Williams or Williams-Beuren syndrome (WBS) is a genetic disease that affects 1: 8000-10,000 individuals. The syndrome has been linked to deletions of 1.5 to 1.8 base pairs on chromosome 7q11.25, which encompass the elastin gene (ELN). The cardiovascular findings associated with WBS are due to the lack of elastin production as a consequence of this gene deletion. Eighty percent of patients with WBS have cardiovascular manifestations, which include supravalvular aortic stenosis and pulmonary artery stenosis - typically the branch pulmonary arteries. Forty-five percent of patients with supravalvular aortic stenosis will also have coronary anomalies. Any artery may be involved, including the mid- thoracic aorta, renal arteries, carotid arteries, and cerebral arteries.


Up to 14% of WBS patients will have a prolonged QTc/JTc interval. This may be a contributing factor to a higher-than-normal incidence of adverse cardiac events related to WBS. Many patients with WBS exhibit increased prolongation of the QTc during periods of increased heart rate, which also occurs in patients with microvascular cardiac disease. The occurrence of ectopic beats may also suggest ischemia. However, a concurrent channelopathy due to the genetic deletion cannot be excluded. In a retrospective study by McCarty et al, patients with supravalvular aortic stenosis but without WBS were compared to patients with supravalvular aortic stenosis and WBS. The results demonstrated that the QTc was significantly prolonged in patients with WBS independent of the degree of myocardial hypertrophy as compared to patients without WBS. Additionally, patients with WBS whom underwent repair of obstructive outflow lesions did not show a regression of the prolonged QTc, which presumably would resolve in patients with supravalvular aortic obstruction without WBS. Further studies are needed to elucidate the etiology of the prolonged QTc (ie the role of channelopathies, microvascular abnormalities and related ischemia, or a combination of both). In general, a prolonged QTc can be an isolated finding or it can occur in the setting of cardiac structural lesions. A prolonged QTc can lead to torsades de pointes and may degrade to ventricular fibrillation. It is prudent to avoid drugs that prolong QTc especially if QTc prolongation is already present. Many medications used for anesthesia and sedation, including the potent inhaled anesthetics, can prolong QTc.


Other features associated with WBS include a “cocktail-like” personality, high degree of anxiety, attention deficit hyperactivity disorder, and aversion to loud noises. Patients with WBS have intelligence quotients around 50-60. Facial characteristics include a broad forehead, stellate iris, wide nasal bridge, upward pointing nose, large mouth with thick lips, periorbital thickness, and pointed chin. Patients with WBS may exhibit hypercalcemia early in life as well as subclinical hypothyroidism and may develop glucose intolerance progressing to diabetes mellitus in adulthood. They also have a propensity for colic as infants, chronic otitis media, poor dentition and scoliosis. The underlying pathophysiology of WBS predisposes these patients to require more medical attention and undergo more procedures than the general population. Additionally, they are 25-100 times more likely to have an adverse cardiovascular event than the general population. A great majority of events occur when receiving sedation or general anesthesia. Factors that increase the risk of adverse cardiac events are greater severity of supravalvular aortic stenosis (gradient >40 mm Hg), bilateral ventricular outflow obstructive lesions, coronary artery involvement, and a prolonged QTc of 460 ms or greater. Many of the adverse cardiovascular events seem to be related to imbalances in the myocardial oxygen supply and demand related to the vasodilatory and tachycardic effects of anesthetic agents. However, not all of the adverse cardiovascular events can be attributed to ischemia as the sole cause.


Of the choices given in this scenario, ondansetron is the most likely trigger for torsades de pointes. It is known to prolong the QTc. In the setting of an uneventful intraoperative course and stable hemodynamics, the timing of ondansetron administration and subsequent presentation of torsades de pointes suggests that this patient with WBS had an abnormal prolonged QTc which was worsened by the ondansetron. Light anesthesia, venous air embolism, and acetaminophen are unlikely causes for torsades de pointes.


References:


Staudt GE, Eagle SS. Anesthetic considerations for patients with Williams syndrome. J Cardiothorac Vasc Anesth. 2021; 35(1): 176-186.


Collins RT, Collins MG, Schmitz ML, Hamrick JT. Peri-procedural risk stratification and management of patients with Williams syndrome. Congenit Heart Dis. 2017; 12(2): 133-142.


Pober BR. Williams-Beuren syndrome. N Engl J Med. 2010; 362(3): 239-252.


McCarty HM, Tang X, Swearingen CJ, Collins RT 2nd. Comparison of electrocardiographic QTc duration in patients with supravalvar aortic stenosis with versus without Williams syndrome. Am J Cardiol. 2013; 111(10): 1501-1504.


Collins RT 2nd, Aziz PF, Swearingen CJ, Kaplan PB. Relation of ventricular ectopic complexes to QTc interval on ambulatory electrocardiograms in Williams syndrome. Am J Cardiol. 2012; 109(11): 1671-1676.


Collins RT 2nd, Aziz PF, Gleason MM, Kaplan PB, Shah MJ. Abnormalities of cardiac repolarization in Williams syndrome. Am J Cardiol. 2010; 106(7): 1029-1033.