 year of age, annually until age 5, and then every 2 years thereafter.
• Imaging of the head and neck vasculature to rule out intracranial vasculopathy is indicated if headaches or other neurological findings are present.
• Likewise, abdominal imaging is indicated if abdominal bruits are appreciated on physical exam or if there is systemic hypertension. In the absence of these findings, renal ultrasonography should be performed at puberty and every 5 years thereafter.
• The timing and intensity of follow-up will depend on the type and severity of the cardiovascular disease. Patients who present with stenoses during the first year of life are more likely to have progressive disease than those who present later.

Medical Management

• Calcium channel blockers or beta-blockers are the drugs of choice for the management of systemic hypertension.
• Angiotensin-converting enzyme inhibitors are contraindicated unless renal artery stenosis has been ruled out.

Interventional Management

• Transcatheter intervention is generally ineffective for the management of SVAS or supravalvar pulmonary stenosis involving the main pulmonary artery.
• Serial balloon angioplasties can be used to treat peripheral pulmonary artery stenosis; however, there is a high rate of aneurysm formation.⁶ Right ventricular pressures will remain unchanged in the setting of main pulmonary artery stenosis.⁶
• Arterial stenting has a high failure rate.

Surgical Management

• SVAS relief is the most common surgical intervention in patients with WS.
• Reoperation is more common in patients with the diffuse type of SVAS.

Anesthetic Considerations^2,4,7,8

• Patients with WS are at a high risk of periprocedural cardiac arrest. Their care should begin with a thorough multidisciplinary evaluation, including the patient’s primary cardiologist and the anesthesiology and procedural teams.
• Preoperative assessment should focus on evaluating cardiovascular lesions, assessing the airway, and managing hypertension and arrhythmias. An overall risk assessment should be conducted to guide resource management (Figure 1).
• Moderate-risk patients presenting for nonurgent surgery should be cared for in a center with pediatric cardiology and anesthesiology capabilities.
• High-risk patients should be transferred to centers with extracorporeal membrane oxygenation (ECMO) capabilities and cared for by pediatric or pediatric cardiac anesthesiologists with WS experience. An ECMO team with a primed ECMO circuit should be readily available.
• ECMO stand-by should also be considered for patients with WS and a history of arrest under anesthesia or with SVAS presenting for their first catheterization.
• Thyroid function, renal function, and electrolyte abnormalities should be assessed in preprocedural laboratory tests.
• Patients with WS should be scheduled for the first case of the day. Fasting times should be minimized, and preoperative IV fluids should be considered.
• Beta-blocker therapy should be continued through surgery.

• Oral premedication should be considered if a peripheral intravenous (IV) catheter is not placed preoperatively.
• Low- and medium-risk patients will generally tolerate a slow, titrated mask induction.
• High-risk patients should undergo a careful IV induction with midazolam, ketamine, and/or etomidate and fentanyl. High-dose propofol should be avoided.
• The hemodynamic goal for induction and maintenance of anesthesia is to maintain myocardial and end-organ perfusion and oxygen delivery:
  • Preserve sinus rhythm and normal heart rate.
  • Maintain normal preload and afterload.
  • Maintain contractility and avoid/limit myocardial depressant medications.
  • Avoid an increase in pulmonary vascular resistance.
    Maintain normal hemoglobin and oxygen saturation.
• Inotropic and/or vasoactive support (phenylephrine, norepinephrine, or low-dose epinephrine) may be required to support myocardial function or normalize systemic vascular resistance. Hypotension should be treated aggressively.
• Invasive pressure monitoring and/or transesophageal echocardiography should be considered based on the severity of myocardial dysfunction and the nature of the surgical procedure.
• Postprocedure, patients with WS should be monitored in a high-acuity setting where there is the capability for resuscitation +/- ECMO deployment in high-risk patients.
• Tachycardia, shivering, and pain should be avoided in the postprocedure period.
• Medium- and high-risk patients should be monitored for at least 6 hours (ideally overnight) prior to discharge.