Prolonged QT in a 13‐Year‐Old Patient with Down Syndrome and Complete Atrioventricular Canal Defect

Abstract

Ann Noninvasive Electrocardiol 2011;16(4):403–406

CASE PRESENTATION

A 13‐year‐old girl with Down syndrome (Trisomy 21) was noted to have QTc prolongation on her 12‐lead EKG. The patient was referred for further evaluation.

The patient was born as a full‐term baby at a local hospital. It was noted that she had a broad face, flattened nose, low set ears, microgenia, epicanthal folds, single transverse palmar crease, and unusual curving of the fingers. Her very first 12‐lead EKG was performed at 13 days of age (Fig. 1) demonstrated normal sinus rhythm, right atrial enlargement, superior QRS axis, and right ventricular hypertrophy. Multiple subsequent 12‐lead EKGs demonstrated evidence of QTc prolongation with nonspecific T wave changes and pronounced U waves (Fig. 2). This finding was thought to be secondary to her moderate mitral valve regurgitation with left ventricular enlargement.

Figure 1.

The very first 12‐lead EKG demonstrating normal sinus rhythm, right atrial enlargement, superior QRS axis, right ventricular hypertrophy, and borderline QTc with pronounced U waves.

Figure 2.

Twelve‐lead EKG after surgical repair of complete atrioventricular canal defect demonstrating clear QTc prolongation and pronounced U waves.

History was otherwise only positive for occasional need to rest after 30 minutes of walking with her parents or while playing with children. Her mother reported that there were no episodes of shortness of breath or palpitations. After several minutes of rest, patient is able to continue with her physical activities. There had been no reported syncope or sustained palpitations.

Drs. Towbin and Knilans: Please discuss the implications of the findings noted in this patient. What is your consideration for differentials at this time? Which tests will you recommend to be carried out for further evaluation?

This teenage female patient with Down syndrome was noted at birth to have typical phenotypic findings of the disorder. The first electrocardiogram reportedly showed sinus rhythm, right atrial enlargement, superior frontal plane QRS axis, and right ventricular hypertrophy. Electrocardiograms have reportedly shown QT interval prolongation, nonspecific T wave changes, and pronounced U waves. Moderate mitral valve regurgitation, left ventricular enlargement, and mild activity intolerance without syncope or palpitations are also reported.

The presence of a superior frontal plane QRS axis on the electrocardiogram of a child with Down syndrome is suggestive of deficiency of the inlet portion of the ventricular septum and displacement of the conduction system. This may occur either as an isolated ventricular septal defect or as part of complete or partial AV canal defect (ostium primum type atrial septal defect in association with a mitral valve cleft). The reported mitral valve insufficiency in this patient would be consistent with either a partial or complete AV canal defect. Complete AV canal in a child at this age would definitely be associated with pulmonary hypertension and partial AV canal might be. This, along with significant mitral valve insufficiency, might account for the mild activity intolerance.

The current electrocardiogram demonstrates an ectopic atrial bradycardia at a rate of 50/min. There is 1:1 conduction to the ventricle with a somewhat short PR interval of 100 msec. The beginning of the QRS complex is slurred with abnormal initial activation in the inferior, lateral, and left lateral precordial leads, suggesting the possibility of an accessory AV connection. The QRS duration is abnormally long, but this appears to be predominantly related to the abnormal initial portion of the QRS with the latter portion being inscribed rapidly. The ventricular preexcitation (if present) does not appear to account for the leftward and superior frontal plane QRS axis. The QT interval is prolonged (absolute value 570 msec and QTc 520 msec when corrected by Bazett's formula) and the T waves are abnormal and late peaking. There are prominent U waves as well.

Bradycardia to this degree and absence of a sinus mechanism is abnormal in a child of this age. Children with Down syndrome have a high incidence of thyroid dysfunction, most commonly hypothyroidism, and this is associated with bradycardia, which could account for a sinus rate slow enough that an ectopic atrial pacemaker would be seen. Hypothyroidism has also been reported as a reversible cause for QT prolongation, even with associated torsades de pointes ventricular tachycardia. Pulmonary hypertension has also been associated with QT interval prolongation and might be another contributing factor. Widening of the QRS complex, possibly associated with ventricular preexcitation, can also contribute to the degree of QT prolongation, although not usually to the degree seen here and would not be expected to cause the abnormal pattern of the T waves. Palpitations were not reported to suggest the possibility of the Wolff–Parkinson–White syndrome. U waves are commonly seen in the setting of bradycardia related to ventricular after‐potentials. The amplitude and morphology of the U waves on the current ECG would be consistent with this.

Recommended testing in this patient would include an echocardiogram to assess for structural heart abnormalities such as partial or complete AV canal or ventricular septal defect. Thyroid function testing and assessment of the hypothalamic‐pituitary‐thyroid axis should also be performed. If significant hypothyroidism is identified, treatment with thyroid hormone could be undertaken prior to further testing for bradycardia and QT interval prolongation. If the patient is euthyroid, genetic testing for mutations associated with the long QT syndrome would be appropriate. Ambulatory electrocardiography would be appropriate to assess the range of intrinsic heart rates and potential need for therapy for bradycardia. An atrial stimulation study (by esophageal means) should be performed to assess the potential presence and risk of anterograde accessory AV connection, assuming that ambulatory electrocardiography does not resolve this issue.

At 2 years of age it was noted that patient had sinus bradycardia with a heart rate at 68 beats/min while at rest and her thyroid function test was within normal limits. Further history was only positive for continuing need to rest after 30 minutes of walking or playing with children. This tended to improve several minutes of rest and the patient was able to continue with her physical activities.

Because of evidence of now pronounced increasing in QTc interval on a 12‐lead EKG, electrophysiology was consulted. Serum potassium was 4.8. Calcium, ionized calcium, and magnesium were within normal limits. Twenty‐four hour Holter demonstrated normal sinus rhythm with sinus bradycardia, at rest and decreased circadian variability. QTc intervals were prolonged throughout the recording, with longest measured QTc intervals of 640 msec. There was no evidence of ventricular ectopy, prolonged sinus pauses, AV conduction abnormality, T wave alternans, or arrhythmias. Transtelephonic monitoring showed sinus bradycardia with evident QTc prolongation and without evidence of ectopy or arrhythmias.

Twelve‐lead EKGs were performed on her family members to look for QTc abnormality and they were within normal limits. Family history is positive for sudden death in her paternal grandfather. By report, he was standing in the garden when he collapsed and suddenly died in his early 60s. Genetic testing on patient's blood sample was performed. The result revealed a novel nonsense pathogenic allelic mutation Arg 228Stop in the KCNJ2 gene, associated with LQT7 or Andersen Tawil syndrome. Subsequent testing of her parents showed her father as positive for the family specific mutation.

Andersen Tawil syndrome is a triad of periodic paralysis, ventricular arrhythmias (with characteristic EKG findings such as prolonged QTc interval), and physical and developmental anomalies. ¹ Affected individuals usually present at first or second decade of life with periodical paralysis after prolonged rest or rest after exercise. Physical characteristics include short stature, low set ears, hyperthelorism, micrognathia, fifth finger clinodactyly, and syndactyly. Sixty percent of affected individuals will have detected mutation of KCNJ2 that is encoding the inward rectifier potassium channel 2 protein (Kir2.1). To date, this is the only gene that is known to be associated with Andersen Tawil syndrome. The presence of pathogenic KCNJ2 mutation confirms the diagnosis. Andersen Tawil syndrome is inherited in autosomal dominant manner. Up to 50% of affected individuals have de novo mutation. Fifty percent of affected individuals will have affected parents.

We have described the patient with known chromosomal abnormality associated with congenital heart defect and newly diagnosed potassium channelopathy. This patient is interesting from several aspects. QTc interval prolongation was noticed from the early age. There is often evidence of nonspecific T wave changes with flattened T waves, borderline QTc prolongation, and pronounced U waves. It is sometimes difficult to distinguish biphasic T waves in LQTS from normal T waves with pronounced U waves in normal population. Mitral valve regurgitation is known to demonstrate prolonged QTc on a 12‐lead EKG. In this case, 12‐lead EKGs at patient's infancy did not always demonstrate marked QTc prolongation, with more of the U wave abnormality being evident. There was no clinical or documented evidence for ventricular arrhythmias during hospitalization for surgical repair, administration of anesthetic and administration of drugs that can prolong QTc interval. Recognition of physical features of Anderson Tawil syndrome was difficult because of additional and overlapping features of Down syndrome being present. Our patient did not have history of periodical paralysis. It is questionable how much therapy with ACE inhibitor that is keeping potassium levels slightly above normal limits contributed to this finding.

EDITORIAL COMMENT

As noted, Andersen Tawil syndrome is a rare inherited condition due to mutations in the gene KCNJ2 that encodes the inward rectifying potassium channel Kir2.1. ² Phenotypically, patients may present with, or be at risk, for musculoskeletal periodic paralysis and cardiac ventricular arrhythmias. The concurrent Down syndrome in this patient mixes the typical dysmorphic features related to Andersen Tawil syndrome and makes the presentation confusing. The 12‐lead ECG demonstrates prominent U waves with a prolonged terminal T wave downslope and a widened T–U junction have been reported to be characteristics consistent with LQT7 (Fig. 2). ³ These mutations may lead to early after depolarizations due to the induction of the Na–Ca exchanger, thought to be the mechanism for arrhythmogenesis. ¹ Another ECG finding more specific to LQT7, and not other types of LQT, is bidirectional ventricular tachycardia. ³

This case demonstrates the importance of heightened awareness for specific clinical conditions even in patients with complex congenital heart disease. In addition, a proper diagnosis in this case has a significant impact on the treatment of this patient. Specifically, extra attention is needed for careful electrolyte management, even more so usual than patients with other types of long QT, to prevent muscular paralysis balanced with stabilizing the risks for ventricular tachyarrhythmias.