in 1992 , brugada syndrome ( bs ) was first described as a new clinical entity characterized by a typical electrocardiogram ( ecg ) pattern { right bundle branch block ( rbbb ) and persistent st - segment elevation in right precordial leads } and sudden cardiac death.1)2 ) after the first formal description in the medical literature , this clinical entity has been increasingly diagnosed.2 - 4 ) in patients with bs , sudden onset of ventricular tachycardia may develop ; when this arrhythmia persists , it can degenerate into ventricular fibrillation , resulting in sudden cardiac death .
bs is known as a disease that is inherited via an autosomal dominant mode of transmission with varying penetration.2)5 ) although this syndrome is commonly known to manifest in adulthood , usually in the fifth decade , some pediatric cases have been reported , including one of a 2 day - old infant.6 ) to the best of our knowledge , there have been no reports on bs in korean children .
a one - month - old male infant presented to the outpatient - department ( opd ) for systolic murmur .
the patient visited opd regularly , and no remarkable symptoms were found . because the vsd was of moderate size without significant hemodynamic compromise ,
when he was 4 months old , ecg revealed significant qrs widening in right precordial leads , with saddle back st elevation in the v3 lead ( fig .
the pattern of ecg changed progressively until 6 months of age , when definitive st elevation with t wave inversion of brugada type 1 pattern was observed ( fig .
1c ) . at 24-hour holter monitoring , rare , premature ventricular contractions ( < 1% )
however , ecg taken during the 2 mg / kg flecainide challenge test revealed a type 1 brugada pattern in both father and mother ( fig .
deoxyribonucleic acid ( dna ) sequencing analysis of the cardiac sodium channel ( scn5a ) revealed a g to t base substitution at nucleotide position 4035 on exon 23 that led to replacement of tryptophan by cysteine at codon 1345 ( c.4035g > t , p.w1345c , heterozygote ) in domain iii of the sodium channel ( fig .
study of the patient 's father revealed no mutation , but the same novel mutation as that of the patient was found in a study of the mother ( fig .
this child with manifest brugada type ecg with scn5a mutation is asymptomatic at this point ; thus , he is being closely monitored without treatment . a 12-year - old boy and his 10-year - old sister
their father had died of sudden cardiac arrest after some alcohol intake at the age of 44 years .
cardiac arrest was suspected to be due to ventricular tachycardia associated with bs by the attending physician .
the brother and sister had no medical history or symptoms , such as chest discomfort , syncope , or palpitation .
on arrhythmia drug test with flecainide , the boy showed typical coved type st elevation in the precordial leads v1 to v3 ( after 13 doses of flecainide 8 mg , 2.7 mg / kg ) ( fig .
4a ) , and the girl also revealed typical coved type st elevation in the precordial leads v1 to v3 ( after 10 doses of flecainide 10 mg , 1.9 mg / kg ) ( fig .
programmed ventricular stimulation test showed no inducible ventricular tachycardia in either patient . genetic study for scn5a
implantable cardioverter - defibrillators ( icds ) are under consideration if symptoms or signs develop .
a one - month - old male infant presented to the outpatient - department ( opd ) for systolic murmur .
the patient visited opd regularly , and no remarkable symptoms were found . because the vsd was of moderate size without significant hemodynamic compromise ,
when he was 4 months old , ecg revealed significant qrs widening in right precordial leads , with saddle back st elevation in the v3 lead ( fig .
the pattern of ecg changed progressively until 6 months of age , when definitive st elevation with t wave inversion of brugada type 1 pattern was observed ( fig .
1c ) . at 24-hour holter monitoring , rare , premature ventricular contractions ( < 1% )
however , ecg taken during the 2 mg / kg flecainide challenge test revealed a type 1 brugada pattern in both father and mother ( fig .
deoxyribonucleic acid ( dna ) sequencing analysis of the cardiac sodium channel ( scn5a ) revealed a g to t base substitution at nucleotide position 4035 on exon 23 that led to replacement of tryptophan by cysteine at codon 1345 ( c.4035g > t , p.w1345c , heterozygote ) in domain iii of the sodium channel ( fig .
study of the patient 's father revealed no mutation , but the same novel mutation as that of the patient was found in a study of the mother ( fig .
this child with manifest brugada type ecg with scn5a mutation is asymptomatic at this point ; thus , he is being closely monitored without treatment .
a 12-year - old boy and his 10-year - old sister were referred to the pediatric cardiology opd for familial history of sudden death .
their father had died of sudden cardiac arrest after some alcohol intake at the age of 44 years .
cardiac arrest was suspected to be due to ventricular tachycardia associated with bs by the attending physician .
the brother and sister had no medical history or symptoms , such as chest discomfort , syncope , or palpitation .
on arrhythmia drug test with flecainide , the boy showed typical coved type st elevation in the precordial leads v1 to v3 ( after 13 doses of flecainide 8 mg , 2.7 mg / kg ) ( fig .
4a ) , and the girl also revealed typical coved type st elevation in the precordial leads v1 to v3 ( after 10 doses of flecainide 10 mg , 1.9 mg / kg ) ( fig .
4b ) . programmed ventricular stimulation test showed no inducible ventricular tachycardia in either patient . genetic study for scn5a
implantable cardioverter - defibrillators ( icds ) are under consideration if symptoms or signs develop .
bs is a disease of adulthood , typically resulting in sudden death during the forties6)7 ) ; however , some cases have reported on childhood bs in patients as young as a few days old . since it was first
formally reported in 1992 , numerous studies and reports on the clinical characteristics or the genetic and molecular aspects of the disease have appeared.2)8)9 ) now bs is regarded as responsible for 4% to 20% of all sudden death , and up to 20% of sudden death without structural heart disease.6)9 ) characteristic ecg patterns were identified soon after the first report : 1 ) type-1 ecg pattern was described in the initial report , where a coved st - segment elevation greater than or equal to 2 mm is followed by a negative t wave in more than 1 right precordial lead ( v1-v3 ) ; 2 ) type-2 ecg pattern is characterized by an st - segment elevation , followed by a positive or biphasic t wave that together compose a saddle - back morphology ; 3 ) type-3 ecg pattern is characterized by a right precordial st - segment elevation less than or equal to 1 mm with either a coved - type or a saddle - back morphology.2)10 ) although all of these 3 ecg patterns can be identified in patients with bs , only the type-1 ecg pattern now defines diagnosis of the syndrome.6)10 ) the proband of the first family in this report showed dramatic progression of the brugada type ecg pattern from simple rbbb to type 1 pattern during the first half of the boy 's infancy ( fig .
1 ) . because the patient in case 1 had vsd and septal aneurysm , the initial rbbb change on ecg
could possibly be associated with the malformation itself . however , as demonstrated in fig .
1 , ecg progression to typical coved type st segment elevation in v1-v3 , which is the characteristic feature of bs , could have led to the diagnosis of bs .
bs can be diagnosed when a type-1 ecg pattern is observed in more than 1 right precordial lead ( v1-v3 ) , with or without a sodium channel blocker agent , and in concurrence with one of the following : documented ventricular fibrillation , polymorphic ventricular tachycardia , inducibility of ventricular arrhythmias with programmed electrical stimulation , family history of sudden death before the age of 45 years , presence of coved - type ecg in family members , syncope , and nocturnal agonal aspiration.2)6)10 ) although some sporadic cases of bs have been reported , it is now understood as an inherited disease , in which a familial occurrence was noted in approximately half of patients.2)4 ) the first description of a related mutation appeared in 1998 and identified the mutation in scn5a , the gene encoding the alpha subunit of the cardiac sodium channel.11)12 ) to date , 100 or more other mutations found in scn5a have been associated with this syndrome , and a second locus was found on chromosome 3p22 - 25 without identification of the causative gene.2)13 ) however , only 20 - 25% of bs shows mutations in scn5a .
our first proband with infantile manifestation had a novel mutation ( c.4035g > t , p.w1345c , heterozygote ) equal to that of the mother . however , the mother was asymptomatic , and brugada type ecg was uncovered only by flecainide injection .
however , there may be another explanation for the spontaneous change of ecg in case 1 during infancy .
this case may have another undefined predisposition because the father of the child showed equivocal type 1 brugada pattern st elevation by flecainide , despite having no documented scn5a mutation . as the scn5a mutation was not found in up to 70% of bs cases
, we can speculate that the father of the patient may have an undefined or unknown mutation causing bs or a genetic polymorphism with predisposal to bs type st change under certain provocations . on the other hand
, we still can not exclude the possibility of a false positive result for the father on the flecainide provocation test , as the specificity of the provocation test has been reported to be 80% in adults , leaving a 20% false positive rate .
however , it should be noted that racial differences could be reflected in the specificity of the provocation test . as a study targeting both adults and children in the korean population has not yet been reported , further study targeting the korean population may help to explain the discrepancy between results from genetic analysis and the provocation test .
current opinions do not support the role of genetic analysis in estimation of risk for bs5 ) ; however , it may be helpful in detection of asymptomatic carriers of the mutation , who may then be provided with clinical monitoring .
scn5a mutations resulted primarily in the production of either a non - conducting sodium channel or accelerated recovery of the sodium channel .
the functional effect of the mutations in transmembrane domain iii , w1345c , has not yet been documented .
several factors have been known to trigger typical brugada - pattern ecg and polymorphic ventricular tachycardia in susceptible individuals .
these factors include autonomic imbalance , electrolyte imbalance , fever , myocardial ischemia , and drugs , including antiarrhythmic agents , psychotropic drugs , alpha adrenergic agonists , potassium channel opening drugs , and first generation antihistamines.5)6 ) the only proven treatment option for bs is an icd.14 ) within the current guidelines , implantation of icd is indicated for patients with bs and aborted cardiac arrest who receive optimal long - term treatment and whose life expectancy in good general condition exceeds one year.5)15 ) in the first report of bs , 3 of the 8 patients were children1 ) ; however , little information on this syndrome during childhood has been available .
it can manifest during childhood , and symptoms may appear during febrile episodes.16 ) symptomatic childhood patients , particularly those presenting with a spontaneous type-1 ecg , may be at a high risk for cardiac events during a relatively short period of follow - up.2 ) the first description of bs in children appeared in the literature in 2000.7)17 ) since that time , many cases of pediatric bs have been reported .
in three japanese studies describing the prevalence and clinical course of childhood bs,7)18 - 20 ) typical ecg patterns of bs were found less frequently than in adult studies ; however , this prevalence increased with age .
the nature of bs is known to be dynamic , and this variability is more prominent in children.20 ) to the best of our knowledge , there have been no reports on bs in korean children .
we reported on childhood bs in two families ; one family had a novel scn5a mutation .
physicians should be aware of this potentially lethal disease , which may manifest even in infancy , resulting in sudden infant death syndrome.4)17 )
 since the first descriptions of brugada as a new clinical entity defined by sudden cardiac death in patients with typical electrocardiogram ( ecg ) patterns , brugada syndrome ( bs ) has been increasingly diagnosed . 
 this syndrome is known as a disease that is inherited via an autosomal dominant trait , and the scn5a mutation has been found in 20 - 25% of bs patients . because bs primarily manifests in adulthood , little information is available on bs during childhood . 
 although there have been several reports on adult bs in korea , pediatric bs has not been reported 
 . herein , we report on childhood bs in two families . 
 one infantile bs patient and his family had a novel scn5a mutation ( c.4035g > t , p.w1345c , heterozygote ) in domain iii of the sodium channel . 