A Noonan-like pediatric patient with a de novo CBL pathogenic variant and an RNF213 polymorphism p.R4810K presenting with cardiopulmonary arrest due to left main coronary artery ostial atresia.

Left main coronary artery ostial atresia (LMCAOA) is an extremely rare condition. Here, we report the case of a 14-year-old boy with Noonan syndrome-like disorder in whom LMCAOA was detected following cardiopulmonary arrest. The patient had been diagnosed with Noonan syndrome-like disorder with a pathogenic splice site variant of CBL c.1228-2 A > G. He suddenly collapsed when he was running. After administering two electric shocks using an automated external defibrillator, the patient's heartbeat resumed. Cardiac catheterization confirmed the diagnosis of LMCAOA. Left main coronary artery angioplasty was performed. The patient was discharged without neurological sequelae. Brain magnetic resonance imaging revealed asymptomatic Moyamoya disease. In addition, RNF213 c.14429 G > A p.R4810K was identified. There are no reports on congenital coronary malformations of compound variations of RNF213 and CBL. In contrast, the RNF213 p.R4810K polymorphism has been established as a risk factor for angina pectoris and myocardial infarction in adults, and several congenital coronary malformations due to genetic abnormalities within the RAS/MAPK signaling pathway have been reported. This report aims to highlight the risk of sudden death in patients with RASopathy and RNF213 p.R4810K polymorphism and emphasize the significance of actively searching for coronary artery morphological abnormalities in these patients.

The impact of the coronavirus disease 2019 pandemic on pediatric hospitalization in Kitami, Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has drastically changed the recommended activities and environment for patients worldwide. Our aim was to assess the impact of COVID-19 on pediatric hospitalizations in Kitami, Japan. METHODS: A retrospective, single-center study was conducted on hospitalized patients aged 0-14 years at the Japanese Red Cross Kitami Hospital. We compared the incidence of pediatric patients hospitalized in 2020 with those in 2017-2019. RESULTS: The number of pediatric hospitalized patients dropped significantly in 2020 compared to that in 2017-2019 (median 43.0 vs 78.5 per month, P < 0.001). The patients were significantly older in 2020 (4.3 vs 3.4 years, P < 0.001). Hospitalization from respiratory (8.5 vs 30.5, P < 0.001) and gastrointestinal infections (3.0 vs 6.0, P = 0.004) significantly decreased. Admission due to respiratory syncytial virus (0.0 vs 4.0, P < 0.001), human metapneumovirus (0.0 vs 1.0, P = 0.005), influenza (0.0 vs 0.0, P = 0.009), adenovirus (0.0 vs 1.0, P = 0.003), and rotavirus infection (0.0 vs 0.0, P = 0.025) also decreased significantly. The <1-5 age groups significantly decreased (<1 year old, 6.5 vs 12.5, P < 0.001; 1-3 years old, 13.0 vs 29.5, P < 0.001; 4-5 years old, 5.5 vs 11.5, P < 0.001). Hospitalization due to foreign body ingestions increased significantly in 2020 (1.0 vs 0.0, P = 0.010). CONCLUSIONS: The COVID-19 control measures inadvertently reduced the number of hospitalized pediatric patients, especially younger children with respiratory and gastrointestinal infections.

Efficacy of cibenzoline for hypertrophic obstructive cardiomyopathy in paediatric patients with RAS/MAPK pathway syndromes.

RASopathies - caused by mutations in the RAS/MAPK signaling pathway - are frequently associated with cardiac diseases, such as hypertrophic obstructive cardiomyopathy. Although cibenzoline is useful for adult hypertrophic obstructive cardiomyopathy patients, little is known about its effect in children. Here, we report two paediatric cases of hypertrophic obstructive cardiomyopathy associated with RASopathies where the condition was improved by cibenzoline.

A rare case of multiple brain abscesses caused by apical periodontitis of deciduous teeth in congenital heart disease: a case report.

BACKGROUND: A brain abscess is a focal infection in which abscesses form in the brain. A brain abscess is a rare but fatal disease when rupture occurs into the ventricles. We report a case of multiple brain abscesses caused by a hematogenous infection from the apical periodontitis of deciduous teeth. CASE PRESENTATION: The patient was a 7-years and 8-months-old male with congenital heart disease. The patient sought medical attention due to fever and headache, for which he was started on three antibiotics with a diagnosis of multiple brain abscesses. Given that apical periodontitis of deciduous teeth was strongly suspected as the source of the brain abscess, the deciduous teeth were extracted. Immediately after deciduous teeth extraction, the patient's headache and neurological symptoms disappeared. CONCLUSIONS: After teeth extraction, a clear shrinkage of the brain abscess was observed, and the patient was discharged from the hospital.

Genetic characterization of a novel recombinant echovirus 30 strain causing a regional epidemic of aseptic meningitis in Hokkaido, Japan, 2017.

A regional epidemic of aseptic meningitis caused by echovirus 30 (E30) occurred in Hokkaido, Japan, during the period of August-December 2017. To investigate their phylogenetic relationship to other human enteroviruses, we determined the complete genomic nucleotide sequences of isolates from this outbreak. Phylogenetic analysis of the viral capsid protein 1 gene showed that the strains were most closely related to E30 strains detected in Germany, France, and Russia in 2013. In contrast, the region encoding the viral protease and the RNA-dependent RNA polymerase had a close phylogenetic relationship to non-E30 enteroviruses detected in the United Kingdom and Switzerland in 2015-2017, suggesting that a recombination event had occurred.

Successful treatment of frequent premature ventricular contractions and non-sustained ventricular tachycardia with verapamil and flecainide in RYR1-related myopathy: a case report.

Background: Ryanodine receptor 1 (RYR1)-related myopathies are a group of congenital muscle diseases caused by RYR1 mutations. These mutations may cause centronuclear myopathy, a congenital neuromuscular disorder characterized by clinical muscle weakness and pathological presence of centrally placed nuclei on muscle biopsy. Mutations in RYR2 cause ventricular arrhythmias that can be treated with flecainide; however, reports of ventricular arrhythmias in RYR1-related myopathies are rare. Herein we report a case of centronuclear myopathy with RYR1 mutations who exhibited frequent premature ventricular contractions (PVCs) and non-sustained ventricular tachycardia (NSVT), which was successfully treated with verapamil and flecainide. Case summary: At 7 months, the patient presented neurological manifestations of hypotonia and delayed motor development. A skeletal muscle biopsy performed at age 4 years led to the diagnosis of centronuclear myopathy. At age 15 years, frequent PVCs and NSVT were identified on the electrocardiogram and 24 h Holter monitoring. Treatment with verapamil was initiated; however, it was not beneficial. Therefore, flecainide was added to the treatment, decreasing the frequency of PVCs and NSVT. Non-sustained ventricular tachycardia disappeared at the age of 21, and PVCs almost disappeared at the age of 22. Genetic testing revealed c.13216delG (p.E4406Rfs*35), c.14874G>C (p.K4958N), and c.9892G>A (p.A3298T) in RYR1, and the compound heterozygosity of variants was confirmed by analysis of the parents. Discussion: This is the first report of ventricular arrhythmia associated with RYR1-related myopathy that was successfully treated with verapamil and flecainide. The combination of verapamil and flecainide may be a useful treatment option for ventricular arrhythmias in patients with RYR1-related myopathies.

A One-Year-Old Girl With Human Parvovirus B19 Infection and Hypocomplementemia Mimicking Incomplete Kawasaki Disease.

Human parvovirus B19 (B19) is a single-stranded DNA virus that targets erythroid progenitor cells in the bone marrow. B19 causes erythema infectiosum in children, transient aplastic anemia, pure red cell aplasia, hydrops fetalis, and contributes to other illnesses. An association between B19 infection and hypocomplementemia and rheumatoid arthritis has been reported, but the underlying mechanisms remain unclear. We report the case of a 1-year-old Japanese girl with persistent fever, skin rash, transient edema of the extremities, hypoalbuminemia, and hypocomplementemia associated with B19 infection. We considered Kawasaki disease (KD) and collagen diseases, particularly systemic lupus erythematosus, in our differential diagnosis. B19 infection might be associated with serological features that suggest systemic lupus erythematosus and may present with clinical symptoms seen in KD. Especially during erythema infectiosum epidemics, we must consider B19 infection in the differential diagnosis of KD patients who demonstrate atypical clinical symptoms and unexplained laboratory findings.

An Immunoglobulin A Vasculitis Case Without Skin Symptoms Complicated With Severe Abdominal Symptoms.

Immunoglobulin A vasculitis (IgAV) primarily affects childhood and can be categorized as immune complex vasculitis. It typically presents with purpura, abdominal pain, arthritis, and nephritis. IgAV can be diagnosed without hesitation when the characteristic skin lesions appear at onset; however, in cases where the abdominal symptoms precede the skin rash or there is no purpura at all, diagnosis can be challenging. Delayed diagnosis of IgAV may be associated with serious abdominal complications, such as gastrointestinal perforation. Here, we describe a girl with IgAV complicated with severe abdominal symptoms and lacking purpura. Despite this lack, the patient's elevated levels of D-dimer and C-reactive protein (CRP), suggestive of vasculitis, and localized small bowel intestinal wall thickening suggested IgAV. After administration of steroids relieved the abdominal symptoms and hypoalbuminemia, treatment was discontinued. Given the limited reports of patients with IgAV complicated with severe abdominal symptoms and no skin symptoms, the diagnosis and management process remains unclear. Therefore, it is imperative to consider IgAV as a differential diagnosis in patients with severe abdominal symptoms. Furthermore, we suggest checking D-dimer, CRP, and coagulation factor XIII activity levels in these patients.

A case report of Leigh syndrome diagnosed by endomyocardial biopsy.

BACKGROUND: Leigh syndrome is a neurodegenerative disorder caused by mitochondrial dysfunction with both phenotypic and genetic heterogeneity. Mitochondrial impairments are usually demonstrated by skeletal muscle biopsy. We report a case of Leigh syndrome diagnosed by endomyocardial biopsy (EMB), not by skeletal muscle biopsy. CASE SUMMARY: At aged 7 months, the patient had delayed motor development. He developed metabolic acidosis triggered by an infection with elevated lactate and pyruvate values in serum and cerebrospinal fluid when he was 1 year old. T2-weighted imaging on magnetic resonance imaging of the brain revealed bilateral hyperintensity in midbrain and dorsal pons. Biopsied skeletal muscle did not show evidence of mitochondrial disease. Left ventricular hypertrophy, bilateral putamen hyperintensity in T2-weighted imaging and a lactate peak in the right basal ganglia in single voxel spectroscopy, and a convulsive seizure appeared at the age of 12, 15, and 16, respectively. When he was 17 years old, biopsied myocardium showed cytoplasmic vacuolization and a marked proliferation of mitochondria within myofibrils pathologically. Respiratory chain enzyme activity of the biopsied myocardium showed decreased activity of complex I. Genetic testing revealed an m.14453 A>G mutation on the MT-ND6 gene. He was finally diagnosed with Leigh syndrome. Administration of oral 5-aminolevulinic acid reduced the frequency of seizures. DISCUSSION: EMB led to the diagnosis of Leigh syndrome. Efforts to find and conduct the biopsy of affected organs are important to diagnose mitochondrial disease. EMB is a useful diagnostic method when there is a difficulty in diagnosing mitochondrial disease by skeletal muscle biopsy.

Atypical Familial Mediterranean Fever in a Japanese Boy with Heterozygous MEFV p.Ser503Cys Exon 5 Variant.

Periodic fever syndromes are heterogeneous diseases. Familial Mediterranean fever (FMF) is one of the hereditary periodic fever diseases caused by a Mediterranean fever (MEFV) gene abnormality. FMF can be categorized as typical or atypical, based on clinical findings and genetic screening. Atypical FMF has a wide variation of clinical findings and disease-causing mutations of MEFV. Therefore, it is sometimes difficult to diagnose an unknown fever as FMF. To date, a large number of various typical and atypical FMF cases have been reported in Japan. Here, we describe a Japanese boy with heterozygous MEFV p.Ser503Cys exon 5 variant who developed periodic fever. He was treated with colchicine; a complete eradication of his fever and various accompanying symptoms have been subsequently achieved for more than a year. Given that there have been a few reports about patients with this variant, little is known about the genetic and phenotypic role of heterozygous MEFV p.Ser503Cys exon 5 variant. It is therefore imperative to consider atypical FMF as a differential diagnosis when a periodic fever is encountered. Furthermore, we suggest that it is worthwhile to integrate MEFV gene analysis with the potential effects of colchicine treatment in patients with periodic fever.

A capillary holder for scanning detection of capillary isoelectric focusing with laser-induced fluorescence.

A holder for a 12 cm long capillary was designed for scanning LIF detection of CIEF. The polyimide coat of a fused-silica capillary has been removed, and 1.5 mm diameter flanges have been attached near both ends. The holder is fixed on the stage of a fluorescence microscope via a translational stage, and a capillary guide is directly fixed on the microscope stage. The guide has a groove and a pressure plate for the capillary to slide in. The holder has two pulling plates with slits of 1 mm to accept the capillary just inside the flanges. The slits and the groove of the guide have been aligned. The motion of the translational stage brings the pulling plate into contact with the flange at the pulled side, and slides the capillary through the guide. The other end of the capillary is free and produces no strain on the capillary. When the motion of the stage is reversed, an unstrained contact is achieved at the other end. The baseline noise from scanning was only 50% larger than that without scanning. The fluorescence-signal variation during scanning was about 4% of the total signal, which was about twice that without scanning.

Outbreak of aseptic meningitis caused by echovirus 30 in Kushiro, Japan in 2017.

BACKGROUND: Echovirus 30 (E30) is one of the most common causative agents for aseptic meningitis. OBJECTIVES: In the autumn of 2017, there was an outbreak caused by E30 in Kushiro, Hokkaido, Japan. The aim of this study was to characterize this outbreak. STUDY DESIGN: Fifty-nine patients were admitted to the Department of Pediatrics, Kushiro Red Cross Hospital (KRCH) with clinical diagnosis of aseptic meningitis. Among those, 36 patients were finally diagnosed as E30-associated aseptic meningitis by the detection of viral RNA using reverse transcription-polymerase chain reaction (RT-PCR) and/or the evidence of more than four-fold rise in neutralizing antibody (NA) titers in the convalescent phase relative to those in the acute phase. We investigated these 36 confirmed cases. RESULTS: The median age was 6 years (range: 6 months-14 years). The positive signs and symptoms were as follows: fever (100%), headache (94%), vomiting (92%), jolt accentuation (77%), neck stiffness (74%), Kernig sign (29%), and abdominal pain (28%). The median cerebrospinal fluid (CSF) white cell count, neutrophil count, and lymphocyte count were 222/µL (range: 3-1434/µL), 144/µL (range: 1-1269/µL), and 85/µL (range: 2-354/µL), respectively. Although the detected viral genes demonstrated same cluster, they were different from E30 strains observed in Japan between 2010 and 2014. CONCLUSION: We mainly showed clinical and virological features of the E30-associated aseptic meningitis outbreak that occurred in Kushiro. To prevent further spread of E30 infection, continuous surveillance of enterovirus (EV) circulation and standard precautions are considered essential.

Aggressive angiomyxoma of the perineum originating from the rectal wall.

Aggressive angiomyxoma (AA) is a rare mesenchymal tumor that preferentially involves the pelvic and perineal regions, and is characterized by frequent local recurrences. We describe here a case of large AA in a 31-year-old woman. The patient was admitted to our hospital with a mass in the perineal region, associated with severe menstrual pain. Although her past medical history was unremarkable, she had spotty pigmentation on the lips. Magnetic resonance imaging showed a large mass in the abdominal pelvis traversing the pelvic diaphragm just to the right of the anus, and the border between the tumor and the rectal wall was indistinct. Pathology examination of a frozen intraoperative specimen suggested AA, and, therefore, we completely resected the tumor, using a combined abdominoperineal approach. The tumor was attached to the right wall of the rectum and the pelvic diaphragm between the anus and the puborectalis. The patient recovered uneventfully and there has not been any evidence of local recurrence for 3 years postoperatively. We consider that abdominoperineal resection may be an appropriate treatment for a large AA infiltrating to the perirectal tissues, because the high recurrence rate of this disease has been attributed to incomplete surgical excision.

Fully automated two-dimensional electrophoresis system for high-throughput protein analysis.

We developed a fully automated electrophoresis system for rapid and highly reproducible protein analysis. All the two-dimensional (2D) electrophoresis procedures including isoelectric focusing (IEF), on-part protein staining, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and in situ protein detection were automatically completed. The system comprised Peltiert devices, high-voltage generating devices, electrodes, and three disposable polymethylmethacrylate (PMMA) parts for IEF, reaction chambers, and SDS-PAGE. Because of miniaturization of the IEF part, rapid IEF was achieved in 30 min. A gel with a tapered edge gel on the SDS-PAGE part realized a connection between the parts without use of a gluing material. A biaxial conveyer was employed for the part relocation, sample introduction, and washing processes to realize a low-maintenance and cost-effective automation system. Performances of the system and a commercial minigel system were compared in terms of detected number, resolution, and reproducibility of the protein spots. The system achieved high-resolution comparable to the minigel system despite shorter focusing time and smaller part dimensions. The resulting reproducibility was better or comparable to the performance of the minigel system. Complete 2D separation was achieved within 1.5 h. The system is practical, portable, and has automation capabilities.

A self-contained polymeric 2-DE chip system for rapid and easy analysis.

We developed a polymeric 2-DE chip system. The chip consisted of an IEF region, an SDS-PAGE region, a valveless connection port, and a sample introduction port. A "junction structure" as a valveless connection port, which allowed separating and connecting the first- and second-dimensional gels, was fabricated between their regions. A "solution inlet" as a sample introduction port was fabricated to perform the liquid and sample introductions without solution leakage. Simultaneous sample monitoring was performed using the on-chip detection system. The performances of the system were demonstrated using commercially available proteins as a standard specimen and tissue-extracted proteins as the real samples. All procedures were employed without any movement of relocation part. This new 2-D separation system realized improved labor-intensive operations and a reduced experimental time.