7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Congenital long QT syndrome: Epidemiology and clinical manifestations : Peter J Schwartz, MD, Michael J Ackerman, MD, PhD : John K Triedman, MD, Samuel Asirvatham, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Mar 20, 2023. INTRODUCTION Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death (SCD) [1,2]. The primary symptoms in patients with LQTS include arrhythmic syncope, arrhythmic syncope followed by generalized seizures, and sudden cardiac arrest (SCA). These LQTS-triggered symptoms stem from a characteristic life-threatening cardiac arrhythmia known as torsades de pointes or "twisting of the points" ( waveform 2A-B) [3,4]. LQTS may be congenital or acquired [1,5]. Likely pathogenic or pathogenic variants in at least 17 genes have been identified thus far in patients with congenital LQTS ( table 1) [5]. However, pathogenic variants in the three canonical genes, KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3), account for approximately 80 to 90 percent of all congenital LQTS cases, with pathogenic variants in the minor LQTS-susceptibility genes contributing approximately 5 percent. An estimated 10 percent of patients satisfying a robust clinical diagnosis of LQTS will have a negative LQTS genetic test. Acquired LQTS usually results from undesired QT prolongation and potential for QT-triggered arrhythmias by either QT-prolonging disease states, QT-prolonging medications ( www.crediblemeds.org), or QT-prolonging electrolyte disturbances ( table 2) [6]. (See "Congenital long QT syndrome: Pathophysiology and genetics".) https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 1/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate While disease-causative variants in numerous genes have been identified in patients with congenital LQTS, two clinical phenotypes have been described that differ in the type of inheritance and the presence or absence of sensorineural hearing loss: The more common autosomal dominant form, originally named the Romano-Ward syndrome, has a purely cardiac phenotype of QT prolongation and QT-triggered cardiac events. (See "Congenital long QT syndrome: Pathophysiology and genetics".) The autosomal recessive form, originally named the Jervell and Lange-Nielsen syndrome, is associated with LQTS and sensorineural deafness, and a more malignant clinical course [7]. (See 'Congenital sensorineural deafness' below.) The epidemiology, clinical features, and conditions that are associated with congenital LQTS will be reviewed here. The diagnosis and management of congenital LQTS in children and adults and the clinical features of acquired LQTS are discussed separately. (See "Congenital long QT syndrome: Diagnosis" and "Congenital long QT syndrome: Treatment" and "Acquired long QT syndrome: Definitions, pathophysiology, and causes" and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".) EPIDEMIOLOGY In contrast with other channelopathies that are less common, the prevalence of congenital LQTS is at least 1 in 2000 live births. This prevalence, derived from a prospective study in over 44,000 infants with the combination of ECG and genetic testing, refers to the infants who have an LQTS- causing genetic variant plus manifest a prolonged QT interval [8]. The prevalence of LQTS including genotype positive/phenotype negative individuals is obviously higher, but difficult to quantify, and is probably close to 1 in 1000 persons overall. The frequency of LQTS-causative variants may be much greater since some pathogenic variants result in only subtle clinical abnormalities and do not come to medical attention. Penetrance is variable and can be as low as 10 to 25 percent [9]. (See "Congenital long QT syndrome: Pathophysiology and genetics".) LQTS is highly penetrant early in life among patients with the Jervell and Lange-Nielsen syndrome, multiple LQTS-causative variants but without deafness, and in the much rarer infantile/toddler forms of malignant LQTS stemming from autosomal dominant or sporadic variants in the CALM-encoded calmodulin proteins (ie, the Calmodulinopathies) [10] and homozygous/compound heterozygous mutations in TRDN-encoded triadin (ie, the Triadin Knockout Syndrome) [11]. (See 'Congenital sensorineural deafness' below.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 2/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate CLINICAL MANIFESTATIONS The clinical manifestations of congenital LQTS are highly variable. The majority of individuals with LQTS are asymptomatic at diagnosis and remain so their entire life. Symptomatic patients present most commonly with LQTS-triggered syncope or syncope followed by generalized seizures. In fact, many patients with LQTS continue to be misdiagnosed as having epilepsy and treated incorrectly with anti-epileptic medications. Uncommonly, the sentinel event can be SCD [1]. Patients without symptoms typically come to medical attention because they have an affected family member and either their surveillance ECG and/or their family-specific genetic variant test has identified them as having LQTS (either phenotypically or genotypically). In addition, asymptomatic individuals with LQTS are being discovered increasingly by a prolonged QTc (QT interval corrected for heart rate) that was detected by an ECG obtained for some other reason including pre-sports participation screening tests. The clinical manifestations of LQTS have been described in several large cohorts, with the following three being the most prominent [12,13]: The largest cohort of patients with LQTS, from the International Long QT Syndrome Registry, included 3343 individuals (all with QTc >440 milliseconds) from 328 families [13]. The proband (or index case) was considered the first affected family member who was identified independently of relatives. A cohort of 287 patients younger than 21 years of age from the registry of the Pediatric Electrophysiology Society included patients who met one of the following criteria [12]: QTc >440 milliseconds OR Both a family history of LQTS and one of the following: unexplained syncope, seizures, or cardiac arrest preceded by exercise or emotion The largest single-center cohort of patients with LQTS in the United States comprising 606 patients with LQTS of which 27 percent experienced at least one LQTS-triggered cardiac event [14]. Patient characteristics Age at diagnosis Patients with congenital LQTS generally come to medical attention within the first three decades of life, although the exact time of presentation is highly variable depending on the severity of symptoms and associated QTc prolongation. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 3/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Among the previously symptomatic patients seen at Mayo Clinic s LQTS clinic, the average age at first symptom was 12 years [14]. Among patients from the Pediatric Electrophysiology Society registry (which only included patients younger than 21 years of age), the mean age at presentation was 6.8 years [12]. Notably, 20 percent presented at less than one month of age, and 36 percent presented between the ages of 9 and 15 years. Among patients from the International Long QT Syndrome Registry, probands were diagnosed at an average age of 21 years, significantly later in life than the average patient from the Pediatric Electrophysiology Society cohort [13]. Affected family members were identified at an average age of 34 years. Frequency of symptoms By definition, most probands (ie, index cases) diagnosed with congenital LQTS will be symptomatic at presentation. However, in populations where ECG screening is performed frequently (eg, competitive athletes and school-based screening programs), a good number of index cases are identified while asymptomatic. Subsequently, the majority of affected family members (usually identified by screening following the proband diagnosis) will be asymptomatic at the time of diagnosis. Among the 606 patients (probands and affected family members combined) from the Mayo Clinic LQTS clinic, 166 patients (27 percent) were symptomatic, with the sentinel event being syncope/seizures in 80 percent, fetal arrhythmia in 12 percent, and cardiac arrest in 8 percent [14]. Among patients from the Pediatric Electrophysiology Society registry, 175 patients (61 percent) were symptomatic at presentation [12]. The presenting symptoms were syncope, seizures, and cardiac arrest in 26, 10, and 9 percent of patients, respectively. Other symptoms included presyncope and palpitations. Among patients from the International Long QT Syndrome Registry, 80 percent of probands were symptomatic with syncope or cardiac arrest at the time of diagnosis [13]. Among the 647 patients with a confirmed mutation causing LQT1, LQT2, or LQT3, there were 87 SCDs (13 percent) prior to initiation of therapy [15]. Influence of puberty, pregnancy and menopause In females with LQTS, cardiac events are most prevalent during puberty compared with other life stages [16]. This was shown in the Rochester registry of 767 females with LQTS; the adjusted yearly cardiac event rate was 8 events per 100 patient years versus 2, 4, and 2 in childhood, young adulthood, and menopause, respectively. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 4/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Pregnancy is accompanied by a variety of changes that can provoke new, or exacerbate previously occurring, arrhythmias. Although there is no increased risk of LQTS-triggered arrhythmias, there is a higher risk of cardiac events in the first six to nine months postpartum in patients with LQTS, particularly for women with LQT2. The effect of pregnancy in patients with congenital LQTS and the possible influence of genotype is discussed separately. Beta blockers are protective [17]. (See "Ventricular arrhythmias during pregnancy", section on 'Long QT syndrome'.) An increased risk of recurrent syncope has also been observed after the onset of menopause among women with LQT2 (hazard ratio [HR] 3.38 during the transition to menopause and 8.10 during the postmenopausal period) [18]. By contrast, the onset of menopause was associated with a reduction in risk of recurrent syncope among women with LQT1 (HR 0.19). Symptoms Patients with LQTS-triggered arrhythmias may present with one or more of the following: Arrhythmic syncope Arrhythmic syncope followed by generalized seizures SCA SCD Patients may present with syncope or SCA if the arrhythmia is sustained or results in hemodynamic collapse, with SCD occurring as the initial manifestation in approximately 13 percent of index cases [15]. A screening ECG should be performed in all patients following a first afebrile, generalized seizure (especially if the "seizure" occurred during exertion or emotional excitement/distress) or unexplained syncope. Even if the syncopal episode has been deemed consistent with neurocardiogenic (vasovagal) syncope, an ECG is still reasonable. However, importantly, the QTc can be prolonged transiently if the ECG was obtained in near proximity to the vasovagal episode and patients have been overdiagnosed with LQTS because of this timing issue [19]. Those with borderline or prolonged QT intervals should be referred to a cardiologist for further evaluation. (See "Congenital long QT syndrome: Diagnosis".) Patients with LQTS who present with arrhythmic syncope or syncope of uncertain origin (and which is not clearly vasovagal in nature) and/or an apparent seizure due to an arrhythmia typically have polymorphic ventricular tachycardia (VT). Syncopal episodes associated with ventricular arrhythmias due to LQTS may have tonic-clonic movements and may be misdiagnosed as a primary seizure disorder, often with tragic consequences [13,20-22]. Distinguishing between a primary seizure disorder and generalized seizures secondary to LQTS may be challenging, and the entities may overlap. In addition, patients with epilepsy and a https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 5/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate recent seizure (within the preceding two years) as well as patients who are taking anti-epileptic medications with sodium channel blocker properties (eg, phenytoin, carbamazepine, gabapentin, etc) appear to have an increased risk of SCD [23]. As an example of the challenge in establishing the correct diagnosis in patients who present with apparent seizures, one report details eight patients who were treated for a seizure disorder for up to five years until arrhythmia was identified as the underlying cause [21]. Of the five patients who had LQTS, QT prolongation on baseline ECG was significant in only one patient and borderline in two other patients, with the diagnosis being established in four patients by the appearance of exercise-induced polymorphic VT with Holter monitoring. Minor abnormalities detected on electroencephalography may have contributed to the delay of the diagnosis of LQTS in four patients. Types of arrhythmias The majority of arrhythmias in patients with congenital LQTS are ventricular tachyarrhythmias, although bradycardia, atrioventricular (AV) block, and atrial arrhythmias are present in a small minority of patients. The range of arrhythmias that can occur in LQTS was illustrated in the Pediatric Electrophysiology Society registry of 287 children, 61 percent of whom were symptomatic at presentation [12]. Ventricular arrhythmias were present in 16 percent, with polymorphic VT (also called torsades de pointes) being most common (6 percent at rest and 9 percent during an exercise test), followed by multiform ventricular premature beats (5 percent), uniform ventricular premature beats (4 percent), and monomorphic VT (1 percent). In addition, bradycardia was present in 20 percent and AV block in 5 percent. Polymorphic VT/torsades de pointes The classic arrhythmia associated with congenital LQTS is a form of polymorphic VT called torsades de pointes. Torsades de pointes is a common presentation in patients with congenital LQTS, as noted among probands from the International Registry, of whom 80 percent presented with syncope or resuscitated cardiac arrest [13]. In fact, if a patient with LQTS is having a true LQTS-attributable symptom it is because they developed torsades de pointes. Polymorphic VT is defined as a ventricular rhythm faster than 100 beats per minute with frequent variations of the QRS axis, morphology, or both [4,24]. In the specific case of torsades de pointes, these variations take the form of a progressive, sinusoidal, cyclic alteration of the QRS axis ( waveform 2A-B). The peaks of the QRS complexes appear to "twist" around the isoelectric line of the recording, hence the name "torsades de pointes" or "twisting of the points." https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 6/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Typical features of torsades de pointes include a markedly prolonged QT interval in the last sinus beat preceding the onset of the arrhythmia, a ventricular rate of 160 to 250 beats per minute, irregular RR intervals, and a cycling of the QRS axis through 180 degrees every 5 to 20 beats [4,24]. Notably, macroscopic T wave alternans (TWA), when identified, is a marker of high cardiac electrical instability and is considered an important warning for imminent torsades de pointes. However, macroscopic TWA is an insensitive risk factor as most patients with symptomatic LQTS have not exhibited TWA on their annual ECGs, stress tests, or Holters. Torsades de pointes episodes usually are short-lived and terminate spontaneously. However, patients may experience multiple episodes of the arrhythmia, and episodes can recur in rapid succession and may induce syncope or progress to ventricular fibrillation ( waveform 3) [4,24]. AV block When AV block is present in patients with congenital LQTS, particularly among neonates, there is a significant increase in the likelihood of cardiac arrhythmias and an associated poor prognosis [25]. While AV block has been noted in 5 percent of patients in the Pediatric Electrophysiology Society cohort, high-grade AV block necessitating permanent pacemaker placement is rare [12]. One mechanism of 2:1 AV block is prolonged ventricular refractoriness, which inhibits alternate depolarizations. True AV conduction abnormalities account for the remaining cases. Bradycardia While sinus bradycardia itself is generally not considered an arrhythmia, the presence of bradycardia (a resting heart rate less than 60 beats per minute) is a common finding in patients with LQTS, occurring in 20 percent of patients in the Pediatric Electrophysiology Society registry and in 31 percent of probands from the International Long QT Syndrome Registry [12,13]. Bradycardia appears to be more common in children during the first three years of life [26]. Bradycardia has also been reported in fetuses and neonates with LQTS [27-29]. Patients with fetal bradycardia (fetal heart rate 110 beats per minute or third percentile or lower for gestational age) should be evaluated for LQTS in the neonatal period with an ECG. (See "Congenital long QT syndrome: Diagnosis".) Atrial arrhythmias Atrial arrhythmias (eg, atrial fibrillation, supraventricular tachycardia, etc) are uncommon in patients with congenital LQTS but appear at a significantly higher frequency than in patients in the general population without LQTS [30,31]. Triggers of arrhythmia Arrhythmias in patients with congenital LQTS are triggered frequently by external events (eg, noise, exercise, stress, etc) and are often pause-dependent (the beat triggering torsades de pointes is preceded by an ectopic beat and a subsequent https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 7/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate pause). In addition, factors that contribute to the development of acquired LQTS, such as medications known to prolong the QT interval and electrolyte disturbances, can provoke arrhythmias in patients with congenital LQTS that is "mild" or previously unknown to the patient. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Pause dependence The duration of repolarization, which is defined by the duration of the T wave and the QRS interval, varies in relation to the preceding RR interval. At higher heart rates, with shorter RR intervals, repolarization accelerates and the QT interval shortens. The opposite occurs during slower heart rates with longer RR intervals. (See "Congenital long QT syndrome: Diagnosis", section on '12-lead ECG'.) Pause dependence refers to the phenomenon in which torsades de pointes is initiated by a "long-short" or "short-long-short" sequence ( waveform 2B). This beat-to-beat variation is usually caused by ectopic beats, which can be either ventricular or supraventricular in origin. Following an ectopic beat, there is a slight pause in which the RR interval lengthens for one beat (the "long" RR in the sequence). This pause causes the following QT interval to prolong. If, during this lengthened QT interval, a second ectopic beat occurs early (a "short" RR interval), during the vulnerable period of repolarization (so-called R-on-T phenomenon), torsades de pointes can develop. Pause-dependent torsades de pointes is common among patients with LQT2 but rare in patients with LQT1 [32]. In a series of 50 patients with congenital LQTS who had the onset of torsades de pointes captured on an ECG, a pause preceded the onset of torsades de pointes in 68 percent of patients with LQT2, compared with none of the patients with LQT1. Other genotypes were not adequately represented in this series to assess the frequency of pause-dependent torsades de pointes. (See 'Influence of genotype on triggers' below.) External triggers Ventricular arrhythmia in patients with congenital LQTS, most often the torsades de pointes type of polymorphic VT, is often initiated by an external trigger, most commonly exercise, particularly swimming and diving, and particularly in patients with LQT1 [12,13,33,34]. In addition to exercise, most of the other common triggers are associated with acute arousal (eg, noise, emotion, sudden wakening from sleep by an alarm clock, telephone, thunder, etc), particularly in LQT2. In addition, the postpartum period represents a transient six- month window of increased risk for LQTS-triggered events for women with LQTS, predominantly LQT2 [35,36]. Emotional stress or physical exertion preceding syncope or seizure is highly suggestive of LQTS- associated arrhythmia [21,37]. Among 175 symptomatic patients in the Pediatric Electrophysiology Society study, symptoms were related to exercise in 67 percent, exercise and https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 8/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate emotion in 18 percent, emotion alone in 7 percent, loud noise and exercise in 3 percent, and anesthesia in 2 percent [12]. Influence of genotype on triggers While numerous genotypes have been described, the great majority of cases of LQTS are accounted for by three genotypes: LQT1 (35 percent), LQT2 (25 to 35 percent), and LQT3 (5 to 10 percent) ( table 1) [33,38]. (See "Congenital long QT syndrome: Pathophysiology and genetics".) There is an association between the triggers that initiate arrhythmic events and the specific genotype of LQTS ( figure 1) [33,39]: Exercise Arrhythmic events in patients with LQT1 are most often related to exercise. In a review of 371 patients with LQT1, exercise accounted for 62 percent of events [33]. The sensitivity of patients with LQT1 to exercise may be related to exaggerated prolongation of the QT interval during exercise [40]. Events related to swimming (occurring either immediately after diving into water or during recreational or competitive swimming activities) may be specific for LQT1 [33,41,42]. However, swimming-related events may also occur with other disorders such as catecholaminergic polymorphic VT [43]. (See "Congenital long QT syndrome: Pathophysiology and genetics" and "Catecholaminergic polymorphic ventricular tachycardia".) Acute arousal Acute arousal events (such as exercise, emotion, or noise) are much more likely triggers in LQT1 and LQT2 than in LQT3 [33,44]. Events triggered by auditory stimuli, such as an alarm clock or telephone ringing, are most typically seen in LQT2 [33,34,41]. Rest/sleep Patients with LQT2 and LQT3 are at highest risk of events when at rest or asleep (68 percent of events), compared with LQT1 in which only 3 percent of events occurred at rest or when asleep [33]. Postpartum period Women with LQTS are at increased risk of LQTS-triggered events in the six to nine months postpartum compared with the 40 weeks of pregnancy and the 40 weeks prior to conception, and this risk is seen almost exclusively in women with LQT2 [35,36]. Medications and electrolyte abnormalities Causes of acquired LQTS, such as certain medications, certain non-cardiac disease states, and certain electrolyte disturbances such as hypokalemia and hypomagnesemia ( table 2), can also precipitate ventricular arrhythmia in patients with congenital LQTS. Patients with phenotypically manifest LQTS may certainly have an increased risk of cardiac events when electrolyte disturbances are present or medications known to lengthen the QT interval are prescribed. In addition, due to incomplete penetrance in many https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 9/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate patients, those without prior phenotypic manifestations of LQTS may develop ventricular arrhythmias only after such an added trigger, the so-called "second hit" hypothesis [45]. There are also an increasing number of reports of "forme fruste" (ie, incompletely manifest) mutations or polymorphisms in LQTS genes in patients with no family history and apparent drug-induced LQTS. The largest study in patients with drug-induced LQTS has shown that 28 percent of 188 patients were carriers of LQTS-causing mutations [46]. As such, when a seemingly sentinel event of drug-induced QT prolongation with or without torsades de pointes is documented, it is important to inquire about past symptoms of potential concern and about their family history. If concerns are raised or if the QTc does not fully normalize after discontinuation of the offending medication, the possibility of congenital LQTS should be evaluated further. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) ASSOCIATED CONDITIONS A number of specific clinical conditions in children are associated with LQTS. These warrant ECG screening and, occasionally, further evaluation for LQTS. Although the majority of LQTS cases occur without associated noncardiac syndromic features, recognition of these non-cardiac features may allow presymptomatic identification of patients with LQTS-plus, (ie, multi-system LQTS) thereby, prompting early treatment to prevent potentially life-threatening arrhythmias. Congenital sensorineural deafness The Jervell and Lange-Nielsen syndrome refers to the autosomal recessive phenotype of congenital LQTS that is associated with profound sensorineural hearing loss and a higher risk for sudden death when compared with autosomal dominant LQTS. We recommend that a 12-lead ECG be performed to screen for LQTS in all children with congenital sensorineural deafness. However, the statistical comparison of a single screening ECG versus serial ECGs for diagnostic accuracy in Jervell and Lange-Nielsen syndrome has not been assessed. (See "Congenital long QT syndrome: Diagnosis".) The Jervell and Lange-Nielsen syndrome has only been identified in patients with either homozygous or compound heterozygous pathogenic variants in KCNQ1 (LQT1) or KCNE1 (LQT5); these genes encode the alpha and beta subunits of the slowly acting component of the outward- rectifying potassium current (IKs, Kv7.1) that is involved in ventricular repolarization ( table 1) [47-49]. Homozygous mutations in KCNQ1 (exact same mutation), compound heterozygous variants in KCNQ1 (two different mutations on the same gene, one on the paternal allele and a different one on the maternal allele), and compound heterozygous variants involving one KCNQ1 pathogenic variant and one KCNE1 pathogenic variant have been identified, the latter being associated to a lower risk [7]. These mutations also disrupt production of endolymph in the stria https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 10/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate vascularis in the cochlea, resulting in the observed deafness [50]. (See "Hearing loss in children: Etiology", section on 'Sensorineural hearing loss'.) LQTS is highly penetrant early in life among patients with the Jervell and Lange-Nielsen syndrome. In a series of 186 patients with the Jervell and Lange-Nielsen syndrome, the QTc was markedly prolonged (mean 557 milliseconds), and clinical manifestations were present early in life, with event rates of 15, 50, and 90 percent by ages 1, 3, and 18, respectively [7]. Cardiac events occurred in 86 percent of the cohort, with 95 percent of events triggered by emotional or physical stress, and SCD rates exceeded 25 percent. High rates of symptoms and sudden cardiac death persisted in spite of beta-blocker therapy. Referral bias may have contributed to these very high event rates, but the young age at onset of symptoms and the poor response to medical therapy suggest the need to consider aggressive therapy in these patients. (See "Congenital long QT syndrome: Treatment".) Sudden infant death syndrome Approximately 5 to 10 percent of cases of sudden infant death syndrome (SIDS), as well as some cases of unexplained intrauterine fetal death, may be caused by LQTS, although the low incidence of SIDS makes it difficult to establish the exact impact on congenital LQTS as a potential etiology [51-58]. Although not endorsed by professional societies thus far, the UpToDate authors advocate for universal ECG screening of all infants at around two to four weeks of age for the early identification of this highly treatable condition of LQTS. (See "Sudden infant death syndrome: Risk factors and risk reduction strategies".) The frequency with which this might occur has been evaluated in large studies of screening ECGs of newborns and in genetic analyses of series of SIDS cases [51,54,55]. In a prospective cohort study, ECGs were recorded on the third or fourth day after birth in 34,442 newborns who were then followed for one year, during which 34 deaths occurred, 24 of which were classified as SIDS [51]. The QTc was significantly longer in the infants who died from SIDS compared with the survivors and those who died from other causes (435 versus 400 and 393 milliseconds, respectively). In fact, 12 of the 24 SIDS infants (50 percent) had a day 3 or day 4 of life ECG with a th QTc >440 milliseconds which was the 97.5 percentile value among the living infants. The odds ratio for SIDS in infants with a QTc 440 milliseconds was 41.3 (95% CI 17.3-98.4). Andersen-Tawil syndrome Andersen-Tawil syndrome, or hypokalemic periodic paralysis with cardiac arrhythmia, is a rare autosomal dominant disorder characterized by episodes of paralysis, ventricular arrhythmias, and dysmorphic features [59]. Subsequent genetic studies identified disease-causative variants in KCNJ2-encoded Kir2.1 as the root cause for some cases of Andersen-Tawil syndrome which subsequently prompted the designation of KCNJ2-mediated https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 11/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate disease as LQT7. However, ATS1, stemming from such KCNJ2 mutations, is preferred over LQT7 since these patients virtually never exhibit true QT prolongation but instead display QTU prolongation [60]. Patients affected with Andersen-Tawil syndrome usually present in childhood with spontaneous attacks of paralysis, which may be associated with low, normal, or elevated potassium levels. The characteristic skeletal and facial phenotype of Andersen-Tawil syndrome includes short stature, hypertelorism, a broad nose, low-set ears, and a hypoplastic mandible [61]. (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.) Patients with hypokalemic periodic paralysis and other typical phenotypic features are diagnosed with Andersen-Tawil syndrome following a 12-lead ECG that reveals QTU prolongation. Characteristic T-U wave morphologies have also been identified in patients with Andersen-Tawil syndrome ( waveform 4) [62]. The ECG features were initially characterized in a series of 39 patients with genetically confirmed ATS1 and then validated in a series of 147 individuals (57 with ATS1, 61 unaffected family members, and 29 with phenotypic features of Andersen-Tawil syndrome, but negative for ATS1). The following abnormalities were identified by visual inspection: Prolonged terminal T wave downslope Biphasic U waves in limb leads Wide T-U junction, in contrast to bifid T waves in LQT2 Enlarged U waves occurring with a distinct isoelectric segment after the end of the T wave Treatment of Andersen-Tawil syndrome is complicated because of the opposing effects of potassium replacement on the QT interval and on skeletal muscle weakness. Elevation of the serum potassium concentration shortens the QT interval and suppresses ventricular arrhythmias, but it may accentuate skeletal muscle weakness. (See "Hypokalemic periodic paralysis", section on 'Andersen syndrome'.) Timothy syndrome There are rare reports of infants with severe QT prolongation and syndactyly involving both fingers and toes, frequently with associated patent ductus arteriosus and other cardiac abnormalities [63,64]. The constellation of QT prolongation (usually marked), syndactyly, and often developmental delays is called Timothy syndrome. The lack of a family history of LQTS suggested that the disorder resulted from spontaneous de novo variants. Although Timothy syndrome is extremely rare, it may be reasonable to obtain a screening ECG to assess the QT interval in children with complex syndactyly [65,66]. SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 12/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Long QT syndrome (The Basics)") SUMMARY AND RECOMMENDATIONS Background Long QT syndrome (LQTS) is a disorder of ventricular myocardial repolarization characterized by a prolonged QT interval (a prolonged QTc, QT interval corrected for heart rate) on the electrocardiogram (ECG) ( waveform 1) that can lead to symptomatic ventricular arrhythmias and an increased risk of sudden cardiac death. LQTS may be congenital or acquired. (See 'Introduction' above and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Clinical presentations The clinical manifestations of congenital LQTS are highly variable. The majority of patients will never have a symptom, while symptomatic patients (before diagnosis and initiation of effective therapies) can present with arrhythmic syncope with or without generalized seizures, or cardiac arrest. Patients without symptoms typically come to medical attention because they have an affected family member or a prolonged QTc is identified on an ECG obtained for some other reason. (See 'Clinical manifestations' above.) https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 13/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate Arrythmia presentation Patients with LQTS-triggered arrhythmias may present with syncope, seizures, or sudden cardiac arrest. Most times, the arrhythmias are transient or self-terminating. (See 'Symptoms' above.) Polymorphic ventricular tachycardia The classic arrhythmia associated with congenital LQTS is a form of polymorphic ventricular tachycardia (VT) called torsades de pointes. Polymorphic VT is defined as a ventricular rhythm faster than 100 beats per minute with frequent variations of the QRS axis, morphology, or both. In the specific case of torsades de pointes, these variations take the form of a progressive, sinusoidal, cyclic alteration of the QRS axis ( waveform 2A-B). The peaks of the QRS complexes appear to "twist" around the isoelectric line of the recording, hence the name torsades de pointes or "twisting of the points." (See 'Polymorphic VT/torsades de pointes' above.) Triggers of arrythmias Arrhythmias in patients with LQTS are frequently triggered by external events (eg, noise, exercise, stress, etc) and are often pause-dependent (the beat triggering the arrhythmia is preceded by an ectopic beat and a subsequent pause). In addition, factors that contribute to the development of acquired LQTS, such as medications known to prolong the QT interval and electrolyte disturbances, can provoke arrhythmias in patients with congenital LQTS that is "mild" or previously unknown to the patient. (See 'Triggers of arrhythmia' above.) Congenital syndromes The autosomal recessive form of congenital LQTS, the Jervell and Lange-Nielsen syndrome, is associated with sensorineural deafness and a more malignant clinical course. We recommend that a 12-lead ECG be performed to screen for LQTS in all children with congenital, bilateral sensorineural deafness. (See 'Congenital sensorineural deafness' above.) Some cases of sudden infant death syndrome and intrauterine fetal demise may be caused by LQTS. (See 'Sudden infant death syndrome' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Schwartz PJ, Ackerman MJ. The long QT syndrome: a transatlantic clinical approach to diagnosis and therapy. Eur Heart J 2013; 34:3109. 2. Moss AJ. Long QT Syndrome. JAMA 2003; 289:2041. 3. El-Sherif N, Turitto G. Torsade de pointes. Curr Opin Cardiol 2003; 18:6. https://www.uptodate.com/contents/congenital-long-qt-syndrome-epidemiology-and-clinical-manifestations/print 14/31 7/6/23, 11:09 AM Congenital long QT syndrome: Epidemiology and clinical manifestations - UpToDate 4. Passman R, Kadish A. Polymorphic ventricular tachycardia, long Q-T syndrome, and