Primary diagnosis of atrioventricular pseudo-block in a neonate with definitive diagnosis of long QT syndrome: diagnostic considerations and therapeutic approaches

Abstract

Introduction

Long QT syndrome (LQTS) is a potentially lethal medical condition that might never be diagnosed and cause sudden cardiac death. It is mainly caused by mutation in electrolyte transporter genes. Due to the significant difference in the treatment approach of heart block and other rhythm disorders that mimic this condition, it is necessary to discriminate these conditions. The occurrence of pseudo-block in electrocardiography features but without disturbance in the function of the conduction system can mask the definite diagnosis of the real underlying disorder, and this issue leads to the selection of an unfavorable treatment protocol and sometimes the sudden death of the patient.

Case presentation

We described an infant who showed evidence of atrioventricular (AV) block in initial electrocardiography (ECG) on his first day, but in further evaluations, the final diagnosis of LQTS was raised. The patient recovered after performing the treatment protocol, which included Mexiletine and beta-blockers. After the genetic test of the parents and the patient, it was determined that a defective allele of the gene had caused the condition.

Conclusion

Our report shows the importance of timely differentiation between heart block and LQTS in neonates and choosing the correct treatment approach to faster patient recovery and prevent sudden death.

Clinical key message

Primary diagnosis of LQTS in neonates might not be a straightforward process due to resembling AV pseudo-block and can cause misleading diagnosis and treatment. Long QT syndrome has several nonspecific presentations. They might be asymptomatic until adulthood and be diagnosed after sudden cardiac death. Preventive measures such as timely initiation of medications, ICD or PPM implantation, and continuous observation by caregivers are the mainstay of survival and quality of life improvement.

Graphical Abstract

The family tree shows the genes that have caused this condition in the parents and the patient.

Introduction

Long QT syndrome (LQTS) was first known as a potential cause of QT interval prolongation, recurrent syncope, congenital deafness, and sudden cardiac death (SCD) due to mutations of genes that control cardiac repolarization-controlling ion channels in 1957 by Lange-Nielsen [1, 2]. The main genes involved in this condition are known as the big three: KCNQ1, KCNH2, and SCN5A [3]. This condition can result in severe, potentially lethal arrhythmia in the early years of life or being asymptomatic until adulthood [4]. This condition’s prevalence is estimated to be almost 1 in 2000, and LQTS consists of 17 subtypes, with LQT1, LQT2, and LQT3 being the most prevalent ones [2]. Clinical manifestations of congenital LQTS include LQTS-attributable syncope, aborted cardiac arrest, and sudden cardiac death [5].

The clinical diagnosis of different forms of arrhythmias without genetic testing is not always straightforward and needs a meticulous and thorough evaluation of inherited features through genes [6]. Sometimes, even though in the initial manifestations, atrioventricular (AV) block is proposed, in further evaluations, the diagnosis of other rhythmic disorders, especially LQTS, is raised. The term pseudo-AV block is used when the pattern of AV block is presented in ECG without intrinsic AV disorders [7]. It is important to distinguish pseudo-block from LQTS in the neonatal period because a delay in treatment may result in SCD during the neonatal period. After all, a delay in treatment may result in malignant cardiac events and SCD [8]. Here, we describe an infant who, in the initial evaluation, showed evidence of AV block in ECG. Still, in further evaluations, the final diagnosis of LQTS was raised, and he completely recovered with the treatment protocol, including mexiletine and beta-blockers.

Case presentation

Presentation, history, and physical examination

The case presented was a female neonate with a birth weight of 1700gr, preterm 33 weeks with a fraternal twin delivery by cesarean section, and heart rate varied from 70 to 90 beats/min admitted to the neonatal intensive care unit (NICU). The systemic blood pressure of the neonate was 75/35 mmHg. The baby was the result of a consanguineous marriage. The mother received Amikacin and Ampicillin antibiotics during pregnancy due to premature rupture of membrane (PROM) 3 days before delivery. No other complication was reported during the pregnancy. Further physical examination showed no obvious anatomical abnormality. Her twin brother had no abnormality except the low weight caused by premature birth and was stable and under observation in the NICU.

Diagnostic and therapeutic methods

In primary neonatal echocardiography, mild left ventricular and right ventricular enlargement along with mild tricuspid regurgitation (TR) with a left ventricular ejection fraction (LVEF) of 50%, a closed patent ductus arteriosus (PDA), and a small atrial septal defect (ASD) were detected. All blood indices were in the normal range in the initial laboratory assessment. The chest x-ray was also normal without abnormal conditions (Fig. 1). The characteristics of baseline ECG included the RR interval of 640 ms, the PP interval of 320 to 330 ms, and the QRS duration of 60 ms. On the second day after birth, serial ECGs and rhythm monitoring, a 2:1 block was detected. After two days, a wide QRS tachycardia, more compatible with torsades de pointes (Fig. 2), was controlled with Magnesium sulfate (30 mg/kg/IV). In ECG, which was obtained on the 4th day of admission, the QT interval was prolonged significantly (around 600 ms); therefore, propranolol was started for the patient (4 mg/kg, three times per day), along with Mexiletine (2/mg/kg, every 8 h) which was added when no response was observed to the propranolol infusion. After starting medical therapy, the rhythm was seen to be sinus in Holter monitoring; the average heart rate was 97beats/min (ranging from 51 to 134 beats/min) without any evidence of AV block, premature atrial complex (PAC) or premature ventricular contractions (PVC). Still, the QT interval was prolonged (Fig. 3).

Fig. 1

The chest x-ray of the neonate with long QT syndrome

Fig. 2

The electrocardiogram shows the Torsades De Point pattern

Fig. 3

The ECG findings in the first Holter monitoring

Conclusion and follow-up

The patient underwent genetic counseling and molecular evaluation of long QT syndrome (LQTS) diagnostic assessment. Direct sequencing of genes showed the following variants, all of which were consistent with the diagnosis of the LQTS2 syndrome: Heterozygous: rs1137617 (C.1956 T > C. P. TYR652 =), rs199472908, (C. C1426G > A, p.V476I), and rs9333649 (p.G572s.c1714G > A) related to KCNH2 gene. Thus, the definitive diagnosis of LQTS2 syndrome was made for the neonate. Her brother's genetic evaluations showed Heterozygous for KCNH2: p.V476L:c.G1426A. After making sure the diagnosis was LQT2 syndrome in both twins, the Mexiletine infusion was discontinued (Table 1).. Parents screening was also done. Their QT interval was in the normal range, but in her twin sister, QT was prolonged, and the LQTS2 was confirmed after genetic testing in the mother and no abnormality in father One week later, the patient was discharged in an appropriate clinical condition and normal sinus rhythm The medical treatment, including propranolol was started and continued in the both twins. During three years of follow-up, the medical therapy continued with the appropriate dose, and there were no symptoms or signs related to LQTS. The process of diagnosis and management is summarized in Fig. 4.

Table 1 Laboratory molecular genetic testing results of the parents and the patient

Fig. 4

Demonstrates a summarized narration of the diagnostic and therapeutic process

Discussion

Neonatal LQTS, occurring in about one in 5000 neonates, is a genetic-based disorder with an autosomal dominant hereditary transmission pattern [11]. About 12% of affected neonates face sudden death, even as the first manifestation of the disorder happens during the first year of life in 4% of them [12]. There are some challenging issues for correct diagnosis of neonatal LQTS, especially if presented as a pseudo block, including low-quality ECG due to movement, small body size, the normal high rate in the neonate that leads to miscalculation of correct QT interval, P and T wave overlap in pseudo block phenomenon. Early detection of LQTS, which is presented as a pseudo block, especially in neonates, is important because the treatment approach for this rhythmic disorder is completely different from that of congenital heart block. For instance, the use of sodium or potassium channel blockers in the treatment of LQTS has serious interference with heart block and can lead to the sudden death of the patient [13]. In this regard, early diagnosis of LQTS in the context of other real rhythmic disorders as a final and definitive diagnosis can be crucial.

This baby was referred to a tertiary neonatal cardiac heart canter with a primary diagnosis of AV block, a less common finding in neonates with long QT syndrome diagnosis. LQT2 is a genetic condition that affects the heart's electrical system, leading to a prolonged QT interval on an ECG. This prolongation increases the risk of dangerous arrhythmias, such as torsades de pointes, and can lead to fainting, seizures, or SCD [14,15,16]. LQT2 pathophysiology is mainly unknown, but it is mentioned in the literature that it is typically caused by mutations in the gene, which encodes the human ether-à-go-go-related gene (hERG) potassium channel [15,16,17]. The crucial role of the hERG channel in the repolarization phase of the cardiac action potential and in helping the heart's electrical activity to return to its baseline after each heartbeat is proven by some studies [18, 19]. They encode the alpha subunit of the IKr gene mutations, which can lead to this channel dysfunction and the consequent abnormal potassium ion flow, which prolongs the repolarization process and lengthens the QT interval [16, 20]. This malfunction disrupts the normal rhythm of the heart, making individuals with LQT2 susceptible to life-threatening arrhythmia, particularly under conditions of stress or physical exertion [21].

The specific mutations that cause LQT2 can vary, but many lead to either a reduced or completely absent function of the hERG channel, resulting in a slower return to baseline electrical activity. Some mutations also make the potassium channel more prone to "inactivation" or closing at inappropriate times. The severity and clinical presentation of LQT2 can vary, with some individuals showing only mild symptoms while others experience frequent arrhythmias and syncope [21, 22]. Diagnosis typically involves genetic testing to identify mutations and electrocardiography to measure the QT interval [23]. Treatment often involves lifestyle modifications, such as avoiding strenuous exercise and stress, along with medications like beta-blockers and, in some cases, an implanted defibrillator to prevent sudden cardiac arrest. The identification of mutations has significantly advanced the understanding and management of LQT2, allowing for personalized treatment plans and improved patient outcomes.

Based on the ACMG/AMP guidelines, indices such as population data, functional data, segregation data, and computational predictions are used to classify variants as 1) Pathogenic, 2) Likely pathogenic, 3) Uncertain significance (VUS), 4) Likely benign, and 5) Benign [24] (Table 2).

Table 2 Classification of different variants of long QT syndrome based on American College of Medical Genetics and Genomics guidelines

We did not implant a cardiac pacemaker due to low birth weight and high risk of surgical mortality and complications. Starting only medical treatment may be risky in this group, but after beginning with B blocker and mexiletine. The rhythm returned to sinus rhythm after some days. After revealing the diagnosis of the LQTS2, the Mexiletine was discontinued, and for a three-year follow-up, we did not have any malignant rhythmic episodes, drug complications, or AV block ECG pattern.

Usually, LQTS cases that present in the neonatal period with symptoms and signs have a malignant nature and are at high risk for cardiac death. In a study by Horigome et al. on patients diagnosed with LQTS in the perinatal period, ten of 31 neonates had AV block. The AV block was more common in neonates diagnosed with LQTS type 3 (83%), and in the LQTS type 3 group, cardiac events were more lethal compared to type 1 or 2 [25].

One important point to consider is patients with LQTS are highly susceptible to sudden cardiac death (SCD) due to various patients suffering from LQTS-acquired heart disease, which can lead to ventricular fibrillation (VF) [26]. Therefore, their arrhythmic events should not always be attributed to congenital syndromes, and the holistic approach should be selected [26]. Moreover, when diagnosed, preventive measures are necessary to avoid any predisposing condition, such as dehydration, hypokalemia, or treatment with particular medications. Performing ECG in syncope, palpitation, or seizure cases was also necessary. Caregivers must closely observe during vigorous exercise, such as swimming. Placement of an automated external defibrillator in the nursery and at the patient’s house is also important in these cases [27].

In conclusion, we recommend comprehensive evaluation in neonates with a primary diagnosis of congenital AV block, especially for LQTS. Appropriate and on-time treatment will help prevent undesirable malignant events. Also, the management of these neonates with drug therapy without pacemaker implantation may be feasible. The most important part of therapists is distinguishing between false diagnosis of AV block and definite diagnosis of LQTS in neonates, and the present researchers were also successful in this direction. Their approach led to the treatment and recovery of the patient. Similar cases of congenital LQTS have been described in Table 3 to summarize some different presentations and clinical progress of these patients.

Table 3 A literature review of neonatal hereditary long Q-T syndromes cases and their management process