Sex-Specific Susceptibility Loci Associated With Coronary Artery Aneurysms in Patients With Kawasaki Disease.

BACKGROUND AND OBJECTIVES: Kawasaki disease (KD) is an acute vasculitis that primarily affects children under age 5 years. Approximately 20-25% of untreated children with KD and 3-5% of those treated with intravenous immunoglobulin therapy develop coronary artery aneurysms (CAAs). The prevalence of CAAs is much higher in male than in female patients with KD, but the underlying factors contributing to susceptibility to CAAs in patients with KD remain unclear. This study aimed to identify sex-specific susceptibility loci associated with CAAs in KD patients. METHODS: A sex-stratified genome-wide association study (GWAS) was performed using previously obtained GWAS data from 296 KD patients and a new replication study in an independent set of 976 KD patients by comparing KD patients without CAA (controls) and KD patients with aneurysms (internal diameter ≥5 mm) (cases). RESULTS: Six male-specific susceptibility loci, PDE1C, NOS3, DLG2, CPNE8, FUNDC1, and GABRQ (odds ratios [ORs], 2.25-9.98; p=0.00204-1.96×10-6), and 2 female-specific susceptibility loci, SMAD3 (OR, 4.59; p=0.00016) and IL1RAPL1 (OR, 4.35; p=0.00026), were significantly associated with CAAs in patients with KD. In addition, the numbers of CAA risk alleles additively contributed to the development of CAAs in patients with KD. CONCLUSIONS: A sex-stratified GWAS identified 6 male-specific (PDE1C, NOS3, DLG2, CPNE8, FUNDC1, and GABRQ) and 2 female-specific (SMAD3 and IL1RAPL1) CAA susceptibility loci in patients with KD.

Newly Developed Sex-Specific Z Score Model for Coronary Artery Diameter in a Pediatric Population.

BACKGROUND: This study aimed to generate a Z score calculation model for coronary artery diameter of normal children and adolescents to be adopted as the standard calculation method with consensus in clinical practice. METHODS: This study was a retrospective, multicenter study that collected data from multiple institutions across South Korea. Data were analyzed to determine the model that best fit the relationship between the diameter of coronary arteries and independent demographic parameters. Linear, power, logarithmic, exponential, and square root polynomial models were tested for best fit. RESULTS: Data of 2,030 subjects were collected from 16 institutions. Separate calculation models for each sex were developed because the impact of demographic variables on the diameter of coronary arteries differs according to sex. The final model was the polynomial formula with an exponential relationship between the diameter of coronary arteries and body surface area using the DuBois formula. CONCLUSION: A new coronary artery diameter Z score model was developed and is anticipated to be applicable in clinical practice. The new model will help establish a consensus-based Z score model.

Identification of B-cell-related HSPG2 and CDSN as susceptibility loci for Kawasaki disease.

Kawasaki disease (KD) is an acute pediatric vasculitis that predominantly affects children under the age of 5 years. To date, genome-wide association studies (GWAS) have identified several KD susceptibility genes (e.g., BLK, CD40, FCGR2A, BCL2L11, and IGHV), which are mainly involved in B cell immunity. In this study, we aimed to identify additional KD susceptibility genes mainly involved in B cell development and functions by analyzing our previous GWAS data and conducting a replication study using new sample. Initially, we selected 30 single nucleotide polymorphisms (SNPs) in B-cell-related genes that were significantly (P < 0.01) associated with KD in our previous GWAS analysis of 247 KD cases with complete type and 1,000 healthy controls. Replication study was performed by genotyping the new 837 KD case samples with Fluidigm system and comparing them with 3,553 control genotypes. Among the 30 candidate SNPs, two were significantly associated with KD (P < 0.001) in the replication study. An even greater association between these SNPs and KD was observed in the combined analysis of GWAS and replication samples: odds ratio (OR) = 1.97 (P = 8.61 × 10-6) for rs2270699 (nonsynonymous SNP: c.10588C > T, p.Arg3530Trp) in the heparan sulfate proteoglycan 2 (HSPG2) gene and OR = 1.28 (P = 1.34 × 10-6) for rs3130992 (intronic SNP) in both the corneodesmosin (CDSN) and psoriasis susceptibility 1 candidate 1 (PSORS1C1) genes. These results suggest that the B-cell-related genes, HSPG2 and CDSN or PSORS1C1, play a role in the development of KD.

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.

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 to 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 to 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.

Coronary artery status of patients with transient fever 24-36 h after first IVIG infusion did not differ from that seen in responsive patients.

BACKGROUND: Current management guidelines for patients with Kawasaki disease (KD) differ in their recommendations for fever observation times when determining resistance to initial intravenous immunoglobulin (IVIG). This retrospective study assessed coronary artery status in patients with transient fever 24-36 h after the completion of a first IVIG infusion. METHODS: Children with KD treated with IVIG between January 2006 and February 2017 were included. Subjects were divided into three groups according to response following the completion of initial IVIG treatment (Group 1, no fever after 24 h; Group 2, transient fever at 24-36 h; Group 3, others). RESULTS: A total of 879 children were evaluated (Group 1, n = 663; Group 2, n = 54; Group 3, n = 162). During the subacute phase, the left main coronary artery (LMCA) diameter z score in both groups was significantly lower than that in Group 3 (Group 1: 1.02, Group 2: 0.87, Group 3: 1.24; Group 1 vs 2, P = 0.298; Group 1 vs 3, P = 0.025; Group 2 vs 3, P = 0.042); similar results were seen with the left anterior descending coronary artery (LAD) diameter z score (Group 1: 0.64, Group 2: 0.38, Group 3: 0.98; Group 1 vs 2, P = 0.083; Group 1 vs 3, P = 0.001; Group 2 vs 3, P = 0.004). The coronary artery (CA) status also did not differ between Groups 1 and 2 during the convalescent phase (z score of LMCA was 0.70 in Group 1 and 0.74 in Group 2, P = 0.790; z score of LAD was 0.42 and 0.46 respectively, P = 0.796; z score of right CA was 0.07 and 0.00 respectively, P = 0.630). A multivariate logistic regression analysis identified total bilirubin level (OR, 2.472; 95% CI, 1.284-4.762; P = 0.007) as the only significant predictor of persisting fever over 36 h in patients with fever 24 h after the completion of initial IVIG. CONCLUSIONS: The CA status of patients with transient fever 24-36 h after the first IVIG infusion did not differ from that seen in responsive patients.

Factors associated with reduction of left ventricular mass in children on peritoneal dialysis.

AIM: This study aimed to investigate sensitive factors involved in left ventricular mass reduction in children with end-stage renal disease (ESRD) undergoing peritoneal dialysis. METHODS: Thirty-five subjects on peritoneal dialysis were enrolled. Two successive echocardiographic and clinical data for each subject were obtained. Blood pressure and left ventricular mass index (LVMI) were indexed through a division with the normal 95th percentile value. Differences in numeric data between two datasets were calculated. RESULTS: The mean age was 12.9 ± 4.6 years. Predictors of left ventricular hypertrophy and its persistence were systolic blood pressure index (P = 0.019 and P = 0.046) and E' velocity (P = 0.035 and P = 0.031) in univariate analysis. However, differences in these predictors between the datasets were not related to the change in indexed LVMI. Reduction in indexed LVMI was correlated to a reduction of indexed left atrial volume (R = 0.638, P = 0.001), trans-mitral A velocity (R = 0.443, P = 0.011), and serum blood urea nitrogen level (R = 0.372, P = 0.028) and an elevation of haemoglobin level (R = -0.374, P = 0.027). CONCLUSION: The extent of circulating volume expansion is potentially the main predictive factor for change of LVMI, because the volume dependent diastolic functional variables correlate to the change of LVMI. Further study with a large number of ESRD children including a group under fluid volume control is needed to investigate the role of volume expansion on the change of LVMI.

A comparative study of established z score models for coronary artery diameters in 181 healthy Korean children.

PURPOSE: The aim of this study was to investigate the statistical properties of four previously developed pediatric coronary artery z score models in healthy Korean children. METHODS: The study subjects were 181 healthy Korean children, whose age ranged from 1 month to 15 years. The diameter of each coronary artery was measured using 2-dimensional echocardiography and converted to the z score in the four models (McCrindle, Olivieri, Dallaire, and Japanese model). Descriptive statistical analyses and 1-sample t tests were performed. RESULTS: All calculated z scores had P values of ≥0.050 using the Kolmogorov-Smirnov test. The one sample t test showed that the mean z scores did not converge to zero except in 1 model, and the mean right coronary artery (RCA) z score was less than zero in all 4 models. The smaller RCA diameter in this study could be associated with the more distal measuring point used to avoid the conal branch. The percentage of subjects with extreme z score values (≥2.0 and ≥2.5) for the left main coronary artery (LMCA) seems to be higher in the Dallaire (4.9% and 3.3%) and Japanese models (7.1% and 3.8%). CONCLUSION: All 4 models showed statistical feasibility of normal distribution. More precise instructions would be needed for the measurement of the RCA. The higher percentage of extreme z scores for the LMCA is compatible with the basic understanding of anatomic variation in the LMCA.

Prediction of unresponsiveness to second intravenous immunoglobulin treatment in patients with Kawasaki disease refractory to initial treatment.

PURPOSE: This study investigated predictors of unresponsiveness to second-line intravenous immunoglobulin (IVIG) treatment for Kawasaki disease (KD). METHODS: This was a single-center analysis of the medical records of 588 patients with KD who had been admitted to Asan Medical Center between 2006 and 2014. Related clinical and laboratory data were analyzed by univariate and multivariate logistic regression analyses. RESULTS: Eighty (13.6%) of the 588 patients with KD were unresponsive to the initial IVIG treatment and received a second dose. For these 80 patients, univariate analysis of the laboratory results obtained before administering the second-line IVIG treatment showed that white blood cell count, neutrophil percent, hemoglobin level, platelet count, serum protein level, albumin level, potassium level, and C-reactive protein level were significant predictors. The addition of methyl prednisolone to the second-line regimen was not associated with treatment response (odds ratio [OR], 0.871; 95% confidence interval [CI], 0.216-3.512; P=0.846). Multivariate analysis revealed serum protein level to be the only predictor of unresponsiveness to the second-line treatment (OR, 0.160; 95% CI, 0.028-0.911; P=0.039). Receiver operating characteristic curve analysis to determine predictors of unresponsiveness to the second dose of IVIG showed a sensitivity of 100% and specificity of 72% at a serum protein cutoff level of <7.15 g/dL. CONCLUSION: The serum protein level of the patient prior to the second dose of IVIG is a significant predictor of unresponsiveness. The addition of methyl prednisolone to the second-line regimen produces no treatment benefit.

Diagnostic characteristics of supplemental laboratory criteria for incomplete Kawasaki disease in children with complete Kawasaki disease.

PURPOSE: In 2004, the American Heart Association (AHA) had published an algorithm for the diagnosis of incomplete Kawasaki disease (KD). The aim of the present study was to investigate characteristics of supplemental laboratory criteria in this algorithm. METHODS: We retrospectively examined the medical records of 355 patients with KD who were treated with intravenous immunoglobulin (IVIG) during the acute phase of the disease. Laboratory data were obtained before the initial IVIG administration and up to 10 days after fever onset. In 106 patients, laboratory testing was performed more than twice. RESULTS: The AHA supplemental laboratory criteria were fulfilled in 90 patients (25.4%), and the frequency of laboratory examination (odds ratio [OR], 1.981; 95% confidence interval [CI], 1.391-2.821; P<0.001) was a significant predictor of it. The fulfillment of AHA supplemental laboratory criteria was significantly associated with refractoriness to the initial IVIG administration (OR, 2.388; 95% CI, 1.182-4.826; P=0.013) and dilatation of coronary arteries (OR, 2.776; 95% CI, 1.519-5.074; P=0.001). CONCLUSION: Repeated laboratory testing increased the rate of fulfillment of the AHA supplemental laboratory criteria in children with KD.

A Rare Case of Childhood Stiff Person Syndrome Associated With Pleuropulmonary Blastoma.

INTRODUCTION: Stiff person syndrome is a rare autoimmune, neurological disorder characterized by progressive rigidity and episodic painful spasms, predominantly affecting the proximal limbs and axial muscles, and leading to progressive disability. We report the case of a child who developed symptoms compatible with stiff person syndrome during treatment for pleuropulmonary blastoma. PATIENT DESCRIPTION: A 3-year, 5-month-old girl was admitted for gradually worsening postural tremor, painful spasms, and generalized stiffness. Since the age of 3 years, she had been on adjuvant chemotherapy for pleuropulmonary blastoma before surgical resection. Brain magnetic resonance imaging and electroencephalographic findings were normal. Although serologic tests for autoimmune disease, including paraneoplastic antibodies and antiglutamic acid decarboxylase antibodies, were unremarkable, her findings were attributed to a paraneoplastic syndrome based on her clinical features and medical history. However, following the planned pulmonary lobectomy, her symptoms were paradoxically aggravated, with continuous motor unit potential at rest on electromyography, which occurs in stiff person syndrome. She gradually improved during postadjuvant chemotherapy with simultaneous immunotherapy including intravenous immunoglobulins and methylprednisolone, and she had recovered completely when evaluated at the 22-month follow-up visit after completion of her treatment for pleuropulmonary blastoma. CONCLUSION: We present the first documented child with stiff person syndrome associated with pleuropulmonary blastoma. The marked clinical improvement following chemotherapy for pleuropulmonary blastoma was yet more proof of the pleuropulmonary blastoma-related stiff person syndrome. In children with a malignancy and stiff person syndrome, a paraneoplastic syndrome should be considered and the treatment for the malignancy must be undertaken.