Extreme Sinus Bradycardia in a 36‐Week Neonate Caused by De Novo Short QT Syndrome: A Case Report

We present a case of significant neonatal bradycardia in an otherwise well 36-week-old infant. Our patient maintained clinical stability despite a heart rate of 50–70 beats per minute (bpm) during the first month of life. Written informed consent from the family obtained to publish this report per the journal's patient consent policy. Our patient is the second child to non-consanguineous parents who have no significant medical history. Her morphology scan was unremarkable, noting a structurally normal heart in addition to her negative non-invasive prenatal testing (NIPT). Given the low-risk pregnancy, this was managed at a non-tertiary public hospital via a midwifery programme. Due to telehealth appointments during the COVID-19 pandemic, the foetal heart rate was not auscultated after 20 weeks until 36 weeks, where foetal bradycardia was noted at 80 bpm. Accordingly, an emergency category-one caesarean section was performed. Our patient cried immediately post-delivery, with good tone and no increased work of breathing; however, she had a heart rate ranging between 60 and 100 bpm. Her oxygen saturations were greater than 90% at 5 min of life, her mean arterial pressure was between 35 and 52 mmHg, and her birth weight was 3 kg. Neither compressions nor respiratory support were commenced as she remained in good clinical condition. Our patient had persistent bradycardia and was admitted to the Special Care Nursery (SCN). A blood gas taken at 3 h of life was consistent with a mild compensated respiratory acidosis. A chest X-ray was completed, which revealed mildly increased cardiac size, and an ECG demonstrated sinus bradycardia (Figure 1). The tertiary children's cardiology team was consulted, advising continued monitoring in SCN and arranging a non-urgent outpatient echocardiogram. Throughout her first day of life, our patient triggered multiple clinical reviews for bradycardia with a heart rate ranging between 60 and 90 bpm but continued to maintain her blood pressure (Figures S1 and S2). Later that evening, she required a brief period of Continuous Positive Airway Pressure (CPAP) for mild work of breathing, and intravenous (IV) antibiotics were commenced for the risk of sepsis. Into Day 3 of life, her heart rate consistently dropped to 55 bpm whilst asleep, and when stimulated, increased to a maximum of 70 bpm (Figure S3). There were extreme bradycardia events captured down to 35 bpm (Figure 2). The patient was loaded with caffeine; however, this did not improve the baseline bradycardia or extreme bradycardic episodes. On Day 5 of life, she was electively transferred to a tertiary children's hospital for cardiology review. She did not require any cardiorespiratory support during the transfer. The echocardiogram showed a small patent foramen ovale, a small patent ductus arteriosus and an otherwise structurally normal heart. Serial ECGs revealed the presence of a short QT interval at 336 msec corrected, suggesting a possible channelopathy. The patient was transferred back for ongoing monitoring in our SCN. After 23 days of continuous cardiac monitoring without any improvement in her heart rate, she was discharged home. Her parents were counselled to complete a First Aid course, given the risk of a cardiac event. Our patient had weekly Holter monitors as an outpatient. At week 6 of life, it became clear that her corrected QT (QTc) interval was shortening, from an initial 336 ms to 270 ms. At this time, her parents were recommended to purchase a defibrillator. Her older sibling was screened and had a normal ECG. Clinical genetics returned at 10 weeks of age, confirming a pathogenic variant in KCNQ1 consistent with a diagnosis of Short QT Syndrome (SQTS) type 2 (KCNQ1 c.421G>A). Of note, both her parents were negative for the same variant. At 6 months of age, our patient was trialled on Quinidine due to ongoing bradycardia (Figure S4) with the aim to prolong the QT interval. This was promptly ceased as she developed heart block. Our patient subsequently underwent insertion of a dual-chamber epicardial pacemaker with a background set at 80 bpm. At 7 months of age, she developed atrial fibrillation (AF) that did not respond to direct current (DC) cardioversion. She was treated with atenolol, aspirin, and clopidogrel. Subsequent echocardiograms have revealed progressive dilated and restrictive cardiomyopathy. To date, our patient's family is exploring future cardiac transplant if her cardiomyopathy continues to progress. Despite her persistent bradycardia and deteriorating cardiac function, our patient has thrived during infancy and is developing normally at 2 years of age. Foetal and neonatal bradycardia can indicate significant compromise and pathology requiring immediate intervention. Foetal bradycardia is an obstetric emergency that can lead to urgent delivery, often caesarean section [1]. In our case, the telehealth antenatal appointments were serendipitous in that earlier detection of sustained bradycardia in a face-to-face examination may have led to premature delivery. Our case was challenging in the post-natal period due to extreme bradycardia episodes that would usually trigger resuscitation measures [2]. There were numerous rapid responses and code blues activated during her time in SCN that caused great concern for the staff, patient's family and retrieval service. This case highlights the importance of clinical judgement when using medical guidelines. She remained stable and did not require intervention despite the extreme observation. The ANZCOR guideline ‘The Resuscitation of the Newborn in Special Circumstances—Congenital Heart Disease’ notes neonates with chronic heart block often require an adjusted resuscitation threshold; focusing on tone, oxygenation and respirations rather than heart rate. Further to this, the guidelines encourage use of early ECG monitoring to assess heart rate [2]. Outside the initial resuscitation, sustained neonatal bradycardia requires investigation. Causes of neonatal bradycardia in a term infant can be classified based on the ECG findings of sinus bradycardia or an atrioventricular block. Neonatal sinus bradycardia may be due to raised intracranial pressure, metabolic acidosis, hypotension, hypoxemia or maternal medications [3]. Sinus bradycardia may also be a sign of sinus node dysfunction from congenital heart disease, neonatal lupus, long (LQTS) and SQTS [4]. For our patient, the SQTS diagnosis was confirmed after prolonged observation, repeated ECGs, and genetic testing. A short QTc interval can be defined as less than 340 ms in females and less than 330 ms in males [5]. A QTc below this range should prompt investigation for possible SQTS even in the absence of symptoms [5]. Additional causes of a short QTc interval include normal variant, electrolyte disturbance, iatrogenic, vagal tone and hyperthermia [6]. SQTS should be considered in patients with a QT less than 360 ms if they have had episodes of ventricular arrhythmia in the absence of structural heart disease [7]. SQTS was first recognised as a clinical syndrome in the year 2000, and since then there have only been a few hundred cases reported in the literature worldwide [6]. Establishing the prevalence of SQTS is challenging given the limited number of cases; a current estimate for a short QT interval in a paediatric population is 1 in 2000 [8]. Thus far, no large-scale study has been able to report the rates of confirmed SQTS in a general paediatric population. To the best of our knowledge, our patient is the first with SQTS reported in the literature in Australia. The SQTS channelopathy is a dysfunction in cardiac potassium or calcium ion channels. This causes abnormal repolarisation and a decreased myocardial refractory period that can be identified as a shortened QTc interval on an ECG. This leads to a significantly increased risk of ventricular and atrial arrhythmias [9]. The first indications of SQTS can present similarly to patients with LQTS including young patients with AF, syncopal events or cardiac arrest [5, 9]. The age of diagnosis has been reported from the neonatal period to adulthood. Neonates and infants can present with cardiac arrest or sinus bradycardia [10, 11]. SQTS has been suggested as a potential cause of Sudden Infant Death Syndrome (SIDS) [10, 11]. Genetic testing for SQTS is still evolving and does not always lead to a confirmatory diagnosis, with up to 80% of patients without a known genetic mutation identified [12]. The genes implicated in SQTS are associated with other channelopathies, including LQTS and Brugada syndrome [13]. The inheritance is autosomal dominant with high phenotypical penetrance. Thus far, nine genetic variants have been associated with SQTS [8]. Of these nine, only three conclusively cause SQTS, all gain of function in potassium channels [8]. A fourth variant has moderate association through chloride/bicarbonate channel loss of function [8]. The remaining five mutations affect calcium and sodium channels; however, association to SQTS is unclear [8]. Our patient was found to have de novo SQTS type 2 (KCNQ1), a potassium channel dysfunction, with only a few cases of this mutation documented worldwide [9]. First-line treatment of SQTS in children is often a trial of sotalol or quinidine (preferred) to prolong the QT interval, and symptomatic patients require an implantable cardioverter defibrillator (ICD) [9]. Caution should be used when treating with quinidine as the desired effect of QT prolongation to reduce arrhythmia may inadvertently promote arrhythmia [7]. A new treatment that is currently under investigation is hydroxyquinidine, which appears to be effective, more readily available worldwide, and to have reduced side effect [14]. Our patient has developed progressive cardiomyopathy and, concerningly, may require cardiac transplant. Reviewing the literature, we have not found another case of SQTS that has caused cardiomyopathy requiring childhood transplantation. Prognosis of SQTS is difficult to qualify due to the rarity of the disease, especially in neonates. The risk of cardiac arrest in the first year of life is 4%, and by 40 years of age, sudden cardiac death is almost 40% [12, 15]. There is currently no data to assess the risk of physical activity in triggering arrhythmias in SQTS. Looking forward, SQTS requires research particularly in identifying further genes, risk factors for arrhythmias, and treatment. One novel area of research is currently exploring the role of pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in addressing the patient-specific channelopathy [12]. As further genes are identified and patients are diagnosed at a younger age, there will be more evidence for neonatal and infant management. Written informed consent from the family obtained to publish this report in accordance with the journal's patient consent policy. As this is a de-identified case report, which does not affect patient outcomes, formal ethics are not required. The authors declare no conflicts of interest. Data S1. Data S2. Data S3. Data S4. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.