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Following a rubella outbreak in 2011, Vietnam implemented a mass measles-rubella vaccination campaign for children aged 1–14 years in 2014–2015, further expanding the target age to 16–17 years in 2016; routine vaccination was introduced in 2014. However, there was concern that a substantial proportion of women of child-bearing age were still susceptible to rubella, with the fear of congenital rubella emergence. Thus, we conducted a prospective cohort study in Nha Trang, Vietnam, from 2017–2018 to investigate pregnant women’s susceptibility to rubella infection, the incidence of congenital rubella infection, and factors associated with susceptibility. Cord blood was tested for rubella-specific immunoglobulin M (IgM) and IgG; neonatal saliva and cord blood specimens were examined for rubella-RNA. We analyzed 2013 mother-baby pairs. No baby was rubella-IgM or rubella-RNA positive. Overall, 20.4% of mothers were seronegative (95% confidence interval, 18.6%–22.1%). The seronegativity was significantly low among mothers aged

A birth cohort study was conducted in Khan Hoa Province, central Vietnam between 2009 and 2012 to determine the seroprevalence of hepatitis B virus (HBV) in pregnant women and their children, and associated risk factors. We enrolled 1987 pregnant women with their babies at the birth phase, and 12.6% (95% confidence interval [CI]: 11.1–14.0) of mothers were hepatitis B surface antigen (HBsAg)+. At 2-year follow-up phase, 1339 (67.4%) children were enrolled of whom 76.6% completed hepatitis B vaccines (HepB) and 1.9% (95% CI: 1.2–2.7) were HBsAg+. When mothers were hepatitis B e antigen (HBeAg)+, 28.3% of children have got infected even with complete HepB. HBV infection in mothers, hepatitis B surface antibody (anti-HBs antibody) below the seroprotective level in children, and mothers with pre-pregnancy low body mass index were associated with HBV infection in children. Meanwhile, HBV infection in children, older maternal age, no or incomplete doses of HepB, and boys were associated with anti-HBs antibody below the seroprotective level in children. Our birth cohort study determined a low rate of congenital HBV infection and associated risk factors in Vietnam, however further studies are needed to advance prevention including anti-viral therapy in pregnant women at high risk., Scientific Reports, 11, art. no. 8676; 2021

A 31-day-old infant was admitted to the pediatric intensive care unit due to shock and anemia. The mother had systemic lupus erythematosus and direct antiglobulin test (DAT)-positive hemolytic anemia. The perinatal course of this infant and the mother was uneventful. Regular health check screenings revealed that activity, growth, and development were unremarkable at birth, 5, and 28 days of life. Passive immune hemolytic anemia due to neonatal lupus erythematosus was diagnosed based on a positive DAT for warm-type IgG antibodies, reticulocytosis, and lupus-specific antibodies at rehospitalization. It was complicated by cytomegalovirus (CMV) antigenemia. Umbilical cord blood and peripheral blood samples obtained from the infant at 5 days after birth were negative for CMV DNA. The infant was curatively treated by intensive care with repeated blood transfusions and antiviral therapy. This is the first report indicating that CMV infection exacerbates hemolytic anemia in patients with maternal red blood cell alloantibodies.

BACKGROUND Because of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan. METHODS This cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups. RESULTS We contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P

Background Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand, which strongly suppresses osteoclasts. Cherubism is a rare autosomal dominant disorder characterized by symmetrical swelling of the jaws, in which the bone is replaced by a fibrous granuloma containing osteoclast-like giant cells. Case presentation We report the efficacy and safety of denosumab treatment in a prepubertal boy with progressive cherubism. The treatment consisting of eight subcutaneous denosumab injections (120 mg/dose) in 6 months not only suppressed the expansion of the osteolytic lesions but also dramatically ossified them. However, a transiently decreased growth rate and rebounded asymptomatic hypercalcemia were associated with the treatment. Conclusions The present case demonstrated the therapeutic potential of denosumab for treatment of cherubism, although adverse effects, especially those on childhood growth, remain obscure. Further studies are needed to establish a safe and effective protocol for denosumab treatment of children.

The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1(c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability,sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows. Magnetic resonance imaging delineated anterior pituitary hypoplasia, ectopic posterior pituitary, invisible pituitary stalk, thinning of the corpus callosum, and hypoplasia of the pons and midbrain. The phenotypically normal parents (first cousins) were heterozygous for the mutation. The results provide further evidence of ROBO1 being involved in the development of the pituitary gland.A recessive mutation of ROBO1 is a potential novel cause of a syndromic disorder associated with combined pituitary hormone deficiency., Journal of Human Genetics, 64, pp.341?346; 2019

Rubella vaccination programs have dramatically reduced the incidence of rubella and congenital rubella syndrome (CRS) in developed countries. However, CRS prevalence is still rising in developing countries where rubella-containing vaccines (RCV) are not included in the immunization program and even in some countries where a part of the population lacks immunity to rubella despite the presence of RCV in the regular immunization program. This review aimed to summarize the clinical features of CRS using data from our studies conducted between 2011 and 2015 in Vietnam,wherein we examined clinical manifestations in Vietnamese children with CRS who were born after the large rubella outbreak of 2011; a series of studies dealing with CRS in North America and Europe after the 1960s epidemic; and those from countries before introduction of RCVs. This review shows that children with CRS have a variety of disabilities such as hearing, visual, developmental, behavioral, cardiac, and endocrine impairments, which have variable severity and may appear in different combinations. Some of these impairments can appear or worsen later in the lives of these children.Physicians should thus complete pediatric, cardiac, auditory, ophthalmologic, and neurologic examinations along with laboratory diagnostic testing soon after birth. These assessments should be repeated during follow-up if congenital rubella infection is suspected in a neonate. Timely intervention for cardiac defects can be lifesaving. Early introduction and continuation of speech, occupational, physical, and behavior therapies and training with appropriate medical interventions by a multidisciplinary team approach are required to maximize quality of life., Vaccine, 37(1), pp.202-209; 2019

Background: Influenza B is one of the major etiologies for acute respiratory infections (ARI) among children worldwide; however, its clinical-epidemiological information is limited. We aimed to investigate the hospitalization incidence and clinical-epidemiological characteristics of influenza B-associated paediatric ARIs in central Vietnam. Methods: We collected clinical-epidemiological information and nasopharyngeal swabs from ARI children hospitalized at Khanh Hoa General Hospital, Nha Trang, Vietnam from February 2007 through June 2013. Nasopharyngeal samples were screened for 13 respiratory viruses using Multiplex-PCRs. Influenza B-confirmed cases were genotyped by Haemagglutinin gene sequencing. We analyzed the clinical-epidemiological characteristics of influenza B Lineages (Victoria/Yamagata) and WHO Groups. Results: In the pre-A/H1N1pdm09 period, influenza B-associated ARI hospitalization incidence among children under five was low, ranging between 14.7 and 80.7 per 100 000 population. The incidence increased to between 51.4 and 330 in the post-A/H1N1pdm09. Influenza B ARI cases were slightly older with milder symptoms. Both Victoria and Yamagata lineages were detected before the A/H1N1pdm09 outbreak; however, Victoria lineage became predominant in 2010-2013 (84% Victoria vs 16% Yamagata).Victoria and Yamagata lineages did not differ in demographic and clinical characteristics. In Victoria lineage, Group1 ARI cases were clinically more severe compared to Group5, presenting a greater proportion of wheeze, tachypnea, and lower respiratory tract infection. Conclusions: The current results highlight the increased incidence of influenza B-related ARI hospitalization among children in central Vietnam in the post-A/H1N1pdm09 era. Furthermore,the difference in clinical severity between Victoria lineage Group1 and 5 implies the importance of influenza B genetic variation on clinical presentation., Influenza and other Respiratory Viruses, 13(3), pp. 248-261; 2018

Japan has been running a nationwide antenatal human T-cell leukemia virus type-1 (HTLV-1) antibody screening program since 2010 for the prevention of HTLV-1 mother-to-child transmission. As part of the program, pregnant women are invited to take an HTLV-1 antibody screening test, usually within the first 30 weeks of gestation, during regular pregnancy checkups. Pregnant women tested positive on the antibody screening test undergo a confirmatory test, either western blotting or line immunoassay. In indeterminate case, polymerase chain reaction (PCR) is used as a final test to diagnose infection. Pregnant women tested positive on a confirmatory or PCR test are identified as HTLV-1 carriers. As breastfeeding is a predominant route of postnatal HTLV-1 mother-to-child transmission, exclusive formula feeding is widely used as a postnatal preventive measure. Although there is insufficient evidence that short-term breastfeeding during ≤3 months does not increase the risk of mother-to-child transmission compared to exclusive formula feeding, this feeding method is considered if the mother is eager to breastfeed her child. However, it is important that mothers and family members fully understand that there is an increase in the risk of mother-to-child transmission when breastfeeding would be prolonged. As there are only a few clinical studies on the protective effect of frozen-thawed breastmilk feeding on mother-to-child transmission of HTLV-1, there is little evidence to recommend this feeding method. Further study on the protective effects of these feeding methods are needed. It is assumed that the risk of anxiety or depression may increase in the mothers who selected exclusive formula feeding or short-term breastfeeding. Thus, an adequate support and counseling for these mothers should be provided. In addition to raising public awareness of HTLV-1 infection, epidemiological data from the nationwide program needs to be collected and analyzed. In most cases, infected children are asymptomatic, and it is necessary to clarify how these children should be followed medically.

Exposure to environmental tobacco smoke (ETS) is an important modifiable risk factor for child hospitalization, although its contribution is not well documented in countries where ETS due to maternal tobacco smoking is negligible. We conducted a birth cohort study of 1999 neonates between May 2009 and May 2010 in Nha Trang, Vietnam, to evaluate paternal tobacco smoking as a risk factor for infectious and non-infectious diseases. Hospitalizations during a 24-month observation period were identified using hospital records. The effect of paternal exposure during pregnancy and infancy on infectious disease incidence was evaluated using Poisson regression models. In total, 35.6% of 1624 children who attended follow-up visits required at least one hospitalization by 2 years of age, and the most common reason for hospitalization was lower respiratory tract infection (LRTI). Paternal tobacco smoking independently increased the risk of LRTI 1.76-fold (95% CI: 1.24-2.51) after adjusting for possible confounders but was not associated with any other cause of hospitalization. The population attributable fraction indicated that effective interventions to prevent paternal smoking in the presence of children would reduce LRTI-related hospitalizations by 14.8% in this epidemiological setting.

Background Acute lower respiratory tract infections (ALRIs) are the most common disease for hospitalized children in Japan. The aim of this study was to identify viruses in children hospitalized for ALRIs and to demonstrate epidemiologic and clinical characteristics in Japan. Methods During a 2-year period from February 2013 to January 2015, we collected nasopharyngeal swab specimens from almost all hospitalized children with ALRIs in Nagasaki, a regional city of Japan, and its environs. Viruses were detected by multiplex polymerase chain reaction from these samples. Results We detected one or more viruses from 259 (69%) of 374 patients, 227 of whom were infected with a single virus, 30 with 2, and 2 with 3 viruses. Detected viruses in this study were rhinovirus (46.4%), respiratory syncytial virus (29.7%), human metapneumovirus (6.8%), parainfluenza virus (5.5%), enterovirus D68 (3.4%), influenza virus (2.7%), adenovirus (2.4%), bocavirus (2.0%) and Coxsackie virus (1.0%). We detected a seasonal shift in respiratory syncytial virus outbreaks from the 2013-2014 to the 2014-2015 seasons. There was no significant difference in clinical course and severity among those viruses. Patients with a history of asthma or underlying diseases were older and more frequently required oxygen therapy than previously healthy patients. Conclusions Viral etiology in hospitalized children with ALRIs in Nagasaki, Japan, was similar to that in many other countries. Enterovirus D68, which was recently recognized as a causative agent of severe ALRIs, was also identified in this study area. Severity of ALRIs may depend on underlying disease rather than type of etiological virus.

Background Studies on the adverse effects of Asian dust (AD) on respiratory function in children are scarce. The objective of this study was to examine the association between AD and respiratory function by measuring peak expiratory flow rates (PEFRs) in asthmatic children. Methods The study was carried out from March to May from 2014 through 2016. One hundred ten children with bronchial asthma were recruited from four hospitals in the Goto Islands and south Nagasaki area in Nagasaki prefecture. The parents were asked to record their children’s PEFRs every morning/evening and clinical symptoms in an asthma diary. AD was assessed from light detection and ranging data, and a linear mixed-effects model was used to estimate the effects of AD on daily PEFR. Time-stratified case-crossover analyses were performed to examine the association between AD and asthma attacks defined by reduction levels in PEFR. Results AD was detected on 11 days in the Goto Islands, and on 23 days in the south Nagasaki area. After adjusting for age, sex, temperature, and daily oxidants, we found a consistent association between AD and a 1.1% to 1.7% decrease in PEFR in the mornings and a 0.7% to 1.3% decrease in the evenings at a lag of 0 to 5 days. AD was not associated with the number of asthma attacks, respiratory symptoms, or other symptoms at any lag days examined. Conclusions Exposure to AD was associated with reduced PEFR, although the effects were not large enough to induce clinically apparent symptoms, in clinically well-controlled asthmatic children.

Background Tubulinopathies include a wide spectrum of disorders ranging from abnormal ocular movement to severe brain malformations, and typically present as diffuse agyria or perisylvian pachygyria with microcephaly, agenesis of the corpus callosum, and cerebellar hypoplasia. They are caused by the dysfunction of tubulins encoded by tubulin-related genes, and the TUBA1A gene encoding alpha-1A tubulin is most frequently responsible for this clinical entity. Porencephaly is relatively rare among patients with the TUBA1A mutations. Mild case of tubulinopathy associated with porencephaly caused by a novel TUBA1A mutation. Case report The patient, a 10-month-old girl, presented with gross motor delay at 4 months of age and convulsions at 7 months of age. Brain magnetic resonance imaging showed porencephaly, occipital polymicrogyria, hypoplasia of the corpus callosum, volume loss of the white matter, dysgenesis of anterior limbs of internal capsules, non-separative basal ganglia, cerebellar hypoplasia, and dysplastic brainstem. We identified a novel de novo heterozygous missense mutation in the TUBA1A gene, c.381C > A (p.Asp127Glu), by whole-exome sequencing. Discussion Microtubules composed of tubulins regulate not only neuronal migration but also cell division or axon guidance. Accordingly, tubulinopathy affects the cortical lamination, brain size, callosal formation, and white matter as seen in the present case. In contrast to the previously reported cases, the present case showed milder cortical dysgenesis with a rare manifestation of porencephaly. The genotype-phenotype correlation is still unclear, and this study expands the phenotypic range of tubulinopathy.

Background The aim of the study was to evaluate outcomes of congenital cytomegalovirus (CMV) cases identified by our urine-filter screening assay after follow-up for more than 2 years, and to observe the clinical outcomes after anti-CMV therapies. Methods Sixty of the 72 congenital CMV cases were enrolled. Forty-three cases asymptomatic at birth, 7 cases symptomatic at birth but untreated with anti-CMV drugs, and 10 symptomatic cases treated with anti-CMV drugs were clinically observed for more than 2 years. Results Among the 43 asymptomatic cases, 3 cases developed hearing loss or language disabilities for which association with congenital CMV has been repeatedly reported and 2 cases demonstrated neurological sequelae of which etiology was unclear, indicating that the rate of CMV-associated late-onset sequelae was 7~12%. All 7 symptomatic infants without treatment developed sequelae, while 3 of the 10 treated cases were free from any sequelae. Conclusions The rate of late-onset sequelae observed in Japan is similar to that reported for cases in the US and European countries. The treatment of symptomatic cases with antiviral agents results in favorable clinical outcomes. Thus, newborn screening of congenital CMV infection by the collection of urine on filter paper is warranted. This article is protected by copyright. All rights reserved.

An increasing number of genetic syndromes present a challenge to clinical geneticists. A deep learning-based diagnosis assistance system, Face2Gene, utilizes the aggregation of "gestalt," comprising data summarizing features of patients' facial images, to suggest candidate syndromes. Because Face2Gene's results may be affected by ethnicity and age at which training facial images were taken, the system performance for patients in Japan is still unclear. Here, we present an evaluation of Face2Gene using the following two patient groups recruited in Japan: Group 1 consisting of 74 patients with 47 congenital dysmorphic syndromes, and Group 2 consisting of 34 patients with Down syndrome. In Group 1, facial recognition failed for 4 of 74 patients, while 13-21 of 70 patients had a diagnosis for which Face2Gene had not been trained. Omitting these 21 patients, for 85.7% (42/49) of the remainder, the correct syndrome was identified within the top 10 suggested list. In Group 2, for the youngest facial images taken for each of the 34 patients, Down syndrome was successfully identified as the highest-ranking condition using images taken from newborns to those aged 25 years. For the oldest facial images taken at ≥20 years in each of 17 applicable patients, Down syndrome was successfully identified as the highest- and second-highest-ranking condition in 82.2% (14/17) and 100% (17/17) of the patients using images taken from 20 to 40 years. These results suggest that Face2Gene in its current format is already useful in suggesting candidate syndromes to clinical geneticists, using patients with congenital dysmorphic syndromes in Japan.

Background The adverse health effects of Asian dust (AD) on the respiratory system of children are unclear. We hypothesized that AD events may lead to increased visits by children to emergency medical centers due to bronchial asthma and respiratory diseases, including bronchial asthma. Methods We used anonymized data on children receiving primary emergency treatment at Nagasaki Municipal Primary Emergency Medical Center, Japan between March 2010 and September 2013. We used Light Detection and Ranging (LIDAR) data to assess AD exposure and performed time-stratified case-crossover analyses to examine the association between AD exposure and emergency department visits. The main analysis was done with data collected from March through May each year. Results The total number of emergency department visits during the study period was 756 for bronchial asthma and 5421 for respiratory diseases, and the number of "AD days" was 47. In school children, AD events at lag day 3 and lag day 4 were associated with increased emergency department visits due to bronchial asthma, with odds ratios of 1.837 (95% confidence interval [CI], 1.212-2.786) and 1.829 (95% CI, 1.179-2.806), respectively. AD events were significantly associated with respiratory diseases among preschool children at lag day 0, lag day 1, and lag day 2, with odds ratios of 1.244 (95% CI, 1.128-1.373), 1.314 (95% CI, 1.189-1.452), and 1.273 (95% CI, 1.152-1.408), respectively. These associations were also significant when the results were adjusted for meteorological variables and other air pollutants. Conclusions The study findings suggested that AD exposure increases emergency department visits by children.

We herein report a de novo hemizygous 9.2-Mb interstitial deletion of chromosome 11p14.1-15.3 in a 3-year-old Japanese girl with short stature, relative macrocephaly, and delayed closure of cranial fontanelles and sutures. She did not show either any motor or mental development delay. This deletion involves 25 genes including NELL1. The loss of the Nell1 function leads to skeletal defects in the cranial vault and vertebral column, and overexpression of Nell1 causes craniosynostosis in mice. These results imply that short stature and an abnormality of membranous ossification could be explained by haploinsufficiency of NELL1 on 11p14.1-p15.3. Further studies are needed to clarify the phenotype in patients with an 11p14.1-15.3 deletion and the pathogenesis of NELL1. © 2016 Wiley Periodicals, Inc.

Background: The cesarean section rate in Vietnam has been increasing especially in urban area. However, limited evidence identified regarding socio-demographic factors of the cesarean section birth. The objective of this study was to determine the current cesarean birth rate and the associated socio-demographic factors among mothers in Nha Trang city, south-central Vietnam. Methods: A community-based cross-sectional study was conducted between October and November in 2016 as part of a Streptococcus pneumoniae carriage survey conducted in 27 communes of Nha Trang city. From each commune, 120 mothers and their children less than 2 years old were randomly selected. Mothers were asked to answer standardized questions regarding socio-demographic information and mode of birth. Multivariate logistic regression was adopted to examine associations between socio-demographic variables and mode of birth. Results: Of 3148 participants, the number of cesarean births was 1396 (44.3 %). Older maternal age (? 30 years old), having another child going to school or kindergarten, monthly income more than 644 USD, gestational weeks at birth over 42 weeks, and low (< 2500 g) or high (? 3500 g) birth weight were associated with higher likelihood of cesarean births. Conclusion: The CS rate obtained in this study was more than twice of what is recommended by the World Health Organization, which is consistent with the previous nation-wide study in Viet Nam. Further monitoring is suggested to examine the non-medical reason for the increased CS rate., Tropical Medicine and Health, 48(1), art.no.57; 2020

Background: Congenital cytomegalovirus (CMV) disease, a common mother-to-child infection, can lead to neurological sequelae. Some clinical trials have shown that oral valganciclovir (VGCV) can improve hearing and neurodevelopmental impairment in infants with congenital CMV disease. However, VGCV has neither been approved in Japan nor other countries as a treatment for this disease by the government health insurance. Methods: This study is a non-randomized, prospective, open-label, multicenter, single-arm clinical trial and will include subjects meeting the following criteria: confirmation of positive CMV-DNA amplification in urine by an in vitro diagnostic test within 21 days of age; congenital CMV disease with one or more central nervous system disorders-microcephaly, hydrocephalus or ventricular enlargement, periventricular calcification, cortical hypoplasia or white matter injury, retinal choroiditis, and abnormal auditory brainstem response (ABR); and infants within 2 months of age with a gestational age >= 32 weeks at birth and weighing >= 1800 g at the time of registration. Subjects will be orally administered 16 mg/kg VGCV twice daily for 6 months. The target number of cases for enrollment between February 3, 2020 and July 31, 2021 is 25. Primary endpoint is the change in whole blood CMV loads before and after 6 months of treatment. The important secondary endpoint is the change in ABR (both best and total ear hearing assessments) before and after 6 months of treatment. The safety endpoints are adverse events and drug side effects. Discussion: To the best of our knowledge, this multicenter, open-label, single-arm study will be the first well-designed clinical trial to evaluate the efficacy of oral VGCV in infants with congenital CMV diseases. The findings will reveal the efficacy and safety of oral VGCV treatments and enable the approval of oral VGCV as a treatment for infants with congenital CMV disease by the government health insurance of Japan.

A 15-year-old girl presented with non-progressive sensorineural hearing impairment in her right ear since her early childhood. She had normal intellectual development. When she was 15 years old, small deep white matter lesions around the lateral ventricles were incidentally detected in brain MRI studies through further investigation of auditory organs. Laboratory data including cerebrospinal fluid analysis and antibodies to aquaporin-4 or myelin-oligodendrocyte glycoprotein were normal. She was diagnosed as a congenital cytomegalovirus (CMV) infection based on the detection of CMV DNA from preserved umbilical cord tissue by real-time polymerase chain reaction. It should be kept in mind that a case of congenital CMV infection with normal intelligence may be underdiagnosed and that sensorineural hearing impairment from early childhood and deep white matter abnormalities can be key features giving rise to suspicion on congenital CMV infection.

Pediatrics international, 61(5), pp.522-523; 2019

Glioblastoma 2 (GLI2) is a mediator of Sonic hedgehog signaling pathway that plays an important role in development of the central nervous system and limbs. Heterozygous GLI2 mutations have been associated with postaxial polydactyly, various pituitary dysfunction, and holoprosencephaly-like phenotype. Herein, we report a Japanese boy who presented with isolated growth hormone deficiency with ectopic posterior pituitary, postaxial polydactyly, atrioventricular septal defect, intellectual disability and dysmorphic facial features including mid-facial hypoplasia. The patient was also complicated with congenital urethral stricture with megacystis, hydronephrosis, and renal hypoplasia/dysplasia, which led to end-stage renal failure by the age of 8 years. Trio-whole-exome sequencing showed a novel de novo heterozygous frameshift mutation in GLI2 (c.3369delG, p.Met1123Ilefs*7) in the patient. This is the first report of possible association between GLI2 mutation and the phenotype of congenital anomalies of the kidney and urinary tract, and subsequent end-stage renal failure. Further studies on the urogenital phenotype in patients with GLI2 mutations may clarify a role of GLI2 in embryonic development of the urinary tract.

Congenital coronary artery abnormalities may cause sudden death, particularly in athletes. Two siblings, aged 10 and 9 years, respectively, were diagnosed with anomalous origin of the right coronary artery on multi-detector computed tomography (MDCT). The right coronary artery arose from the left coronary cusp, and was wedged between the aorta and pulmonary artery. This was also noted on cardiac ultrasonography (UCG), but in general this might not be seen on electrocardiography at rest. Although the surgical indications are unclear in the case of unproven ischemia, early recognition of the condition may reduce risk of the cardiac events during exercise. The majority of proximal coronary artery anomalies can be screened for on UCG, and confirmed on MDCT, which yields more precise clinical details and is less invasive than angiography. This is the first report of familial cases of anomalous origin of the right coronary artery in Asia.

Phenylketonuria (PKU) and related hyperphenylalaninemia (HPA) are caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). The incidence of PKU in Nagasaki prefecture is higher than that in all parts of Japan (1/15 894 vs 1/120 000). To investigate the genetic background of patients with HPA in Nagasaki prefecture, mutation analysis was done in 14 patients with PKU or mild HPA. Homozygous or compound heterozygous PAH mutations were identified in all the patients. The spectrum of PAH mutations in the cohort was broad and similar to those in all parts of Japan and East Asian countries. R53H is the most common mutation in patients with mild HPA. The present results provide further support for genotype-phenotype correlations in patients with HPA. The high incidence of PKU in Nagasaki, the westernmost part of Japan, might be due to migration of people with PAH mutations from China and Korea, and geographic factors.

Silver?Russell syndrome (SRS) is a congenital developmental disorder characterized by intrauterine and postnatal growth failure, craniofacial features (including a triangular shaped face and broad forehead), relative macrocephaly, protruding forehead, body asymmetry and feeding difficulties. Hypomethylation of the H19 differentially methylated region (DMR) on chromosome 11p15.5 is the most common cause of the SRS phenotype. We report the first SRS patient with hypomethylation of the H19-DMR and maternally derived 15q11.2-q13.1 duplication. Although her clinical manifestations overlapped with those of previously reported SRS cases, the patient’s intellectual disability and facial dysmorphic features were inconsistent with the SRS phenotype. Methylation analyses, array comparative genomic hybridization, and a FISH analysis revealed the hypomethylation of the H19-DMR and a maternally derived interstitial 5.7?Mb duplication at 15q11.2-q13.1 encompassing the Prader?Willi/Angelman critical region in the patient. On the basis of the genetic and clinical findings in the present and previously reported cases, it is unlikely that the 15q duplication in the patient led to the development of hypomethylation of the H19-DMR and it is reasonable to consider that the characteristic phenotype in the patient was caused by the coexistence of the two (epi)genetic conditions. Further studies are needed to clarify the mechanisms leading to methylation aberrations in SRS., Journal of Human Genetics, 62(10), pp.919-922; 2017

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

To investigate susceptibility to and factors associated with rubella infection among pregnant mothers and to estimate the burden of congenital rubella infection (CRI) in Vietnam where rubella-containing vaccine (RCV) is not included in the routine immunization program, we conducted a prospective cohort study in Nha Trang, Vietnam between 2009 and 2010. Rubella-specific immunoglobulin-M and immunoglobulin-G were investigated in cord blood samples by enzyme immunoassay. Corresponding clinical-epidemiological data were analyzed and the national congenital rubella syndrome (CRS) incidence was estimated using modeling. We enrolled 1988 pairs of mothers aged 17-45 years and their newborn babies. No mothers had received RCV. Multivariate analysis revealed that mothers aged 17-24 (aOR 2.5, 95% CI: 1.7-3.8) or 25-34 (1.4, 1.0-2.1) years were more likely to be susceptible than those aged 35-45 years. Overall 28.9% (574/1988, 95% CI: 26.9-30.9%) of mothers were seronegative. The CRI rate was 151 (95% CI: 0-322) per 100,000 live births. Modeling estimated that 3788 babies (95% CI: 3283-4143) were born with CRS annually in Vietnam with an overall CRS incidence of 234 (95% CI: 207-262) cases per 100,000 live births. A substantial proportion of women of childbearing age (WCBA) are at risk of rubella infection during pregnancy and this can result in a high frequency of miscarriage or burden of CRS across Vietnam. Prompt introduction of RCV into national immunization program with catch-up vaccination to children and WCBA will reduce CRI in Vietnam., Vaccine, 32(10), pp.1192-1198; 2014

This study investigated the characteristics of congenital rubella syndrome (CRS)-associated cardiac complications, particularly patent ductus arteriosus (PDA). We reviewed the medical records of patients with CRS who were admitted to the Children’s Hospital 1 in Vietnam between December 2010 and December 2012, and patients with CRS who underwent PDA transcatheter occlusion therapy at the cardiology department between December 2009 and December 2015. We compared the characteristics of PDA treated with transcatheter closure between children with CRS (CRS-PDA) and those without CRS (non-CRS-PDA) who underwent PDA transcatheter closure between July 2014 and December 2015. One-hundred-and-eight children with CRS were enrolled. Cardiac defects (99%), cataracts (72%), and hearing impairment (7%) were detected. Fifty CRS-PDA and 290 non-CRS-PDA patients were examined. CRS-PDA patients had smaller median birthweight (p < 0.001), more frequent pulmonary (p < 0.001) and aortic stenosis (p < 0.001), higher main pulmonary artery pressure, and higher aortic pressure in systole/diastole (p < 0.001 for each) than did non-CRS-PDA patients. The proportion of tubular-type PDA was higher in CRS-PDA patients (16%) than in non-CRS-PDA patients (3%) (p = 0.020). Tubular-type PDA was frequently seen in patients with CRS and accompanied by pulmonary/systemic hypertension and pulmonary/aortic stenosis; in these patients, more cautious device selection is needed for transcatheter PDA closure., Scientific Reports, 9(1), art.no.17105; 2019

Background Congenital cytomegalovirus (CMV) infection and neonatal herpes are major mother-to-child infections, and analyses of the important clinical issues, including risk factors for prognosis, are essential. Methods A secondary survey of congenital CMV infection and neonatal herpes was performed using questionnaires for cases reported in the primary survey between 2006 and 2008. Results Univariate analysis of 71 cases of congenital CMV infection showed that intrauterine growth restriction (IUGR) or other specific findings on fetal ultrasonography (US), microcephaly, intracranial calcification, disseminated intravascular coagulation, abnormal findings on computed tomography, and the use of i.v. gammaglobulin were all significantly correlated with poor outcome (death or severe sequelae). Multivariate analysis showed that only IUGR was significantly associated with poor outcome. Hearing impairment is one of the major abnormalities associated with congenital CMV infection. Automatic auditory brainstem response (automatic ABR) appeared to be useful for detection of hearing impairment in comparison with conventional ABR. Moreover, univariate analysis showed that specific fetal US or abnormal magnetic resonance imaging findings were correlated with sensorineural hearing loss. In 24 cases of neonatal herpes, fever and seizure were correlated with poor outcome on univariate analysis. All patients received acyclovir treatment, although substantial numbers of patients in severe clinical categories (disseminated or central nervous system diseases) received a low dose of acyclovir (

Background: Ganciclovir is a therapeutic choice for extremely premature infants with severe postnatal cytomegalovirus disease, but little is known about its optimal dose size and dosing interval for them. Case presentation: We treated an extremely premature female infant with postnatal cytomegalovirus infection with intravenous administration of ganciclovir since 49 days of life (postmenstrual age of 31 weeks). After ganciclovir treatment was initiated at a dose of 5 mg/kg every 12 h, cytomegalovirus loads in the peripheral blood were markedly decreased. However, since plasma ganciclovir trough level was too high, the interval was extended to every 24 h. Subsequently, the trough level and the estimated 12-h area under the concentration-time curve (AUC0-12) were decreased from 3.5 mg/L to 0.3 mg/L and 53.9 mg ・ h/L to 19.2 mg ・ h/L, respectively, resulting in an exacerbation of viremia and clinical condition. Adjustment of dosing interval from 24 h to 12 h led to a peak level of 4.2 mg/L, trough level of 1.1 mg/L, and AUC0-12 of 31.8 mg ・ h/L, resulting in a marked suppression of viral load. Conclusions: Monitoring the therapeutic drug levels and cytomegalovirus loads is useful in obtaining a proper treatment effect and preventing overdosage during ganciclovir therapy in premature infants with postnatal cytomegalovirus infection., BMC Pediatrics, 16, 141; 2016

Since the initial discovery of RSV-A ON1 in Canada in 2010, ON1 has been reported worldwide, yet information regarding its clinical impact and severity has been controversial. To investigate the clinical relevance of RSV-A ON1,acute respiratory infection (ARI) cases enrolled to our population-based prospective pediatric ARI surveillance at Khanh Hoa General Hospital, Central Vietnam from January 2010 through December 2012 were studied. Clinical-epidemiological information and nasopharyngeal samples were collected. Multiplex PCR assays were performed for screening 13 respiratory viruses. RSV-positive samples were further tested for subgroups (A/B) and genotypes information by sequencing the G-glycoprotein 2nd hypervariable region. Statistical analysis was performed to evaluate the clinical-epidemiological characteristics of RSV-A ON1. A total of 1854 ARI cases were enrolled and 426 (23.0%) of them were RSV-positive. During the study period, RSV-A and B had been co-circulating. NA1 was the predominant RSV-A genotype until the appearance of ON1 in 2012. RSV-related ARI hospitalization incidence significantly increased after the emergence of ON1. Moreover, multivariate analysis revealed that risk of lower respiratory tract infection was 2.26 (95% CI: 1.37–3.72) times, and radiologically-confirmed pneumonia was 1.98 (95% CI: 1.01–3.87) times greater in ON1 compared to NA1 cases. Our result suggested that ON1 ARI cases were clinically more severe than NA1.

A 76-year-old woman was diagnosed with chronic active Epstein-Barr virus (EBV) infection (CAEBV) with sustained fever, anemia, numbness of the lower limbs, and liver dysfunction. The patient had an unusual anti-EBV antibody profile and high viral load, positive rheumatoid factor, and cryoglobulinemia. She suffered from recurrent hemosputum with pleural effusion and thrombocytopenia caused by CAEBV infection, and she died in July 2008. Here, we present a rare case of CAEBV infection with cryoglobulinemia in an elderly patient.

We report for the first time the single photon emission computed tomography (SPECT) findings of a patient with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) associated with Kawasaki disease, which showed hypoperfusion of the bilateral cingulate gyri, thalamus, basal ganglia, brainstem, and cortex of the frontal lobes. These findings indicate that the pathogenesis of MERS is based on cerebral hypoperfusion due to vasculitis or cerebrovascular dehydration.

Background: Coronary artery lesions (CAL) are a serious complication of Kawasaki disease (KD). The increased serum E-selectin level during the acute phase of KD and the association of E-selectin gene (SELE) polymorphisms with the prevalence of coronary artery disease in adults suggest a possible association between SELE polymorphisms and the development of CAL in KD patients. Methods: The subjects consisted of 177 KD patients, including 59 with and 118 without CAL, and 305 healthy controls. Two single nucleotide polymorphisms (SNP) of SELE, 98G>T (rs1805193) and Ser128Arg (rs5361), were genotyped by direct sequencing and the high-resolution melting curve method, respectively. The allele distributions were assessed using the chi-squared test. Results: There were no significant differences in the T allele frequency at 98G>T between KD patients and controls (1.4% vs 1.0%, P= 0.55) or between KD patients with and without CAL (1.7% vs 1.3%, P= 0.77). Similarly, there were no differences in the distribution of the C allele (128Arg) at Ser128Arg between KD patients and controls (4.5% vs 3.4%, P= 0.40) or between KD patients with and without CAL (4.2% vs 4.7%, P= 0.86). Conclusion: Although no association was detected between these SELE polymorphisms and the prevalence of KD or the development of CAL, this may have been due to the study limitations, including a low frequency of the minor alleles and a small sample size. A larger-scale association study is needed in order for a definitive conclusion to be made as to whether these SNP are associated with susceptibility to KD or not.

Objective To examine the association between gestational weight gain and maternal body mass index (BMI) among Vietnamese women and the risk of delivering an infant too small or too large for gestational age. Methods A prospective health-facility-based study of 2989 pregnant Vietnamese women was conducted in the city of Nha Trang in 2007–2008. Cubic logistic regression was used to investigate the association of interest. Infants were classified into weight-forgestational-age categories according to weight centiles for the Asian population. Gestational age was based on the date of last menstrual period and adjusted by the results of first-trimester ultrasound. Findings BMI was low (< 18.5), normal (18.5–22.9) and high (≥ 23.0) in 26.1%, 65.4% and 8.5% of the women, respectively. In each of these BMI categories, the percentage of women who delivered infants too small for gestational age was 18.1, 10.0 and 9.4, respectively, and the mean gestational weight gain was 12.5 kg (standard deviation, SD: ± 3.6), 12.2 kg (SD: ± 3.8) and 11.5 kg (SD: ± 4.7), respectively. Among women with low BMI, the risk of delivering an infant too small for gestational age ranged from approximately 40% if the gestational weight gain was < 5 kg to 20% if it was 5–10 kg. Conclusion Having a low BMI, commonly found in Viet Nam, puts women at risk of delivering an infant too small for gestational age, especially when total maternal gestational weight gain is < 10 kg.

Objective: Down syndrome (DS) patients share certain neuropathological features with Alzheimer disease patients. A randomized, double-blind, placebo-controlled study was performed to investigate the efficacy and safety of donepezil, an Alzheimer disease drug, for DS patients. Method: Twenty-one DS patients with severe cognitive impairment were assigned to take donepezil (3 mg daily) or a placebo for 24 weeks, and evaluated for activities in daily lives by concisely modified International Classification of Functioning, Disability and Health (ICF) scaling system. Results: ICF scores significantly increased without any adverse effects in the donepezil group in comparison to those in the placebo control. Among the individual functions tested, there was a dramatic improvement in the global mental functions and in specific mental functions. Conclusions: Donepezil may effectively and safely improve overall functioning of DS patients with severe cognitive impairment.

Background: Epidemiology of cytomegalovirus (CMV) infection varies widely, depending on ethnicity and socioeconomic status. A seroepidemiological survey was conducted to determine CMV infection among pregnant women in Nagasaki Prefecture, Japan. Methods: We measured serum CMV-specific immunoglobulin (Ig) M and IgG at the first and third trimesters. IgG avidity was determined when both CMV-IgG and CMV-IgM were positive. Results: Of 339 pregnant women, 296 (87.3%) were CMV-IgG-positive at the first trimester. Of 267 paired sera, one (0.37%) had CMV-IgG seroconversion, another one (0.37%) had CMV-IgM seroconversion, and 12 had both CMV-IgG and CMV-IgM, two (0.75%) of whom had low IgG avidity, suggesting recent infection. Thus, the incidence of primary CMV infection during pregnancy was 0.74–1.5%. Assuming the rate of in utero transmission following maternal primary infection to be approximately 40%, the incidence of congenital infection is estimated to be 0.3–0.6%. Conclusion: Although CMV seroprevalence among pregnant women has been decreasing in industrialized regions including other parts of Japan, CMV-seroprevalence remains high in Nagasaki. Thus, epidemiology of CMV infection seems variable within Japan, a country generally considered to be ethnically and socioeconomically homogeneous. However, 40–80 infants may be congenitally infected and 15–27% (or 6–22) of them may ultimately suffer from certain neurological sequelae annually in Nagasaki Prefecture, so where annual live births are approximately 13,300, congenital CMV infection seems to be a significant public health problem in such an apparently low-risk region as Nagasaki.

Aim: TT virus (TTV) is genetically variable and widespread without apparent pathogenicity; however, its epidemiological features in children were not fully understood, partly because blood sampling is often unacceptable for healthy children. We therefore used saliva specimens to investigate epidemiology of TTV infection in early childhood. Methods: Saliva samples were collected from 83 1-month-old, 110 4-month-old and 49 42-month-old children. Peripheral blood mononuclear cells (PBMC) and saliva samples were obtained in pairs from 19 healthy adults aged 40 ± 7 years. TTV DNA was detected and quantified by real-time PCR and classified into five genogroups (G1–G5) by a series of PCRs using genogroup-specific primer pairs. Results: TTV DNA was detected in 6, 34 and 90% of children aged 1, 4 and 42 months, respectively, and in 84% of adults. Comparable levels of TTV DNA were detected in pairs of saliva and PBMC. TTV loads in saliva were much higher in children than in adults. G3 was the most common genogroup in all age groups. The second most prevalent was G4 at 1–4 months of age and G1 thereafter. Conclusion: The prevalence of TTV infection reached a plateau at or before 42 months; however, somehow different epidemiologic features were observed among genogroups.

Purpose: To define the most appropriate time for surgery for medically intractable epilepsies in infants and young children. Methods: First we examined retrospectively the changes in developmental quotients (DQs) during the clinical course and the clinical factors affecting the DQ in 39 consecutive patients younger than 15 years, who underwent surgical treatment for intractable epilepsy. Second, we examined prospectively five new patients for early detection of developmental arrest or regression by periodic developmental assessments and whether this could lead to early surgical intervention, eventually resulting in minimal developmental defects. Results: Retrospective studies revealed that the DQ progressively decreased with age and that the reduction of DQ was related to continuing frequent seizures in many patients. The prospective studies demonstrated that periodic developmental assessments could detect the reduction of DQ at 5 months or later after onset of frequent seizures in three patients. In two other patients, operations were performed before reduction of DQs, and their postoperative DQ levels were normal. The postoperative recovery of DQ was complete in one patient whose operation was performed 3 months after reduction of DQ, whereas it was incomplete in two others whose operations were carried out at 12 and 14 months after reduction, respectively. Furthermore, three patients with norrnal developmental outcome had shorter periods between the onset of frequent seizures and the operation (≤7 months) than those of two patients with developmental delay (≥17 months). Conclusions: To minimize the developmental defects, periodic developmental assessments should be initiated when frequent seizures have occurred, and surgery should be considered as soon as possible when DQ reduction is recognized.

Background: Echocardiography remains the cornerstone of diagnosis of cardiac complications in patients with Kawasaki disease (KD), and is also useful for the diagnosis of incomplete KD (i-KD). Since echocardiographic evaluation is based on somewhat subjective assessment by pediatric cardiologists, objective diagnostic measures by which general pediatricians can screen high-risk patients or make diagnosis of i-KD are desired. Objective: To assess D-dimer and fibrinogen degradation products (FDP) as possible markers of coronary vascular damage in KD patients. Design/Methods: Between June 2008 and March 2014, we recruited 121 KD patients: 86 with complete KD (c-KD) treated with intravenous immunoglobulin (IVIG), 10 with c-KD treated only with aspirin (a-KD), 16 with i-KD fulfilling four major criteria, and seven with severe refractory KD (s-KD). Control patients included five with Henoch-Schonlein purpura (HSP), 15 with fibrile convulsion (FC), and 39 with pneumonia. We retrospectively checked their medical records, echocardiography, and blood test results on admission and after IVIG therapy. Results: Peak D-dimer values (normal range < 1.0 μg/ml) were significantly higher in c-KD (2.9±2.4) than in a-KD (1.1±0.7), FC (0.8±0.4) and pneumonia (1.3±1.1) groups (p < 0.05). Peak FDP value in the c-KD group was 6.8±4.7 μg/ml (< 5.0). Peak D-dimer and FDP values were the highest in the HSP group, followed by the s-KD group, and were comparable between the i-KD and c-KD groups. D-dimer values (2.9±1.4) at post IVIG were higher than those on admission (1.8±1.1) (p < 0.0001), while there was no significant change in FDP values. There was no significant difference in D-dimer or FDP values between KD with cardiac finding(s) and without. WBC and CRP values had no correlation with those of FDP or D-dimer. Receiver operating characteristic analysis determined a cut-off value of 1.1 μg/ml for D-dimer for c-KD, with the area under the curve (AUC) 0.85, sensitivity 0.95, specificity 0.59 and probability 0.44. Similarly, a cut-off value for FDP was determined as 2.5 μg/ml with AUC 0.90, sensitivity 0.89, specificity 0.70 and probability 0.40. Conclusions: Elevated D-dimer and FDP values help assist diagnosis of i-KD, but cannot predict cardiac complications in KD patients.

We report a case of Langerhans' cell histiocytosis (LCH) occurring after a living donor liver transplantation (LDLT) for fulminant hepatitis. A 9-month-old girl underwent an LDLT for fulminant hepatitis of an unknown cause. The histology of the native liver did not show any findings of LCH. On postoperative day 42, her Epstein-Barr virus (EBV)-DNA and cytomegalovirus antigenemia were both found to be positive. As a result, she was treated with antiviral agents and a reduction of the immunosuppression dosage. On postoperative day 98, acute rejection occurred, and she was treated with FK506, methylprednisolone, and finally, anti-CD3 murine monoclonal antibody was added. Subsequently, the EBV was re-activated. Thereafter, skin eruptions, swelling of the systemic lymph nodes, and pancytopenia appeared on postoperative day 127. LCH was diagnosed based on the typical histological findings as LCH, CD1a, and S-100-positive cells in her skin and a lymph nodes biopsy. She was treated by chemotherapy. The symptoms disappeared a few weeks after the start of the chemotherapy, and a clinical remission of LCH was obtained. We could not detect any evidence of EBV infection in the tumor cells. In spite of the fact that her LCH lesions thereafter remained in remission, she died of hepatic failure at 22 months after undergoing the liver transplantation. In conclusion, we discuss the factors influencing the occurrence of LCH in our patient after LDLT, while also evaluating the relationship between LCH and the immunosuppressive therapy administered to this patient.

近年,小児の特発性腸重積症例の減少が多くの施設で報告されている.しかし地域での発症数は地形,交通状況,病院の規模・数・配置により患者が地域を越えて移動する場合があるためその検討は容易ではない.今回われわれは他の地域から比較的隔離され患者の移動が少ない長崎市とその近郊の小児をコホートとして,小児特発性腸重積症の発生推移について検討した. 1980年から1999年までの20年間に経験した小児特発性腸重積症521例と長崎市近郊の出生数を比較検討したところ,症例数・出生数共に減少傾向を認めたものの,症例数を出生数で除した腸重積症発生率は明らかな増加,あるいは低下を認めなかった.