Molecular Autopsy With Banked Cord Blood Reveals Brugada Syndrome in Past Sudden Death Case.

Molecular autopsy has recently been gaining attention as a means of postmortem diagnosis; however, it is usually performed using the victim's blood sample at the time of death. Here, we report the first case of a deceased infant with Brugada syndrome whose diagnosis was made with banked cord blood. A seemingly healthy 1-year-old male infant collapsed while having a fever; this collapse was witnessed by his mother. Despite cardiopulmonary resuscitation, he died of ventricular fibrillation. No abnormalities of cardiac structure were identified on autopsy. Genomic samples were not stored at the time because of a lack of suspicion for familial arrhythmia. Five years later, his sister showed Brugada electrocardiogram pattern while febrile from Kawasaki disease. Their father showed a spontaneous type 1 Brugada electrocardiogram pattern. A heterozygous SCN5A p.R893C variant was found by genetic testing in the proband's father and sister. Furthermore, the proband's genetic testing was performed using his banked cord blood, which identified the same variant. Family history of Brugada syndrome with an SCN5A-R893C variant and clinical evidence led to a postmortem diagnosis of Brugada syndrome in the proband. Identification of this variant in this case later contributed to verifying SCN5A-R893C as a pathogenic variant through data accumulation. Banked cord blood may prove useful for conducting molecular autopsies in previously undiagnosed cases of sudden death in which genomic samples were not stored.

Initial intravenous immunoglobulin therapy without aspirin for acute Kawasaki disease: a retrospective cohort study with a Bayesian inference.

OBJECTIVE: To clarify the necessity of acetylsalicylic acid (ASA) administration combined with intravenous immunoglobulin (IVIG) therapy in the treatment of acute Kawasaki disease. DESIGN: Retrospective cohort study. SETTING: Multicentre. PARTICIPANTS: This study included 735 patients with Kawasaki disease aged ≤10 years and hospitalised between 4 and 10 days of illness in eight Japanese hospitals from January 2016 to December 2020. EXPOSURES: High-dose (HD) ASA was administered with initial IVIG to 333 patients in 6 hospitals (HD group). ASA was not administered routinely to 402 patients in the other two hospitals, and low-dose ASA was only administered when patients developed coronary artery lesions or pericardial effusion (non-HD group). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the presence of coronary artery lesions, defined as a coronary artery diameter >+2.5 SD of body surface area within 1 month of onset. The secondary outcome was responsiveness to the initial IVIG therapy. Adjusted risk ratios for the outcomes were calculated using modified Poisson regression models. Bayesian analysis was conducted to estimate the posterior probability of the treatment effect of HD ASA under several prior distributions. RESULTS: The incidence of coronary artery lesions was not significantly higher in the HD group than in the non-HD group (12/333 (3.6%) vs 15/402 (4.0%)). The proportion of non-responders to initial IVIG was similar between the two groups (HD group: 78/333 (23%); non-HD group: 83/402 (22%)). In the Bayesian analysis, considering a difference of ≤2% to be of no clinical importance, there was only a 9.3% chance of reduced risk of coronary artery lesions in the HD group compared with the non-HD group even with a strongly enthusiastic prior for HD treatment. CONCLUSIONS: Compared with HD ASA treatment, treatment without ASA in the acute phase of Kawasaki disease was not associated with increased complications from Kawasaki disease.

Telethonin variants found in Brugada syndrome, J-wave pattern ECG, and ARVC reduce peak Nav 1.5 currents in HEK-293 cells.

BACKGROUND: Telethonin (TCAP) is a Z-disk protein that maintains cytoskeletal integrity and various signaling pathways in cardiomyocytes. TCAP is shown to modulate α-subunit of the human cardiac sodium channel (hNav 1.5) by direct interactions. Several TCAP variants are found in cardiomyopathies. We sought to investigate whether TCAP variants are associated with arrhythmia syndromes. METHODS: Mutational analyses for TCAP were performed in 303 Japanese patients with Brugada syndrome, arrhythmogenic right ventricular cardiomyopathy, and J-wave pattern ECG. Using patch-clamp techniques, electrophysiological characteristics of hNav 1.5 were studied in HEK-293 cells stably expressing hNav 1.5 and transiently transfected with wild-type (WT) or variant TCAP. RESULTS: We identified two TCAP variants, c.145G>A:p.E49K and c.458G>A:p.R153H, in four individuals. p.E49K was found in two patients with ARVC or BrS. p.R153H was found in two patients with BrS or J-wave pattern ECG. No patient had variant hNav 1.5. Patch-clamp experiments demonstrated that peak sodium currents were significantly reduced in cells expressing p.R153H and p.E49K compared with WT-TCAP (66%, p.R153H; 72%, p.E49K). Voltage dependency of peak IV curve was rightward-shifted by 5 mV in cells expressing p.E49K compared with WT-TCAP. Voltage dependency of activation was not leftward-shifted by p.R153H, while voltage dependency of steady-state inactivation was leftward-shifted by p.E49K. CONCLUSIONS: We found two TCAP variants in the patients with BrS, J-wave pattern ECG, and ARVC that can cause loss-of-function of the hNav 1.5 in heterologous expression systems. Our observation suggests that these variants might impair INa and be associated with the patients' electrophysiological phenotypes. Further studies linking our experimental data to clinical phenotypes are warranted.

Heart Rate, Responsiveness to Intravenous Immunoglobulin, and Coronary Artery Aneurysms in Kawasaki Disease.

OBJECTIVE: To evaluate whether heart rate (HR) was associated with intravenous immunoglobulin (IVIG) responsiveness or development of coronary artery lesions (CALs) in patients with Kawasaki disease. STUDY DESIGN: We conducted a retrospective cohort study using data from in patients with Kawasaki disease who were hospitalized in our institution from 2006 to 2016. The patients were divided into 5 groups according to the age- and temperature-adjusted HR z score (HRZage/temp) just before IVIG administration. The ORs of outcomes were estimated by using logistic regression models, with the middle group set as the reference. RESULTS: Of the 322 patients, a total of 98 patients (30%) were refractory to initial IVIG treatment. The patients whose HRZage/temp belonged to the lowest group were at the highest risk of being refractory to the initial IVIG treatment (OR 2.10 [95% CI 1.01-4.37]). Multivariable analyses showed the same trend, though this was not statistically significant. The patients with the highest HRZage/temp were most likely to develop CALs (OR 2.61 [95%CI 0.86-7.92]). CONCLUSIONS: In patients with Kawasaki disease , HRs has a different relationship with IVIG responsiveness and CALs. Low HRZage/temp might be associated with high risk of being refractory to the initial IVIG treatment, while the risk of developing CALs increased among those whose HRs were high. Further studies are necessary to investigate the mechanisms regarding HR and these outcomes in Kawasaki disease.

A New Z Score Curve of the Coronary Arterial Internal Diameter Using the Lambda-Mu-Sigma Method in a Pediatric Population.

BACKGROUND: Several coronary artery Z score models have been developed. However, a Z score model derived by the lambda-mu-sigma (LMS) method has not been established. METHODS: Echocardiographic measurements of the proximal right coronary artery, left main coronary artery, proximal left anterior descending coronary artery, and proximal left circumflex artery were prospectively collected in 3,851 healthy children ≤18 years of age and divided into developmental and validation data sets. In the developmental data set, smooth curves were fitted for each coronary artery using linear, logarithmic, square-root, and LMS methods for both sexes. The relative goodness of fit of these models was compared using the Bayesian information criterion. The best-fitting model was tested for reproducibility using the validation data set. The goodness of fit of the selected model was visually compared with that of the previously reported regression models using a Q-Q plot. RESULTS: Because the internal diameter of each coronary artery was not similar between sexes, sex-specific Z score models were developed. The LMS model with body surface area as the independent variable showed the best goodness of fit; therefore, the internal diameter of each coronary artery was transformed into a sex-specific Z score on the basis of body surface area using the LMS method. In the validation data set, a Q-Q plot of each model indicated that the distribution of Z scores in the LMS models was closer to the normal distribution compared with previously reported regression models. Finally, the final models for each coronary artery in both sexes were developed using the developmental and validation data sets. A Microsoft Excel-based Z score calculator was also created, which is freely available online (http://raise.umin.jp/zsp/calculator/). CONCLUSIONS: Novel LMS models with which to estimate the sex-specific Z score of each internal coronary artery diameter were generated and validated using a large pediatric population.

Incidence of death from congenital toxoplasmosis in 0-4-year-old children in Japan.

Congenital toxoplasmosis is caused by Toxoplasma gondii. The incidence of death due to congenital toxoplasmosis in Japan from 1974 to 2007 was calculated using the autopsy database of the Japanese Society of Pathology and vital statistics from the Ministry of Health, Labour and Welfare. Two neonatal deaths due to congenital toxoplasmosis were reported during that time. As there were 161,195 neonatal deaths during this period and 32,465 autopsies were performed, the yearly neonatal death from congenital toxoplasmosis was calculated as 2 × 161,195/32,465/34 = 0.29 and the autopsy rate as 32,465/161,195 = 0.2014 (20.14%). The calculated number of annual deaths in infants was 0.82 and in children aged 1-4 years it was 2.09; thus, although few, deaths from congenital toxoplasmosis do still occur in neonates, infants, and young children. Therefore, obstetricians and pediatricians should be aware of the potential for congenital toxoplasmosis, and pregnant women should make every effort to avoid T. gondii infection.

Refractory cholestasis presenting as cholangiolitis in an Rh (E)-incompatible neonate.

Cholestasis in neonates is infrequently associated with Rh isoimmunization, and usually resolves within a month. The suggested pathophysiology is inspissated bile and hepatocellular damage. We report a rare case of refractory cholestasis presenting with cholangiolitis in a newborn with anti-E isoimmunisation. The cholangiolitis was disclosed by immunohistochemical investigation of conjugated hyperbilirubinaemia and by liver biopsy, which showed a number of CD8(+) lymphocytes within the portal tract damaging the interlobular bile duct. Bilirubin levels dramatically decreased after 14-day corticosteroid therapy (prednisolone, 2 mg/kg/day) implying that the cause of cholestasis could be immune-mediated cholangiolitis.

A case of massive meconium peritonitis in utero successfully managed by planned cardiopulmonary resuscitation of the newborn.

We report a case of emergent massive meconium peritonitis due to intrauterine volvulus without malrotation. Fetal ascites was detected on a regular ultrasonographic examination, and fetal distress was found on cardiotocographic monitoring. The mother had noticed a slight decrease in fetal movements over the preceding 24 hours. Prenatal magnetic resonance imaging allowed us to distinguish the meconium from fetal peritoneal fluid and to evaluate the degree of compression of the fetal thoracic cavity. The infant was delivered by emergency cesarean section and demonstrated tense abdominal ascites with edema at birth. She required cardiopulmonary resuscitation and immediate paracentesis.

Management of two pregnancies in a woman with mixed connective tissue disease, pulmonary fibrosis, frequent pneumothorax and oxygen inhalation therapy along with a published work review.

Two pregnancies in a woman on oxygen inhalation therapy before pregnancy, due to pulmonary fibrosis and frequent pneumothorax that are secondary to mixed connective tissue disease, were managed safely. As usual for this condition, the patient was rather older and her ordinary daily life was restricted. This is a truly very rare case of a successful pregnancy in these circumstances. In a published work review using key words such as "pregnancy", "mixed connective tissue disease" and "oxygen inhalation therapy", no similar case could be found. For the management of such high-risk patients, close cooperation of the obstetrician, clinical immunologist, clinical pneumologist and neonatologist in the same hospital is indispensable.

Kawasaki disease with lymphadenopathy and fever as sole initial manifestations.

AIM: Initial presentation with only cervical lymphadenopathy and fever is one of the pitfalls in the diagnosis of Kawasaki disease (KD). As the number of such patients is small, their clinical features have remained uncertain. The purpose of the present study is to characterise the features of such KD patients, especially in comparison with those of patients with common onset. METHODS: We conducted a retrospective review of the medical records of 136 consecutive KD patients admitted to Kobe City General Hospital from April of 2000 to March of 2006. Twenty-nine of the 136 patients initially presented with only cervical lymphadenopathy and fever and were classified into the lymphadenopathy-KD (LKD); they were compared with the remaining 107 KD patients with other presentations (other-KD). RESULTS: Age, days of fever to diagnosis, and duration of fever were significantly higher or longer in LKD patients, who also showed higher C-reactive protein levels and neutrophil alkaline phosphatase activity. There were no significant differences between two groups in gender, duration of hospitalization, frequency of high-dose intravenous immunoglobulin (IVIG) administration, coronary artery lesions (CALs), white blood cell or platelet counts, and levels of hemoglobin or albumin on admission. CONCLUSIONS: Although a delay in diagnosis and stronger inflammation were found in LKD patients, such differences did not have any significant effect on patients' outcomes as assessed by the frequency of IVIG administration and the presence of CALs.

Procedures for prevention of perinatal group B streptococcal diseases: a multicenter questionnaire survey of hospitals in the Kyoto Neonatal Disease Study Group, Japan.

To explore clinical protocols for the prevention of early-onset group B Streptococcus (EOGBS) disease of the newborn in Japan, we conducted a multicenter questionnaire survey. Of 32 regional centers participating in the Kyoto Neonatal Study Group, 28 provided usable data concerning prevention practices undertaken between 2000 and 2004. Twenty-three (82%) of the 28 hospitals implemented bacteriological screening to identify maternal GBS carriage, and all 23 hospitals administered intrapartum antibiotics to all screening-positive pregnant women. There were no institutes that used risk-based strategies. In the 23 hospitals, bacteriological screening was conducted mostly by lower vaginal swab alone (n = 18). Eighteen hospitals performed screening once during pregnancy, either before 34 weeks' gestation (n = 6) or between 35 and 37 weeks' gestation (n = 12). Oral antepartum antibiotics, when carriage was identified, were administered at 12 (52%) hospitals. Twenty institutes used penicillins for intrapartum prophylaxis. However, the loading dose for chemoprophylaxis ranged from 0.5 to 2 g, and the interval between repeat administrations ranged from 4 to 12 h. Although the results indicated that more than 80% of the hospitals surveyed had introduced some screening-based prevention practices, the timing of the bacteriological screening during the pregnancy, the number of screenings, and the screening sites, as well as the antibiotics used, and their dosage, varied widely. Because of these highly variable methods, the efficacy of the implementation of preventive practices could not be determined. This study is the first to have described preventive practices for EOGBS disease in Japan in the era of Centers for Disease Control and Prevention guidelines. In light of the above results, a larger study under a unifying protocol would be warranted.

Molecular and clinical analyses of Japanese patients with carbamoylphosphate synthetase 1 (CPS1) deficiency.

Carbamoylphosphate synthetase I deficiency (CPS1D) is a urea-cycle disorder characterized by episodes of life-threatening hyperammonemia. Correct diagnosis is crucial for patient management, but is difficult to make from clinical presentation and conventional laboratory tests alone. Enzymatic or genetic diagnoses have also been hampered by difficult access to the appropriate organ and the large size of the gene (38 exons). In this study, in order to address this diagnostic dilemma, we performed the largest mutational and clinical analyses of this disorder to date in Japan. Mutations in CPS1 were identified in 16 of 18 patients with a clinical diagnosis of CPS1D. In total, 25 different mutations were identified, of which 19 were novel. Interestingly, in contrast to previous reports suggesting an extremely diverse mutational spectrum, 31.8% of the mutations identified in Japanese were common to more than one family. We also identified two common polymorphisms that might be useful for simple linkage analysis in prenatal diagnosis. The accumulated clinical data will also help to reveal the clinical presentation of this rare disorder in Japan.

Reversible vascular changes in children with cerebral infarction.

A case of cerebral infarction in a 4-year-old male is described. The child presented with an acute onset of right hemiplegia, central facial palsy, and dysarthria. He had no predisposing factors for cerebral infarction. A computed tomography scan showed a diffuse low-density area in the territory of the left miiddle cerebral artery. Magnetic resonance angiography disclosed multiple irregular narrowings in the left anterior and middle cerebral arteries. He recovered spontaneously from the stroke with minimal long-term complications, and repeated angiography disclosed a complete regression of the vascular changes 2 months after the stroke. There was no recurrence of stroke after 2-year follow-up. This case demonstrates the importance of longitudinal angiographic follow-up in childhood cerebral infarction of idiopathic origin.