Identification of rare coding variants associated with Kawasaki disease by whole exome sequencing

Kawasaki disease (KD) is an acute pediatric vasculitis that affects genetically susceptible infants and children. To identify coding variants that influence susceptibility to KD, we conducted whole exome sequencing of 159 patients with KD and 902 controls, and performed a replication study in an independent 586 cases and 732 controls. We identified five rare coding variants in five genes (FCRLA, PTGER4, IL17F, CARD11, and SIGLEC10) associated with KD (odds ratio [OR], 1.18–4.41; p = 0.0027–0.031). We also performed association analysis in 26 KD patients with coronary artery aneurysms (CAAs; diameter > 5 mm) and 124 patients without CAAs (diameter < 3 mm), and identified another five rare coding variants in five genes (FGFR4, IL31RA, FNDC1, MMP8, and FOXN1), which may be associated with CAA (OR, 3.89–37.3; p = 0.0058–0.0261). These results provide insights into new candidate genes and genetic variants potentially involved in the development of KD and CAA.

IgA Levels Are Associated with Coronary Artery Lesions in Kawasaki Disease

Background and Objectives@#Kawasaki disease (KD) is an acute systemic vasculitis that affects the coronary arteries. Abnormal immune reactions are thought to contribute to disease pathogenesis. The effect of immunoglobulin (Ig) isotype (IgG, IgA, IgM, and IgE) on inflammatory data and clinical outcomes of patients with KD was examined. @*Methods@#Ig levels in 241 patients with KD were measured during the acute, subacute, convalescent, and normal phases of the disease. @*Results@#Compared with reference Ig values, IgG, IgA, and IgM levels were significantly higher in the subacute phase, while IgE levels were elevated in 73.9% (178/241) of patients with KD in all clinical phases. However, high IgE levels were not associated with clinical outcomes, including intravenous immunoglobulin unresponsiveness and coronary artery lesions (CALs).Significantly more CALs were observed in the high IgA group than in the normal IgA group (44.7% vs. 20.8%, respectively; p<0.01). In addition, IgA levels in the acute phase (p=0.038) were 2.2-fold higher, and those in the subacute phase were 1.7-fold higher (p <0.001), in the CAL group than in the non-CAL group. IgA concentrations increased along with the size of the coronary artery aneurysm (p <0.001). Furthermore, there was a strong correlation between IgA levels and CAL size (r=0.435, p<0.001), with a high odds ratio of 2.58 (p=0.022). @*Conclusions@#High IgA levels in patients with KD are prognostic for the risk of CALs.

IgA Levels Are Associated with Coronary Artery Lesions in Kawasaki Disease

Background and Objectives@#Kawasaki disease (KD) is an acute systemic vasculitis that affects the coronary arteries. Abnormal immune reactions are thought to contribute to disease pathogenesis. The effect of immunoglobulin (Ig) isotype (IgG, IgA, IgM, and IgE) on inflammatory data and clinical outcomes of patients with KD was examined. @*Methods@#Ig levels in 241 patients with KD were measured during the acute, subacute, convalescent, and normal phases of the disease. @*Results@#Compared with reference Ig values, IgG, IgA, and IgM levels were significantly higher in the subacute phase, while IgE levels were elevated in 73.9% (178/241) of patients with KD in all clinical phases. However, high IgE levels were not associated with clinical outcomes, including intravenous immunoglobulin unresponsiveness and coronary artery lesions (CALs).Significantly more CALs were observed in the high IgA group than in the normal IgA group (44.7% vs. 20.8%, respectively; p<0.01). In addition, IgA levels in the acute phase (p=0.038) were 2.2-fold higher, and those in the subacute phase were 1.7-fold higher (p <0.001), in the CAL group than in the non-CAL group. IgA concentrations increased along with the size of the coronary artery aneurysm (p <0.001). Furthermore, there was a strong correlation between IgA levels and CAL size (r=0.435, p<0.001), with a high odds ratio of 2.58 (p=0.022). @*Conclusions@#High IgA levels in patients with KD are prognostic for the risk of CALs.

Brachial Artery Thrombosis in an 8-year-old Boy with Antiphospholipid Antibodies Induced by Mycoplasma pneumoniae Infection: a Case Report

Antiphospholipid antibodies may be produced in cases involving autoimmune diseases and can sometimes be caused by infections, such as Mycoplasma pneumoniae infection. However, antiphospholipid antibodies causing thrombosis associated with M. pneumoniae pneumonia in children have rarely been reported. We report a case of an 8-year-old boy with M. pneumoniae pneumonia with antiphospholipid antibodies, complicated by brachial artery thrombosis. He was found to have antiphospholipid antibodies and low protein S levels. The brachial artery thrombus was removed via thrombectomy. The titers of antiphospholipid antibodies turned normal within 5 months. This is a rare case of M. pneumoniae infection with brachial artery thrombosis associated with transient antiphospholipid antibodies.

Self-Expandable Stents in Vascular Stenosis of Moderate to Large-Sized Vessels in Congenital Heart Disease: Early and Intermediate-Term Results

BACKGROUND AND OBJECTIVES: Vascular stenosis after surgical repair frequently occurs in congenital heart disease. Although conventional balloon dilation is a useful option for stenotic lesions, restenosis may occur. Consequently, balloon expandable stents have been used; however, there are a limited number of balloon expandable stents in our country. Here, we report the early and intermediate-term outcomes of self-expandable stents in vascular stenosis of moderate to large-sized vessels in congenital heart disease. METHODS: Twelve self-expandable stents were implanted in 9 patients between February 2012 and January 2019. The median age and weight were 12 years (range, 4–39 years) and 38 kg (range, 19–69 kg), respectively. The patients were followed-up for a median duration of 43 months (range, 1–83 months) after stent implantation. RESULTS: Nine self-expandable stents were implanted in the pulmonary artery, 2 stents in the right ventricle to the pulmonary artery conduit, and 1 stent in the coarctation. The narrowest diameter of the stented vessel increased from 5.7±3.2 mm to 12.6±3.4 mm (p<0.05). The mean pressure gradient across the stenotic lesion decreased from 23.0±28.2 mmHg to 3.2±3.6 mmHg (p<0.05). Distal migration of the stent occurred in 1 patient, and significant neointimal ingrowth was noted in 1 patient. CONCLUSIONS: The self-expandable stent may be a useful option to relieve vascular stenosis in moderate to large-sized vessels with acceptable intermediate-term outcomes.

Self-Expandable Stents in Vascular Stenosis of Moderate to Large-Sized Vessels in Congenital Heart Disease: Early and Intermediate-Term Results

BACKGROUND AND OBJECTIVES@#Vascular stenosis after surgical repair frequently occurs in congenital heart disease. Although conventional balloon dilation is a useful option for stenotic lesions, restenosis may occur. Consequently, balloon expandable stents have been used; however, there are a limited number of balloon expandable stents in our country. Here, we report the early and intermediate-term outcomes of self-expandable stents in vascular stenosis of moderate to large-sized vessels in congenital heart disease.@*METHODS@#Twelve self-expandable stents were implanted in 9 patients between February 2012 and January 2019. The median age and weight were 12 years (range, 4–39 years) and 38 kg (range, 19–69 kg), respectively. The patients were followed-up for a median duration of 43 months (range, 1–83 months) after stent implantation.@*RESULTS@#Nine self-expandable stents were implanted in the pulmonary artery, 2 stents in the right ventricle to the pulmonary artery conduit, and 1 stent in the coarctation. The narrowest diameter of the stented vessel increased from 5.7±3.2 mm to 12.6±3.4 mm (p<0.05). The mean pressure gradient across the stenotic lesion decreased from 23.0±28.2 mmHg to 3.2±3.6 mmHg (p<0.05). Distal migration of the stent occurred in 1 patient, and significant neointimal ingrowth was noted in 1 patient.@*CONCLUSIONS@#The self-expandable stent may be a useful option to relieve vascular stenosis in moderate to large-sized vessels with acceptable intermediate-term outcomes.

Assessment of the Clinical Heterogeneity of Kawasaki Disease Using Genetic Variants of BLK and FCGR2A

BACKGROUND AND OBJECTIVES@#Patients with Kawasaki disease (KD) are clinically heterogeneous because its diagnosis is based solely on clinical observation and there are no definitive biomarkers. We dissected the clinical heterogeneity of KD patients using the KD-associated genetic variants.@*METHODS@#We performed a genetic association analysis in several KD subgroups categorized by clinical characteristics using the KD-associated variants of the B lymphoid tyrosine kinase (BLK; rs6993775) and Fc gamma receptor II a (FCGR2A; rs1801274) in a large number of case (n=1,011) and control (n=4,533) samples.@*RESULTS@#BLK and FCGR2A were very significantly associated with KD in Korean KD patients (odds ratio [OR],1.48; p=4.63×10⁻¹¹ for BLK, and OR, 1.26; p=1.42×10⁻⁴ for FCGR2A). However, in KD subgroup analysis, we found that neither BLK nor FCGR2A were associated with either incomplete Kawasaki disease (iKD) type patients or those older than 5 years of age (p>0.2), suggesting that patients with iKD or those older than 5 years of age are a unique subgroup of KD. In genetic association analysis after excluding iKD patients and those older than 5 years old, we found that BLK was associated with all KD subgroups, whereas FCGR2A was specifically associated with male KD patients younger than 1 year of age (OR, 2.22; p=2.35×10⁻⁵).@*CONCLUSIONS@#KD is a clinically and genetically heterogeneous disease. These findings will provide new insights into the clinical and genetic heterogeneity of KD.

Assessment of the Clinical Heterogeneity of Kawasaki Disease Using Genetic Variants of BLK and FCGR2A

BACKGROUND AND OBJECTIVES: Patients with Kawasaki disease (KD) are clinically heterogeneous because its diagnosis is based solely on clinical observation and there are no definitive biomarkers. We dissected the clinical heterogeneity of KD patients using the KD-associated genetic variants. METHODS: We performed a genetic association analysis in several KD subgroups categorized by clinical characteristics using the KD-associated variants of the B lymphoid tyrosine kinase (BLK; rs6993775) and Fc gamma receptor II a (FCGR2A; rs1801274) in a large number of case (n=1,011) and control (n=4,533) samples. RESULTS: BLK and FCGR2A were very significantly associated with KD in Korean KD patients (odds ratio [OR],1.48; p=4.63×10⁻¹¹ for BLK, and OR, 1.26; p=1.42×10⁻⁴ for FCGR2A). However, in KD subgroup analysis, we found that neither BLK nor FCGR2A were associated with either incomplete Kawasaki disease (iKD) type patients or those older than 5 years of age (p>0.2), suggesting that patients with iKD or those older than 5 years of age are a unique subgroup of KD. In genetic association analysis after excluding iKD patients and those older than 5 years old, we found that BLK was associated with all KD subgroups, whereas FCGR2A was specifically associated with male KD patients younger than 1 year of age (OR, 2.22; p=2.35×10⁻⁵). CONCLUSIONS: KD is a clinically and genetically heterogeneous disease. These findings will provide new insights into the clinical and genetic heterogeneity of KD.

Chronological Echocardiographic Changes in Healthy Term Neonates within Postnatal 72 Hours Using Doppler Studies

BACKGROUND: This study evaluated echocardiographic changes in full-term healthy neonates during early transitional period from postnatal 0–72 hours at 12-hour intervals by echocardiography. METHODS: This was a prospective, observational, and longitudinal single-center cohort study. Morphometric, functional, systolic, diastolic, and tissue Doppler imaging (TDI) parameters (patent ductus arteriosus [PDA], aorta, superior vena cava [SVC], stroke volume [SV], cardiac output [CO], cardiac index [CI], early diastolic flow velocity [E], late diastolic flow velocity [A], early filling in TDI [E′], peak systolic annular velocity in TDI [S′], late velocity peak in TDI [A′], and myocardial performance index [MPI]) were evaluated in left ventricle (LV) and right ventricle (RV) with 56 newborns. RESULTS: Sizes and peak velocities of PDA before postnatal 24 hours were significantly changed than those after postnatal 24 hours. Aortic velocity time integral (VTI), systolic blood pressure (BP), LV SV/kg, LV CO/kg, LV CI, and SVC flow/LV CO before 24 hours showed significantly changes than those after 24 hours. Also, LV and RV MPI before 24 hours were significantly higher than those after 24 hours. LV E/E′ was significantly higher than RV E/E′. CONCLUSION: Postnatal 24 hours is critical time for hemodynamic closure of PDA because aortic VTI, systolic BP, LV SV, LV CO, LV CI, and SVC flow/LV CO showed simultaneously significant changes after 24 hours at the same time as 24 hours of physiological closure of PDA. Chronological and dramatic changes of systolic, diastolic, and TDI parameters during early postnatal period can be used to compile normal baseline data of healthy full-term neonates.

Clinical Features of Critical Congenital Heart Disease in Term Infants with Hypoxemia: A Single-Center Study in Korea

PURPOSE: This study was performed to determine the clinical features of full-term infants with hypoxemia detected by pulse oximetry and to establish the diagnosis of critical congenital heart disease (CCHD). METHODS: We retrospectively reviewed the medical records of neonates who had been admitted to the neonatal intensive care unit within 2 weeks of birth at Korea University Ansan Hospital between January 2013 and October 2017 (n=450). We classified these neonates based on the presence of hypoxemia at admission and investigated neonatal characteristics, initial symptoms, echocardiographic findings, and final diagnosis associated with hypoxemic diseases. RESULTS: Of 450 term infants, 265 infants (58.9%) were identified hypoxemia by pulse oximetry at admission. The most common symptoms of them were cyanosis and tachypnea. Among them, 80.1% of infants (214/265) were diagnosed with respiratory tract disease and 8.3% of infants (22/265) had congenital heart disease. Thirteen infants (13/265, 4.9%) had CCHD and were treated with urgent surgery or transcatheter intervention within 28 days of birth. Majority of infants with respiratory tract disorder were transferred from hospital immediately after birth, but 46.1% of infants (6/13) with CCHD remained asymptomatic after birth and were admitted after 48 hours after birth. In addition, other hypoxemic illnesses were identified as neonatal infectious and neurological diseases. CONCLUSION: This study showed the importance of assessment in neonates with hypoxemia, including those diagnosed with CCHD. The possibility of CCHD should be considered in the differential diagnosis in neonates demonstrating hypoxemia after 48 hours of birth. A larger prospective study is needed to assess the effectiveness and outcomes of pulse oximetry for neonatal screening in Korea.

Identification of LEF1 as a Susceptibility Locus for Kawasaki Disease in Patients Younger than 6 Months of Age

Kawasaki disease (KD) is an acute febrile vasculitis predominately affecting infants and children. The dominant incidence age of KD is from 6 months to 5 years of age, and the incidence is unusual in those younger than 6 months and older than 5 years of age. We tried to identify genetic variants specifically associated with KD in patients younger than 6 months or older than 5 years of age. We performed an age-stratified genome-wide association study using the Illumina HumanOmni1-Quad BeadChip data (296 cases vs. 1,000 controls) and a replication study (1,360 cases vs. 3,553 controls) in the Korean population. Among 26 candidate single nucleotide polymorphisms (SNPs) tested in replication study, only a rare nonsynonymous SNP (rs4365796: c.1106C>T, p.Thr369Met) in the lymphoid enhancer binding factor 1 (LEF1) gene was very significantly associated with KD in patients younger than 6 months of age (odds ratio [OR], 3.07; p(combined) = 1.10 × 10⁻⁵), whereas no association of the same SNP was observed in any other age group of KD patients. The same SNP (rs4365796) in the LEF1 gene showed the same direction of risk effect in Japanese KD patients younger than 6 months of age, although the effect was not statistically significant (OR, 1.42; p = 0.397). This result indicates that the LEF1 gene may play an important role as a susceptibility gene specifically affecting KD patients younger than 6 months of age.

Laboratory Markers in Incomplete Kawasaki Disease according to Coronary Artery Outcome

BACKGROUND AND OBJECTIVES@#We defined laboratory marker profiles typical of incomplete Kawasaki disease (iKD) during illness, especially with respect to the presence of a coronary artery abnormality such as coronary artery dilation or aneurysm.@*METHODS@#This retrospective study examined the clinical and laboratory markers of patients with iKD over time, along with those of patients with complete KD (cKD) and febrile controls.@*RESULTS@#Of 795 patients, 178 had iKD, 504 had cKD and 113 were febrile controls. During the transition from the acute to subacute phase, the age-adjusted hemoglobin levels and platelet counts were significantly lower and higher, respectively, in the subacute phase than in the acute phase in both iKD and cKD patients, which differed from those of febrile controls. Lower levels of acute and subacute age-adjusted hemoglobin levels in iKD patients (odds ratio [OR], 0.538 and 0.583; p=0.006 and 0.018, respectively) and higher subacute platelet counts in cKD patients (OR, 1.004; p=0.014) were correlated with the risk of coronary dilation. A higher acute neutrophil-to-lymphocyte ratio was associated with aneurysm only in cKD patients (OR, 1.059; p=0.044).@*CONCLUSIONS@#The iKD patients share KD-specific laboratory marker profiles in terms of complete blood cell counts and acute phase reactant levels with cKD patients. However, the factors predicting coronary dilation differ according to the phenotype; lower acute and subacute age-adjusted hemoglobin levels predict coronary dilation only in iKD patients.

Laboratory Markers in Incomplete Kawasaki Disease according to Coronary Artery Outcome

BACKGROUND AND OBJECTIVES: We defined laboratory marker profiles typical of incomplete Kawasaki disease (iKD) during illness, especially with respect to the presence of a coronary artery abnormality such as coronary artery dilation or aneurysm. METHODS: This retrospective study examined the clinical and laboratory markers of patients with iKD over time, along with those of patients with complete KD (cKD) and febrile controls. RESULTS: Of 795 patients, 178 had iKD, 504 had cKD and 113 were febrile controls. During the transition from the acute to subacute phase, the age-adjusted hemoglobin levels and platelet counts were significantly lower and higher, respectively, in the subacute phase than in the acute phase in both iKD and cKD patients, which differed from those of febrile controls. Lower levels of acute and subacute age-adjusted hemoglobin levels in iKD patients (odds ratio [OR], 0.538 and 0.583; p=0.006 and 0.018, respectively) and higher subacute platelet counts in cKD patients (OR, 1.004; p=0.014) were correlated with the risk of coronary dilation. A higher acute neutrophil-to-lymphocyte ratio was associated with aneurysm only in cKD patients (OR, 1.059; p=0.044). CONCLUSIONS: The iKD patients share KD-specific laboratory marker profiles in terms of complete blood cell counts and acute phase reactant levels with cKD patients. However, the factors predicting coronary dilation differ according to the phenotype; lower acute and subacute age-adjusted hemoglobin levels predict coronary dilation only in iKD patients.

Consortium-Based Genetic Studies of Kawasaki Disease in Korea: Korean Kawasaki Disease Genetics Consortium

In order to perform large-scale genetic studies of Kawasaki disease (KD) in Korea, the Korean Kawasaki Disease Genetics Consortium (KKDGC) was formed in 2008 with 10 hospitals. Since the establishment of KKDGC, there has been a collection of clinical data from a total of 1198 patients, and approximately 5 mL of blood samples per patient (for genomic deoxyribonucleic acid and plasma isolation), using a standard clinical data collection form and a nation-wide networking system for blood sample pick-up. In the clinical risk factor analysis using the collected clinical data of 478 KD patients, it was found that incomplete KD type, intravenous immunoglobulin (IVIG) non-responsiveness, and long febrile days are major risk factors for coronary artery lesions development, whereas low serum albumin concentration is an independent risk factor for IVIG non-responsiveness. In addition, we identified a KD susceptibility locus at 1p31, a coronary artery aneurysm locus (KCNN2 gene), and the causal variant in the C-reactive protein (CRP) promoter region, as determining the increased CRP levels in KD patients, by means of genome-wide association studies. Currently, this consortium is continually collecting more clinical data and genomic samples to identify the clinical and genetic risk factors via a single nucleotide polymorphism chip and exome sequencing, as well as collaborating with several international KD genetics teams. The consortium-based approach for genetic studies of KD in Korea will be a very effective way to understand the unknown etiology and causal mechanism of KD, which may be affected by multiple genes and environmental factors.

Pediatric Heart Failure: Current State and Future Possibilities

Heart failure is a complex pathophysiological syndrome that can occur in children from a variety of diseases, including cardiomyopathies, myocarditis, and congenital heart disease. The condition is associated with a high rate of morbidity and mortality and places a significant burden on families of affected children and to society as a whole. Current medical therapy is taken largely from the management of heart failure in adults, though clear survival benefit of these medications are lacking. Ventricular assist devices (VADs) have taken an increasingly important role in the management of advanced heart failure in children. The predominant role of these devices has been as a bridge to heart transplantation, and excellent results are currently achieved for most children with cardiomyopathies. There is an ongoing investigation to improve outcomes in high-risk populations, such as small infants and those with complex congenital heart disease, including patients with functionally univentricular hearts. Additionally, there is an active investigation and interest in expansion of VADs beyond the predominant utilization as a bridge to a heart transplant into ventricular recovery, device explant without a heart transplantation (bridge to recovery), and placement of devices without the expectation of recovery or transplantation (destination therapy).

A Case of Congenital Hypertrophic Cardiomyopathy

Congenital hypertrophic cardiomyopathy (HCMP) is a very rare congenital heart disease. Here, we report a case of neonatal HCMP, which was confirmed by two-dimensional echocardiography and autopsy. The HCMP rapidly progressed and the patient's condition deteriorated, despite the treatment for congestive heart failure.

A Case of Sick Sinus Syndrome in Extremely Low Birth Weight Infant with Annular Pancreas

Sick sinus syndrome (SSS) is a disorder characterized by sinus node dysfunction. Although the condition is most common in the elderly, it can occur in children including neonates and its recognition and treatment are important. The diagnosis of SSS is based on the presence of sinus bradycardia, sinus arrest or exit block, combinations of sinoatrial and atrioventricular nodal conduction disturbances, and atrial tachyarrhythmias documented in the Holter recordings. In most children with SSS, previous history of congenital heart malformation or cardiac surgery is noted. SSS is also seen in the children including neonates without heart disease or other contributing factors, however SSS is most often idiopathic. The treatment of SSS depends on the basic rhythm problem, but generally involves the placement of a cardiac pacemaker. We report a case of SSS in extremely low birth weight infant without congenital heart disease and suggest that the treatment system is necessary for preterm infants with SSS.

Alteration of CD4+CD25+Foxp3+ T cell level in Kawasaki disease / 소아과

PURPOSE: Exaggerated pro-inflammatory reactions during the acute phase of Kawasaki disease (KD) suggest the role of immune dysregulation in the pathogenesis of KD. We investigated the profiles of T regulatory cells and their correlation with the clinical course of KD. METHODS: Peripheral blood mononuclear cells were collected from 17 KD patients during acute febrile and subacute afebrile phases. T cells expressing CD4, CD25, and Foxp3 were analyzed using flow cytometry, and the results were correlated with the clinical course of KD. RESULTS: The percentage of circulating CD4+CD25highFoxp3+ T cells among CD4+ T cells was significantly higher during the subacute afebrile phase than during the acute febrile phase (1.10%+/-1.22% vs. 0.55%+/-0.53%, P=0.049). Although levels of CD4+CD25lowFoxp3+ T cells and CD4+CD25-Foxp3+ T cells were only slightly altered, the percentage of CD4+CD25+Foxp3- T cells among CD4+ T cells was significantly lower during the subacute afebrile phase than during the acute febrile phase (2.96%+/-1.95% vs. 5.64%+/-5.69%, P=0.036). Consequently, the ratio of CD25highFoxp3+ T cells to CD25+Foxp3- T cells was higher during the subacute afebrile phase than during the acute febrile phase (0.45%+/-0.57% vs. 0.13%+/-0.13%, P=0.038). CONCLUSION: Decreased CD4+CD25highFoxp3+ T cells and/or an imbalanced ratio of CD4+CD25highFoxp3+ T cells to CD4+CD25+Foxp3- T cells might play a role in KD development. Considering that all KD patients were treated with intravenous immunoglobulin (IVIG), recovery of CD4+CD25highFoxp3+ T cells during the subacute afebrile phase could be a mechanism of IVIG.

A childhood case of spinal tuberculosis misdiagnosed as muscular dystrophy / 소아과

Tuberculosis is primarily a pulmonary disease, but extra-pulmonary manifestations are not uncommon, especially in children and adolescents. Ten percent of extra pulmonary tuberculosis localizes to the bones and joints, and 56% of such cases affect the spine. We treated a childhood case of spinal tuberculosis misdiagnosed as muscular dystrophy in a patient without specific constitutional symptoms. We report this case because the patient had an unusual presentation of spinal tuberculosis.

ERRATUM: A childhood case of spinal tuberculosis misdiagnosed as muscular dystrophy / 소아과

No abstract available.