Association of steroid administration with larger coronary artery abnormalities in patients with Kawasaki disease.

We sought to elucidate the risk profiles of patients with Kawasaki disease who developed coronary artery abnormalities through a retrospective analysis with special reference to steroid treatment. Demographics of the patients were obtained from medical records, and characteristics of the coronary artery abnormalities were evaluated by echocardiography and coronary angiography, which included number, location, size, and length of coronary artery abnormalities (we evaluated by cardiac catheterisation with the American Heart Association classification with segments). We divided the patients into two groups based on steroid use and compared their characteristics and the complications of coronary artery abnormalities and cardiac events. A total of 29 patients were diagnosed with coronary artery abnormalities by echocardiography and coronary angiography during the study period (24 male; median age, 24 months [range: 2-84 months]). Eighteen patients were treated with aspirin and intravenous immunoglobulin (63%, non-steroid group), whereas 11 received aspirin and intravenous immunoglobulin plus steroids (37%, steroid group). No significant differences were found in the number and location of coronary artery abnormalities between the steroid and non-steroid groups. However, the size and number of segments for coronary artery abnormalities were significantly larger and shorter, respectively, in the steroid group (z-score: non-steroid group 6.3 versus steroid group 8.7; p < 0.01). The coronary artery abnormality segments under steroid use were also shorter (non-steroid group versus steroid group, two segments versus one segment; p = 0.02). Coronary artery abnormality size was larger in patients who used steroids than that of non-steroids. This study showed that steroid use significantly affected coronary artery abnormality size in patients with Kawasaki disease. However, cardiac complications from coronary artery abnormalities and cardiac events were comparable between the steroid and non-steroid groups. Further prospective, multicentre studies are needed to confirm these findings.

TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan.

PURPOSE: The aim of this study is to evaluate the usefulness of T cell receptor excision circle (TREC) and/or kappa-deleting recombination excision circle (KREC) measurements integrated with diagnostic next-generation sequencing (NGS) analysis using a severe combined immunodeficiency (SCID) newborn screening (NBS) program. METHODS: TREC and/or KREC values were measured in 137,484 newborns between April 2017 and December 2021 using EnLite TREC (n = 80,791) or TREC/KREC kits (n = 56,693). For newborns with positive screening results, diagnostic NGS analysis was performed with a 349-gene panel to detect genetic mutations associated with primary immunodeficiencies (PIDs). RESULTS: A total of 145 newborns (0.11%) had abnormal TREC and/or KREC values, and a genetic diagnosis was established in 2 patients with SCID (1 in 68,742 newborns) (IL2RG-SCID and reticular dysgenesis) and 10 with non-SCID PIDs with T and/or B cell deficiencies (1 in 13,748 newborns) using NGS analysis. Furthermore, TREC values of 2849 newborns were measured and confirmed the significant correlation between the results of both TREC and TREC/KREC kits (P < 0.001) and naïve T cell counts. CONCLUSIONS: We performed the first large-scale TREC and TREC/KREC NBS programs in Japan. Our NBS programs followed by the diagnostic NGS analysis for newborns with abnormal TREC and/or KREC values are useful for the early identification and rapid molecular evaluation of not only SCID but also different non-SCID PIDs.

Conception by assisted reproductive technology in infants with critical congenital heart disease in Japan.

RESEARCH QUESTION: What is the proportion of infants born as a result of assisted reproductive technology ART across different types of neonatal critical congenital heart disease (CCHD) in a Japanese population? DESIGN: A retrospective analysis of 418 consecutive infants with CCHD that required catheter treatment or surgery within the first 28 days of life or ductal-dependent lesions, in two paediatric centres in Japan, between January 2014 and December 2019. The proportion of ART in infants with each type of CCHD was evaluated. The proportion of ART in infants with univentricular heart defect (UVH) compared with those with biventricular heart defect (BVH) was evaluated. RESULTS: The study group included 229 boys and 189 girls, with a gestational age of 38 ± 2 weeks. Overall, 61 infants (14.6%) were conceived by fertility treatment with 46 (11.0%) conceived by ART. Univentricular heart defect and BVH were identified in 111 infants (26.6%) and 307 infants (73.4%), respectively. The proportion of infants conceived by ART was significantly higher in UVH (16.2%) than in BVH (9.1%) (OR 2.28, 95% CI 1.11 to 4.68, P = 0.025), regardless of maternal age and maternal history of miscarriage. CONCLUSIONS: The proportion of ART in infants with CCHD, especially UVH, was high. These findings could form the basis of a rationale for carrying out fetal echocardiography in fetuses conceived by ART.

Elevated non-invasive liver fibrosis markers and risk of liver carcinoma in adult patients after repair of tetralogy of Fallot.

BACKGROUND: Congestive hepatopathy and hepatocellular carcinoma is a serious complication after Fontan procedure. Liver fibrosis due to hepatic congestion could occur also in adult patients after repair of tetralogy of Fallot (rTOF). However, the incidence and severity remain unclear. METHODS: A total of 111 patients with adult congenital heart disease between 2009 and 2016 were enrolled. Liver fibrosis markers and hemodynamic parameters assessed by cardiac magnetic resonance imaging and catheterization were analyzed in 50 rTOF patients having significant pulmonary regurgitation and/or stenosis, 50 Fontan patients and 11 controls. RESULTS: Liver fibrosis markers in patients with rTOF were significantly higher than controls, and tended to be lower than Fontan patients (median, hyaluronic acid: 25.8 vs. 15.9 vs. 40.8, type IV collagen: 129 vs. 113 vs. 166, ng/mL, p < 0.05, respectively). Patients with rTOF showed abnormal hyaluronic acid levels more frequently than controls, and less frequently than Fontan patients (22% vs. 0% vs. 38%, respectively, p < 0.05). Multivariate analyses indicated a positive association of right atrial pressure with type IV-collagen or hyaluronic acid levels (each, p < 0.001, p = 0.003). Abdominal ultrasonography revealed hepatic congestion in 50% of rTOF patients tested. Liver biopsy of the two rTOF patients with highest hyaluronic acid levels showed pathological evidence of moderate and severe (F2 and F3) liver fibrosis and one had combined hepatocellular and cholangiocarcinoma. CONCLUSIONS: We first demonstrated elevated liver fibrosis markers in adult patients with rTOF. These levels may help to predict the progressive liver disease as well as consider the timing of pulmonary valve replacement.

Procalcitonin levels predicting the infliximab response of immunoglobulin resistant Kawasaki disease.

OBJECTIVE: To search the predictive factors of infliximab resistance in intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD) patients. STUDY DESIGN: Twenty-seven patients with KD who received infliximab after 4-5 g/kg of IVIG therapy from 2013 to 2015 were consecutively recruited in this study. They were divided into two groups: patients who responded to infliximab (infliximab-responsive group, n = 15) and patients who required additional therapy for the disease control (infliximab-resistant group, n = 12). We analyzed the clinical and laboratory parameters just before the infliximab treatment including serum levels of procalcitonin and cytokines with respect to the infliximab response. RESULTS: Serum procalcitonin concentration (P = 0.017), neutrophils to lymphocytes ratio (P = 0.013), and % neutrophils (P = 0.004) were higher, and serum sodium concentration (P = 0.017) was lower in infliximab-resistant group than those of infliximab-responsive group, respectively. Multivariate logistic regression analyses indicated that higher procalcitonin concentration (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.00-5.00, P = 0.046) and lower sodium levels (OR 0.64, 95% CI 0.32-1.00, P = 0.047), but not other variables, were associated with infliximab-resistance. Serum procalcitonin concentrations positively correlated with the serum levels of interleukin-6, soluble tumor necrosis factor receptor type 1 and type 2, respectively. Analyses of the receiver operating characteristic (ROC) curve showed that the cut-off value of procalcitonin 2.0 ng/ml had 58.3% of sensitivity and 93.3% of specificity. ROC analysis yielded an area under the curve (AUC) of 0.739 to predict infliximab-resistance. CONCLUSION: Serum procalcitonin might be an effective biomarker to predict infliximab resistance in severe KD patients who are refractory to IVIG treatment.

Cancer Management in Kabuki Syndrome: The First Case of Wilms Tumor and a Literature Review.

A 3-year-old Japanese girl treated for hypoplastic left heart syndrome and Dandy-Walker syndrome was diagnosed with Kabuki syndrome (KS) with a mutation of KMT2D; c.13285C>T:p.Q4429*. Concurrently, macrohematuria portended the diagnosis of Wilms tumor. Postoperative chemotherapy has achieved complete remission despite a prolonged and reduced regimen due to liver dysfunction and convulsions. Cancer predisposition has been suggested for KS due to oncogenic mutations in KMT2D or KDM6A. The first case of nephroblastoma exemplified the treatability of malignancies in KS patients, as shown in the 9 cases reviewed. Active screening and intervention are recommended for the cure of malignancy in KS children.

Effective shunt closure for pulmonary hypertension and liver dysfunction in congenital portosystemic venous shunt.

OBJECTIVE: Congenital portosystemic venous shunt (CPSVS) is a rare vascular malformation with a high risk of mortality from pulmonary arterial hypertension (PAH), but the treatment outcome of CPSVS closure remains elusive. Our aim was to investigate the clinical features and establish the optimal management of CPSVS with or without PAH. METHODS: Twenty-four patients with CPSVS treated in Kyushu University Hospital between 1990 and 2015 were enrolled in this study. The patients were divided into a PAH group (n = 9) and a non-PAH group (n = 15). Clinical characteristics and outcomes were evaluated. RESULTS: The first manifestation of CPSVS at diagnosis (28.5 [1-216] months) was hypergalactosemia in 13 (54%) or PAH in six (25%) patients. PAH was the cause of all three deaths. The PAH group had higher levels of serum total bile acid, manganese, and total bilirubin, along with higher pulmonary vascular resistance index (PVRI) than the non-PAH group (7.2 [5.1-38.1] vs 1.2 [0.5-3.3] unit/m2 , P < 0.001). Five of nine PAH patients underwent CPSVS closure at a median of 38 months (range 21-118) after PAH diagnosis. Pulmonary artery pressure improved after CPSVS closure with PAH-specific therapy, but normal range was not achieved. CPSVS closure improved the hepatic synthetic function of four PAH patients. Eigh-t of 15 non-PAH patients who received CPSVS closure did not develop PAH for a median of 34.5 months (range 6-164) after the procedure. CONCLUSIONS: CPSVS closure with PAH-specific therapy successfully controlled PAH. Early CPSVS closure may prevent the occurrence and progression of PAH with CPSVS.

Prolonged PR Interval at Birth Predicting the High Occurrence of Fatal Atrioventricular Block in Hypoplastic Left Heart Syndrome.

Infants with hypoplastic left heart syndrome (HLHS) are at high mortality especially when they are associated with bradyarrhythmias. However, the risk factor of developing high-grade atrioventricular block (HAVB) is still unclear. Seventy-three patients with HLHS in our institutions from 2002 to 2011 were enrolled. The survival rate was assessed by the anatomical types, treatments, occurrence of HAVB, severe tricuspid regurgitation (TR), and restrictive atrial septal defect (ASD) along with electrocardiogram findings at birth. There were 23 (32%) cardiogenic and 7 (10%) non-cardiogenic deaths. The occurrence rate of HAVB but not severe TR or restrictive ASD was higher in 30 deceased patients than in 43 survived patients [7 (23%) vs. 1 (2.3%), p = 0.0038]. The overall mortality rate was higher in patients with HAVB than in those without it (p = 0.0002). Of 7 deceased patients with HAVB, 6 HAVB occurred within 10 days post-surgery, and 3 HAVB led to the early death. The mortality rate of patients with prolonged PR (≥ 0.15 s) but not wide QRS (> 0.08 s) or prolonged QTc (> 0.43 s) at birth was higher than each without it (p = 0.0106). Multivariate analysis indicated that prolonged PR but no other variables was independently associated with the mortality (hazard ratio: 2.948, p = 0.0104). Prolonged PR at birth in HLHS infants predicts the development of fatal HAVB.

High incidence of progressive stenosis in aberrant left subclavian artery with right aortic arch.

Right aortic arch with aberrant left subclavian artery (RAA/aLSCA) is a rare aortic arch anomaly. The clinical association of aLSCA stenosis with RAA/aLSCA has not yet been fully elucidated. The aim of this study was to investigate the diagnosis, incidence, management and outcome of aLSCA stenosis in infants with prenatally diagnosed RAA/aLSCA. Ten fetuses who were diagnosed as having RAA/aLSCA in Kyushu University Hospital between January 2011 and December 2014 were enrolled. The maternal and child medical records were reviewed to investigate sex, gestational age at the fetal diagnosis, gestational age and body weight at birth, the findings of computed tomography (CT), Doppler ultrasonography of the vertebral artery and angiography, and the complications and outcomes of aLSCA stenosis. In 8 of 10 patients, aLSCA stenosis was identified on the first CT examination after birth. No patients had dysphagia or respiratory distress. The stenosis spontaneously resolved in 3 patients. In 4 of the 5 remaining patients, aLSCA stenosis progressed, including one case in which complete occlusion occurred-the case was associated with retrograde flow from the left vertebral artery supplying the distal LSCA. Balloon angioplasty was successfully used to treat stenosis in two cases. The subclavian steal phenomenon and developmental problems were not observed in any patients. aLSCA stenosis was identified in 80% of patients with RAA/aLSCA after birth. The early detection and elective treatment of stenotic lesions may be required to prevent complete occlusion during the development of the cardiovascular and cerebrovascular systems.

Cardiovascular Malformations in CHARGE Syndrome with DiGeorge Phenotype: Two Case Reports.

Both CHARGE syndrome and DiGeorge anomaly are frequently accompanied by cardiovascular malformations. Some specific cardiovascular malformations such as interrupted aortic arch type B and truncus arteriosus are frequently associated with 22q11.2 deletion syndrome, while conotruncal defects and atrioventricular septal defects are overrepresented in patients with CHARGE syndrome. CHD7 gene mutation is identified in approximately two-thirds of patients with CHARGE syndrome, and chromosomal microdeletion at 22q11.2 is found in more than 95% of patients with 22q11.2 deletion syndrome. CHARGE syndrome is occasionally accompanied by DiGeorge phenotype. We report two patients with dysmorphic features of both CHARGE syndrome and 22q11.2 deletion syndrome. Although both of the two cases did not have 22q11.2 deletion, they had typical dysmorphic features of 22q11.2 deletion syndrome including cardiovascular malformations such as interrupted aortic arch type B. They also had characteristic features of CHARGE syndrome including ear malformation, genital hypoplasia, limb malformation, and endocrinological disorders. CHD7 gene mutation was confirmed in one of the two cases. When a patient with cardiovascular malformations frequently associated with 22q11.2 deletion syndrome does not have 22q11.2 deletion, we suggest that associated malformations characteristic of CHARGE syndrome should be searched for.

Surgical strategy according to the anatomical types of congenital portosystemic shunts in children.

BACKGROUND: Congenital portosystemic shunts (CPSS) with intrahepatic portal vein (IHPV) hypoplasia or absence cause encephalopathy or pulmonary hypertension (PH). Acute shunt closure may result in postoperative portal hypertension. The aim of this study was to propose a surgical strategy according to the anatomical types of CPSS and IHPV. METHODS: Twenty-three CPSS patients were diagnosed from1990 to 2015. All patients were evaluated by computed tomography, angiography, and PV pressure monitoring under a shunt occlusion test. CPSS were categorized into 5 types according to the anatomical shunt location. RESULTS: The median age at diagnosis was 34months. Three of 23 total patients, who had an extrahepatic portosystemic shunt with a hypoplastic IHPV, died before treatment initiation because of severe PH. Fourteen cases received surgical or interventional treatment at the median age of 5years. A total of 6 cases received surgical therapy, including liver transplants for 2 absent IHPV cases. The remaining 8 cases received interventional coiling. All shunt ligations were successfully accomplished in 1-stage ligation without any complications. After the treatment, the hypoplastic IHPV gradually enlarged with an efficient portal inflow. CONCLUSION: A precise pretreatment anatomical evaluation of CPSS and IHPV types is mandatory for the selection of surgical treatment. LEVEL OF EVIDENCE: Diagnostic study - level II and treatment study - level III.

Management of congenital diaphragmatic hernia with transposition of the great arteries.

Congenital diaphragmatic hernia (CDH) is a relatively rare malformation, but it has a high mortality rate. Its association with congenital heart disease lowers survival rate due to severe acidosis and desaturation caused by persistent pulmonary hypertension of the neonate. We describe herein a case of CDH with transposition of the great arteries and intact ventricular septum, in a patient who was prenatally diagnosed, managed with extracorporeal oxygenation (ECMO) support and successfully treated with both CDH repair and Jatene procedure, with no respiratory or circulatory sequelae. In conclusion, precise prenatal estimation is essential, and ECMO is a useful therapeutic option in these complex cases.

Early progression of atherosclerosis in children with chronic infantile neurological cutaneous and articular syndrome.

OBJECTIVE: Chronic inflammation plays a key role in the development of atherosclerosis. Early progression of atherosclerosis has been reported in patients with RA. Cryopyrin-associated periodic syndromes (CAPS) are autosomal dominant autoinflammatory disorders caused by heterozygous NLRP3 gene mutations. Chronic infantile neurological cutaneous and articular (CINCA) syndrome is the most severe form of CAPS and patients display early onset of rash, fever, uveitis and joint manifestations. However, there has been no previous report on atherosclerosis in patients with CAPS. The objective of this study is to assess the development of atherosclerosis in patients with CINCA syndrome. METHODS: Intima-media thickness (IMT) of the carotid arteries, stiffness parameter ß, ankle brachial index (ABI) and pressure wave velocity (PWV) were evaluated by ultrasonography in 3 patients with CINCA syndrome [mean age 9.0 years (S.D. 5.3)] and 19 age-matched healthy controls [9.3 years (S.D. 4.3)]. RESULTS: The levels of carotid IMT, stiffness parameter ß and PWV in CINCA syndrome patients were significantly higher than those in healthy controls [0.51 mm (S.D. 0.05) vs 0.44 (0.04), P = 0.0021; 6.1 (S.D. 1.7) vs 3.9 (1.0), P = 0.0018; 1203 cm/s (S.D. 328) vs 855 (114), P = 0.017, respectively]. CONCLUSION: Patients with CINCA syndrome showed signs of atherosclerosis from their early childhood. The results of this study emphasize the importance of chronic inflammation in the development of atherosclerosis. Further analysis on atherosclerosis in young patients with CINCA syndrome may provide more insights into the pathogenesis of cardiovascular disease.

Evaluation of echogenicity of the heart in Kawasaki disease.

Pathologic studies of the heart in patients with Kawasaki disease (KD) revealed vasculitis, valvulitis, myocarditis, and pericarditis. However, there have been no studies on the quantitative determination of multi-site echogenicity of the heart in KD patients. It is also undetermined whether the degree of echogenicity of each site of the heart in patients with KD might be related to the response to intravenous immunoglobulin (IVIG) treatment. In 81 KD patients and 30 control subjects, we prospectively analyzed echogenicity of the heart. Echogenicity was measured in four sites: coronary artery wall (CAW), mitral valve (MV), papillary muscle (PM), and ascending aortic wall (AAo wall) by the calibrated integrated backscatters (cIBs). The cIB values of all measurement sites at acute phase in KD patients were significantly higher than those in control subjects (KD patients vs control subjects; CAW, 19.8 ± 6.2 dB vs 14.5 ± 2.0 dB, p < 0.05; MV, 23.3 ± 5.3 dB vs 16.0 ± 3.3 dB, p < 0.05; PM, 22.4 ± 5.1 dB vs 12.7 ± 1.9 dB, p < 0.05; AAo wall, 25.3 ± 5.6 dB vs 18.3 ± 3.4 dB, p < 0.05). The cIB values of CAW at the acute phase in IVIG nonresponders were significantly higher than those in responders. Conclusion: Echogenicity of the heart in KD patients at the acute phase increased not only in the coronary artery wall but also in other parts of the heart. Echogenicity of CAW might be helpful in determining the unresponsiveness of IVIG treatment.

Aortic regurgitation associated with critical aortic stenosis in a fetus.

Aortic regurgitation in association with aortic stenosis is rare in the fetus. Findings have shown that severe aortic regurgitation is worsened by the increase in systemic vascular resistance after birth, resulting in low cardiac output, hypoxemia, and neonatal death. This report describes a unique case of aortic regurgitation with aortic stenosis, severe mitral regurgitation, retrograde flow in the aortic arch, and an enormous left atrium with a restrictive foramen ovale in a fetus. In this case, aortic regurgitation was diminished immediately after birth, indicating that spontaneous improvement in aortic regurgitation after birth should be taken into account when the final prognosis is predicted.

Measurement of the fetal isovolumetric contraction time in the fetus with a left ventricular aneurysm.

We present a case of an antenatally diagnosed congenital aneurysm of the left ventricle in which fetal cardiac contractility was evaluated by measuring the fetal isovolumetric contraction time (ICT). The workup of the fetus at 26 weeks' gestation led to the identification of a left ventricle aneurysm. Initially, the value of ICT of the left ventricle indicated adequate cardiac function. However, the fetal ICT was gradually prolonged, suspecting deteriorated cardiac contractility. Following an uncomplicated term delivery, a postnatal echocardiogram showed normal cardiac function. It is considered that because of the hypokinesis of the wall of the left ventricular aneurysm, the ICT did not fully predict cardiac function in this setting.