Life Threatening Broad QRS Tachycardia in an Infant with Conduction Disorder and SCN5A Mutation

1  Introduction

We present the case of an infant with a rapid wide complex tachycardia during fever (38.8°C), who presented at baseline ECG sinus bradycardia and conduction disorder related to SCN5A gene mutation inherited from the mother. In recent years some VT episodes in infants or small children have been related to mutations of the SCN5A gene encoding for the cardiac sodium channel. Apart from the children with a baseline or drug-induced typical Brugada ECG pattern, some of these young patients present with an atypical conduction disorder and have been recently labelled as “Brugada-like” children [1].

2  Clinical Descriptions

A previously healthy 8 months old child presented during a febrile illness at the emergency room of our hospital because of pallor, lethargy, hypotension, tachypnea and variation in intensity of the first heart sound. The standard ECG showed a rapid broad complex tachycardia with a heart rate of 300 beats/min (Fig. 1 panel A). A regular sinus rhythm returned during sedation with isoflurano before external defibrillation. The ECG showed sinus bradycardia (72 beats/min), prolonged PR interval (0.20 s), a conduction defect (RBBB + anterior fascicular block-type), wide QRS complex (0.10 s), normal ventricular repolarization, normal QTc interval (Fig. 1 panel B). Immediately his color and peripheral perfusion improved. The echocardiogram showed a structural normal heart with normal coronary arteries. During hospitalization a transesophageal electrophysiological study (EPS) was performed using the method previously defined [2] for evaluation of supraventricular tachycardia (SVT). Written Consent was obtained from patient’s family. Midazolam (0.1 mg/kg) was administered for sedation. 5–45 mA current was transmitted by a FIAB programmable Cardiac Stimulator 8817 for 5–20 ms. Stimulation was started by 10 mA for 10 ms with a heart rate faster than the baseline and was adjusted according to the stimulus threshold. Single and double extrastimuli and rapid atrial pacing in the baseline state and after isoproterenol iv infusion have not been induced SVT. Negative evaluation for metabolic disorders, infectious, and toxicological pathogeneses of VT. Every etiologies of nonspecific QRS duration lengthening, hyperkalemia, drugs, myocardial ischemia, were excluded prior to genetic testing for a channelopathy. Parents refused any type of medications for the child and also invasive EPS. For 7 years follow-up, he remained asymptomatic without any recurrences of tachycardia and an exercise test performed on the treadmill was normal. Since his abnormal basal ECG with conduction defect, normal structural heart, we have been induced to perform genetic testing. The molecular analysis performed at 6 years, showed a missense mutation in the sodium voltage-gated channel α sub-unit 5 (SCN5A) gene (Refseq: NM_198056.2 base substitution: c.5219G > A; Aminoacid Analysis: p.G1740E; heterozygote genotype). At present, this variant is to be considered likely pathogenetic (class 4: ACMG Variant classification), taking into account the consistency with the clinical suspicion, the frequency in the general population and according to the guidelines of the American College of Medical Genetics and Genomics [3].

Figure 1: A. ECG shows a rapid broad complex tachycardia with a heart rate of 300 beats/min and AV dissociation. B. ECG shows sinus bradycardia (72 beats/min), prolonged PR interval (0.20 s), a conduction defect (RBBB + anterior fascicular block-type), wide QRS complex (0.10 s), normal ventricular repolarization, normal QTc interval

His mother presented also the same gene mutation but she is asymptomatic until now with a normal baseline ECG (Fig. 2).

Figure 2: Mother’s ECG shows sinus rhythm at 60 beats/min, normal AV conduction, normal QRS interval and morphology, normal ventricular repolarization, normal QTc interval

2.1 Discussion

Life threatening VT in infants is a rare event. The role of fever as a precipitating factor for ventricular arrhythmias in subjects with sodium channel disorders is well recognized [4–7]. These episodes are often life threatening because of the potential degeneration into ventricular fibrillation. In this scenario a comprehensive clinical evaluation is mandatory for the exclusion of common predisposing conditions such as congenital structural cardiac defects, previous cardiac surgery, cardiomyopathies, metabolic disorder or viral myocarditis. Moreover, it is essential to rule out primary arrhythmic disorders. Sometimes a very fast broad complex tachycardia is difficult to diagnose when not all typical signs of VT are present as “fusion” or “capture” beats or VA dissociation. During VT, dissociation between atrial and ventricular activity during tachycardia is a hallmark of VT but sometimes P waves could be difficult to recognize during a broad QRS tachycardia if heart rate is very fast and have to look other signs or look for not electrocardiographic signs such as variations in jugular pulsations, the loudness of the first heart sound, and changes in systolic blood pressure [8]. Our working diagnosis was viral myocarditis or supraventricular tachycardia. Our case report showed an ECG with heart rate of 300 beats/min with not clear signs of AV dissociation but RS interval > 100 ms in precordial leads [9] and negative concordance was highly suggestive for VT although the basic electrocardiogram showed anterior fascicular block-type. According to the last ESC guideline [10] we checked all signs to do differential diagnosis between VT and atrial flutter: though the AV dissociation was not clear on the ECG (Fig. 1A), QRS wide > 120 ms, regular R-R interval, high ventricular rate, chest lead negative concordance and RS in precordial leads are all suggestive signs of VT. Moreover, in emergency room other colleagues administered adenosine bolus that did not patent atrial flutter and our transesophageal EP study did not induce supraventricular arrhythmia like atrial flutter.

Loss of function mutations in depolarizing channels may present as rapid monomorphic VT, VF, or syncope in infants having an intraventricular conduction delay [1]. Kanter et al. [1] sustained the hypotesys that infants having ventricular arrhythmias and intraventricular conduction delay while in sinus rhythm may have a loss-of-function depolarizing channel mutation, particularly in the normal structural and functional heart. They consider these clinical phenotype to be Brugada-like, because there are differences from classical adult Brugada syndrome (BrS) and from many reports of childhood BrS.

The first gene to be linked to the Brugada syndrome is SCN5A, the gene encoding for the α-subunit of the voltage-gated cardiac sodium channel (Nav1.5) [11]. To date, nearly a quarter of BrS patients were found to be SCN5A variants carriers and more than 300 SCN5A variants were BrS-related mutations including missense variants, non-sense variants, nucleotide insertion/deletions, and splice site variants. BrS-related SCN5A variants are usually loss-of-function variants and mainly located in the region between DI and DII, intracellular connection between DIII and DIV region, P ring and D-terminal of DIII region including SCN5A polymorphism [11–13].

The p.G1740E variant is to be considered likely pathogenetic according to ACMG Variant classification (class 4). No functional in vitro studies are reported, and the variant is not described in the scientific literature as a mutation. Several in silico computational algorithms (SIFT, PolyPhen-2, Align-GVGD) support a deleterious effect of the variant on the gene or on the gene product (conserved regions, evolutionary line, impact on splicing). The p.G1740E variant is located in the DIV-S5/S6 domain believed to be critical for the function of the SCN5A protein and where other pathogenic or possibly pathogenic variants have been reported. In particular, a variant is known (p.G1740R) which affects the same amino acid residue reported in association with Brugada Syndrome [13–15].

Above ECG signs during tachycardia, not inducibility of SVT at EPS and its onset during fever, genetic results about SCN5A mutation led us to hypothesize a diagnosis of VT.

In recent years some authors have identified a subgroup of children presenting with rapid VT also showing intraventricular conduction delay at the baseline ECG [16]. In such a group of patient genetic testing commonly identify mutations of the SCN5A or CACNB2 gene encoding for the cardiac sodium and calcium channel, respectively. We did a “Brugada like” diagnosis.

In conclusion we add one more case of very rare syndrome in children called phenotype “Brugada like”.

As SCN5A is the main gene related to Brugada Syndrome, we support the hypotesis that the above clinical scenario of fever, ventricular tachycardia and conduction disorder at baseline ECG, could be related to cardiac sodium-channel dysfunction due to a “Brugada like” phenotype associated to SCN5A G1740E variant.

This case report confirm that genetic testing is mandatory in infants with baseline conduction disorder and associated wide QRS tachycardia. Although their intermediate-term follow-up is mostly favourable, additional life-threatening arrhythmias may occur. Follow-up outpatient appointments include clinical evaluation 24 h ECG monitoring once a month. Moreover, we suggest aggressively treat fevers with ibuprofen and acetaminophen. We describe a first case of a broad complex tachycardia diagnosed as a monomorphic VT during fever in a child with SCN5A mutation with a long term follow up without medical therapy.

Authorship: The authors confirm contribution to the paper as follows: study conception and design: E. Caruso, A. Di Pino; data collection: S. Farruggio; analysis and interpretation of results: Paolo Guccione, Mohammadrafie Khorgami; draft manuscript preparation: E. Caruso. All authors reviewed the results and approved the final version of the manuscript.

Funding Statement: The authors received no specific funding for this study.

Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.