The CXCL10-CXCR3 axis plays an important role in Kawasaki disease.

The precise pathogenesis of Kawasaki disease remains unknown. In an attempt to elucidate the pathogenesis of KD through the analysis of acquired immunity, we comprehensively examined the immunophenotypic changes in immune cells such as lymphocytes and monocytes along with various cytokines, focusing on differences between pre- and post- treatment samples. We found high levels of CXCL9 and CXCL10 chemokines that decreased with treatment, which coincided with a post-treatment expansion of Th1 cells expressing CXCR3. Our results show that the CXCL10-CXCR3 axis plays an important role in the pathogenesis of KD.

Successful Treatment for Hepatoblastoma in Trisomy 18: A Case Report.

Children with trisomy 18 tend to develop hepatoblastoma. Since the introduction of appropriate management for organ malfunction, individuals with trisomy 18 have come to have a longer life expectancy. However, the predisposition to hepatoblastoma becomes a significant issue for the quality of a case. Here, we present a rare multifocal hepatoblastoma involving predominantly Couinaud segments 5 and 7 in a 10-month-old boy with trisomy 18. Though the first-line cisplatin monotherapy resulted in unsatisfactory tumor shrinkage, the second-line neoadjuvant chemotherapy administrating irinotecan and vincristine gave rise to significant tumor reduction in volume, leading to the completion of partial resection of the liver without the microscopic residual disease. The patient has been free from recurrence for 44 months. Because anatomical right hepatectomy can cause circulatory instability, including acute onset of pulmonary hypertension in trisomy 18 patients, physicians should balance treatment benefits and potential adverse effects. Our successful experience utilizing a combination of efficacious and less cardiotoxic neoadjuvant chemotherapy followed by the partial hepatectomy encourages physicians to treat a patient with trisomy 18 and tackle hepatoblastoma with a genetic background.

A registry study of Kawasaki disease patients with coronary artery aneurysms (KIDCAR): a report on a multicenter prospective registry study three years after commencement.

The long-term prognosis of patients with Kawasaki disease (KD) complicated by coronary artery aneurysms (CAA) is still unclear. The present, multicenter registry study aimed to study the factors associated with coronary events (CE) and determine an appropriate management method for patients with KD complicated with CAA. Patients with KD with onset after 2015 and with a medium-sized or large CAA having an actual diameter ≥ 4 mm or a Z-score ≥ 5.0 at 30 days and later after KD onset were included in the annual survey. The primary endpoint was the time-dependent incidence of CE. Associated factors were also examined. In total, 179 patients from 53 centers were enrolled and followed up for a median of 501 days. The median age at KD onset was 2.2 years, 137 patients were male (77%), 47 had incomplete KD (26%), and 36 had large CAA (20%). CE occurred in 13 patients (7%; 95% confidence interval: 4-12%); eight (62%) experienced CE within 1 year, and all the patients experienced a CE within 2 years. All but one patient received antiplatelet drugs and warfarin. Patients with a large CAA had significantly more CAA (2.8 vs. 1.7, p < 0.001), more cases of warfarin use (86% vs. 43%, p < 0.001), and were more likely to have CE (28% vs. 2%, p < 0.001) than those with a medium-sized CAA. On univariate Cox regression analysis, the factors significantly associated with CE were large CAA (hazard ratio (HR): 17.0), three or more CAA (HR: 23.3), and beaded CAA (HR: 15.9). Multivariable Cox regression analysis revealed that the only associated factor was a large CAA. CONCLUSION: Patients with a large CAA were more likely to have a CE within 2 years. Antithrombotic therapy with warfarin did not eliminate the CE risk, and better therapies are desirable. WHAT IS KNOWN: • Coronary artery aneurysms are a serious complication of Kawasaki disease, and coronary events are sometimes fatal. • In previous, retrospective studies in Japan, large aneurysms, male sex, and refractoriness to initial immunoglobulin therapy were considered risk factors for coronary events. WHAT IS NEW: • Of 179 patients with a medium sized or large aneurysm, 13 (7%) experienced coronary events, all of which occurred within 2 years of onset. Factors significantly associated with coronary events were large aneurysms, three or more aneurysms, and beaded aneurysms.

Nonsurgical treatment of cerebral ischemia associated with ACTA2 cerebral arteriopathy: a case report and literature review.

Mutations in ACTA2 gene can lead to multisystemic smooth muscle dysfunction, including cerebrovascular disease. Treatment strategies for this rare entity remain controversial, and patients are at increasing risk of neurological sequelae. We herein present the case of an 11-year-old boy previously diagnosed with an ACTA2 gene mutation who developed repetitive transient ischemic attacks and treated with bosentan, an oral endothelin receptor antagonist. Magnetic resonance imaging revealed bilateral, periventricular white matter T2 hyperintensities, and magnetic resonance angiography identified several abnormalities including fusiform dilatation in the proximal segments of internal cerebral arteries, together with followed by terminal segmental stenosis. The distal branches showed a markedly straightened course with no increase in lenticulostriate collaterals. Magnetic resonance imaging also revealed an increase in the number and size of large periventricular white matter lesions located in the left frontal lobe with the progression of ischemic symptoms. Instead of revascularization surgery, the administration of bosentan was started due to the high risk of perioperative ischemic sequelae. After bosentan initiation, the patient's repetitive episodes of cerebral ischemia ceased, and there has been no increase in the number of white matter lesions for 7 years. Bosentan might be beneficial for treating cerebral ischemia associated with ACTA2 cerebral arteriopathy by maintaining the dilatation of stenotic vessels and adequate systemic blood flow and should be considered before performing revascularization surgery.

Outcomes of Dilated Cardiomyopathy in Japanese Children　- A Retrospective Cohort Study.

BACKGROUND: There has been no nationwide survey on the prognosis of pediatric dilated cardiomyopathy (DCM) in Japan. Therefore, we designed this retrospective multicenter study to investigate the long-term survival rate in pediatric patients with DCM in Japan.Methods and Results:In this multicenter retrospective observational study, data were reviewed for 106 patients aged <18 years who had been diagnosed with DCM at any 1 of 18 Japanese institutions between 1990 and 2014. The median age at diagnosis was 2.0 years and the median duration of observation was 3.3 years. Most DCM patients were diagnosed because of symptoms of heart failure. On echocardiography, the median left ventricular end-diastolic dimension z score was 5.4 and fractional shortening was 0.10. Freedom from death or transplantation rates at 1, 3, 5, 10, and 20 years after diagnosis were 76%, 66%, 64%, 58%, and 43%, respectively. Freedom from death rates at 1, 5, 10, and 20 years after diagnosis were 81%, 75%, 72%, and 53%, respectively. The incidence of heart transplantation at 1, 5, 10, and 20 years after diagnosis was 6%, 15%, 20%, and 20%, respectively, suggesting that only 15% of patients in Japan underwent heart transplantation within 5 years of diagnosis. CONCLUSIONS: In Japan, the prognosis of pediatric DCM is poor and the rate of heart transplantation is low.

Prenatal diagnosis of congenital absence of aortic valve associated with restrictive foramen ovale: Hemodynamic features and clinical outcome.

We present the case of a fetus with absent aortic valve (AAV), mitral regurgitation (MR), and restrictive foramen ovale (FO) who survived in utero but died of severe hypoxia after birth. We reported previously two cases of "inverse circulatory shunt" in AAV with MR, that is, blood from the ascending aorta flowing into the left ventricle through aortic regurgitation, to the left atrium due to MR, to the right atrium through FO, to the right ventricle, then to the pulmonary arteries, and to the ascending aorta through the ductus. In the present case, restrictive FO prevented inverse circulatory shunt, but resulted in postnatal death.

Persistent QT Prolongation in a Child with Gitelman Syndrome and SCN5A H558R Polymorphism.

Gitelman syndrome (GS) is an inherited renal tubular disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and low urinary calcium excretion. While it is considered a benign disease, severe ventricular arrhythmia and sudden cardiac death related to the prolongation of the QT interval have been reported in rare cases. Herein we report a 13-year-old girl with GS who presented with persistent prolongation of the QT interval, even after being treated for hypokalemia and hypomagnesemia. Genetic analysis identified SCN5A H558R polymorphism, which modulates the function of myocardial sodium channel, and SLC12A3 A588V mutation, which causes GS. The SCN5A polymorphism and GS-related electrolyte disturbance might have contributed to the persistent QT prolongation in this patient. Although no ventricular arrhythmias were recorded in this case, careful cardiac surveillance should be applied for avoiding life-threatening cardiac events.

Low risk of treatment resistance in Down syndrome with Kawasaki disease.

BACKGROUND: A Japanese nationwide survey has reported that Down syndrome (DS) is a less-frequently occurring comorbidity in Kawasaki disease (KD). Although altered immune responses are frequently observed in DS, no studies have focused on the treatment response and risk for coronary artery abnormalities (CAA) in DS patients with KD. The aim of this study was therefore to evaluate the clinical manifestations, treatment response and prevalence of CAA in DS with KD. METHODS: We retrospectively reviewed the medical records of DS patients with KD from 2005 through 2012. The survey questionnaires were sent to facilities nationwide, and clinical data regarding KD in DS were collected. A control group consisted of non-DS patients with KD who were managed at Toho University. RESULTS: Of the 94 233 children diagnosed with acute KD from 2005 to 2012, 16 children with acute KD also had DS (0.017%). The DS-KD patients were significantly older than the non-DS patients (median, 8 years vs 1 year, P < 0.05, respectively). Half of the DS patients had incomplete KD. Although 50% of the DS children were at high risk of immunoglobulin resistance, all children responded to initial treatment and none had CAA. CONCLUSIONS: All DS-KD patients responded to initial i.v. immunoglobulin (IVIG) or aspirin despite having a high risk of IVIG resistance, and none of the DS patients had CAA. This suggests that the risk of treatment resistance and development of CAA may be not higher in DS patients with acute KD.

Variable severity of cardiovascular phenotypes in patients with an early-onset form of Marfan syndrome harboring FBN1 mutations in exons 24-32.

A subgroup of patients with Marfan syndrome (MFS) who have mutations in exons 24-32 of the FBN1 gene manifests severe atrioventricular valve insufficiency and skeletal problems as early as the neonatal period. These patients usually die in the first 2 years of life, thus a region between exons 24 and 32 of FBN1 is recognized as a critical region for this neonatal form of MFS (nMFS). Here, we report five consecutive patients who manifested a cardiovascular phenotype until infancy with mutations in the critical region for nMFS. Although three of these patients showed severe mitral regurgitation and died before reaching 1 year of age, the remaining two patients survived for over 5 years under medical and/or surgical interventions. Two splicing mutations and one missense mutation were identified in the three deceased patients, whereas two missense mutations were found in the two survivors. Currently, the clinical severity of patients with early-onset MFS harboring mutations in the critical region for nMFS seem to be more variable than ever thought, and intensive treatments are recommended even in this subgroup of patients with MFS.

Prenatal Diagnosis of Congenital Absence of Aortic Valve: A Report of Two Cases with Different Outcomes and a Literature Review.

Congenital absence of aortic valve (AAV) is a rare cardiac anomaly associated with high mortality. We present 2 prenatally diagnosed cases of AAV. In both cases, fetal echocardiography showed no aortic valve tissue and free aortic regurgitation. At 24 weeks' gestation, case 1 showed a hypoplastic hypocontractile left ventricle and mitral atresia, but did not develop hydrops and was born at term. Bilateral pulmonary arterial banding was performed with continuous infusion of prostaglandin E1 at 5 days of age followed by Norwood and bidirectional Glenn procedures at 3 months of age. The hypoplastic non-compliant left ventricle and mitral atresia might have limited aortic regurgitation. Case 2 showed hydrops at 23 weeks' gestation. An enlarged hypocontractile left ventricle and massive mitral insufficiency were noted. The regurgitant flow was directed to the right atrium through a foramen ovale. This peculiar hemodynamic established a malignant circuit which was arbitrarily called 'inverse circulatory shunt'. Intrauterine death occurred at 28 weeks' gestation. An autopsy showed absent aortic valve leaflets but three tiny membranous remnants. Hemodynamic evaluation by fetal echocardiography should include the documentation of the presence of and assessment of the grade of aortic regurgitation, mitral regurgitation and blood flow through a foramen ovale as well as left ventricular function.

Emergency coronary artery bypass grafting for cardiogenic shock due to left main coronary artery obstruction caused by Kawasaki disease in a 4-year-old boy.

We describe the case of a 4-year-old boy whose clinical course after Kawasaki disease resulted in coronary artery bypass grafting (CABG) due to acute myocardial infarction (AMI) causing cardiogenic shock. He had developed an ischemic cardiomyopathy due to severe localized stenosis of the left main coronary artery (LCA) and went into cardiogenic shock due to AMI on the day before a scheduled operation. He underwent successful emergency CABG within 4 h of MI. Postoperatively his neurological status was intact. This is the first report of a successful emergency CABG in a small child with cardiogenic shock due to LCA occlusion. CABG should be undertaken in small patients when appropriate indications exist, if bodyweight is >10 kg.

Analysis of Coronary Arterial Aneurysm Regression in Patients With Kawasaki Disease by Aneurysm Severity: Factors Associated With Regression.

Background Coronary arterial aneurysms (CAAs) associated with Kawasaki disease (KD) significantly affect prognosis. However, the clinical course of CAAs and factors associated with CAA regression have not been well analyzed. Methods and Results The cohort of the Z-Score 2nd Project Stage study, a multicenter, retrospective, cohort study involving 44 institutions in Japan including 1006 patients with KD, was examined. CAAs were classified by the z score of their internal diameter in the acute phase: small (z<5), medium (5≤z<10), and large (z≥10). The lower limit of small CAA was based on the Japanese Ministry of Health, Labour and Welfare criteria. In the right coronary artery, the CAA regression rates 10 years after diagnosis were 95.5% for small, 83.2% for medium, and 36.3% for large. In the proximal left anterior descending artery, the regression rates 10 years after diagnosis were 95.3% for small, 80.1% for medium, and 28.8% for large. Cox regression analysis showed that diagnosis under the age of 1 year and onset of KD in 2010 to 2012 for the right coronary artery and the left anterior descending artery, and female for the right coronary artery were significantly associated with a high regression rate, whereas large CAAs for the right coronary artery and the left anterior descending artery were significantly associated with a low regression rate. Conclusions The current study, the largest Japanese study of its kind, found that small aneurysm, recent onset, and diagnosis under the age of 1 year predict regression, and that even giant aneurysms could regress. These data may contribute to long-term management of coronary aneurysms. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000010606.

Congenital right ventricular diverticulum formed by pulmonary regurgitative jet flow in a fetus with tetralogy of Fallot and absent pulmonary valve.

Congenital ventricular diverticulum is a rare anomaly with an unclear pathology. Here, we report a male fetus at 24 weeks of gestation, diagnosed with right ventricular diverticulum associated with tetralogy of Fallot and absent pulmonary valve. The diverticulum was located at the anterosuperior wall of the right ventricle and faced into the massive pulmonary regurgitation flow jet. Intrauterine fetal death from heart failure resulted at 26 weeks of gestation. An autopsy revealed significant subendocardial fibrosis in the diverticular wall without inflammatory cell infiltration. Clinical and pathologic features suggested that the regurgitative blood flow contributed to the formation of the right ventricular diverticulum.

An autopsy case of acute myocarditis with unique lymph node findings characterized by the proliferation of reactive plasmablasts.

We report an autopsy case of acute myocarditis, in which the mediastinal lymph nodes exhibited unique findings. A 15-year-old Japanese boy was diagnosed with the secondary onset of acute myocarditis. No viruses were identified. Autopsy confirmed acute lymphocytic myocarditis. Lymphadenopathy was observed, especially in pulmonary hilar/mediastinal areas. Microscopically, interfollicular areas were uniformly filled with medium-sized, round cells that resembled lymphocytes. They were immunohistochemically CD3- CD5- CD19+ CD20- CD79a- Pax-5- CD138+ MUM1+ LMP1- EBNA2- cytoplasmic IgG+ IgA- and IgM-. No monotypia was observed for kappa and lambda light chains, and multiplex polymerase chain reaction analyses of immunoglobulin heavy chain variable region diversity demonstrated oligoclonal peaks, suggesting reactive change. IgG+ or VS38c+ cells frequently co-expressed Ki-67 (up to 80%). We considered these cells abundantly present in lymph nodes to be reactive plasmablasts because they were early plasma cells with proliferative activity.

Novel ELN mutation in a Japanese family with a severe form of supravalvular aortic stenosis.

BACKGROUND: Supravalvular aortic stenosis (SVAS) is one of the congenital cardiovascular diseases characterized by stenosis of the aorta. The stenotic lesions occur anywhere above the aortic valve in the aortic tree as well as pulmonary arteries and eventually leads to circulatory failure. The disease gene has been identified on the elastin gene (ELN) and two types of SVAS have been categorized; a familial type and an isolated type with the de novo mutation. METHODS: Fluorescent In situ hybridization (FISH) analysis and gene sequencing were performed in a two-generation family in which severe form of SVAS was diagnosed. RESULTS: None of the patients tested showed microdeletion of ELN, LIMK1, and D7S613. A novel nonsense mutation of ELN (c.160G>T (p.(Gly54*)), RNA not analyzed) was found in exon 3 in three members; two of them died suddenly due to rapid progression of SVAS with possible arrhythmia in early infancy. A point mutation in the 5' untranslated region, which was previously suggested to be associated with SVAS, did not co-segregate with the SVAS phenotype and found to be SNPs. CONCLUSION: Our report shows a broad spectrum of clinical features in family members sharing the identical mutations, suggesting a potential contribution of modifier gene(s) or interactions with environmental factors.

Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events.

Importance: Few studies with sufficient statistical power have shown the association of the z score of the coronary arterial internal diameter with coronary events (CE) in patients with Kawasaki disease (KD) with coronary artery aneurysms (CAA). Objective: To clarify the association of the z score with time-dependent CE occurrence in patients with KD with CAA. Design, Setting, and Participants: This multicenter, collaborative retrospective cohort study of 44 participating institutions included 1006 patients with KD younger than 19 years who received a coronary angiography between 1992 and 2011. Main Outcomes and Measures: The time-dependent occurrence of CE, including thrombosis, stenosis, obstruction, acute ischemic events, and coronary interventions, was analyzed for small (z score, <5), medium (z score, ≥5 to <10; actual internal diameter, <8 mm), and large (z score, ≥10 or ≥8 mm) CAA by the Kaplan-Meier method. The Cox proportional hazard regression model was used to identify risk factors for CE after adjusting for age, sex, size, morphology, number of CAA, resistance to initial intravenous immunoglobulin (IVIG) therapy, and antithrombotic medications. Results: Of 1006 patients, 714 (71%) were male, 341 (34%) received a diagnosis before age 1 year, 501 (50%) received a diagnosis between age 1 and 5 years, and 157 (16%) received a diagnosis at age 5 years or older. The 10-year event-free survival rate for CE was 100%, 94%, and 52% in men (P < .001) and 100%, 100%, and 75% in women (P < .001) for small, medium, and large CAA, respectively. The CE-free rate was 100%, 96%, and 79% in patients who were not resistant to IVIG therapy (P < .001) and 100%, 96%, and 51% in patients who were resistant to IVIG therapy (P < .001), respectively. Cox regression analysis revealed that large CAA (hazard ratio, 8.9; 95% CI, 5.1-15.4), male sex (hazard ratio, 2.8; 95% CI, 1.7-4.8), and resistance to IVIG therapy (hazard ratio, 2.2; 95% CI, 1.4-3.6) were significantly associated with CE. Conclusions and Relevance: Classification using the internal diameter z score is useful for assessing the severity of CAA in relation to the time-dependent occurrence of CE and associated factors in patients with KD. Careful management of CE is necessary for all patients with KD with CAA, especially men and IVIG-resistant patients with a large CAA.