Hiroko Boda

A PDE3A mutation in familial hypertension and brachydactyly syndrome

Hypertension and brachydactyly syndrome (HTNB) with short stature is an autosomal-dominant disorder. Mutations in the PDE3A gene located at 12p12.2-p11.2 were recently identified in HTNB families. We found a novel heterozygous missense mutation c.1336T>C in exon 4 of the PDE3A gene in a Japanese family with multiple HTNB patients. This mutation was found to be completely linked to the family members who inherited this condition. The mutation, resulting in p.Ser446Pro, was located within the cluster region of reported mutations. This mutation may also affect the phosphodiesterase activity of PDE3A to reduce the cyclic AMP level in the cell and thereby influencing the development of limbs and the function of the cardiovascular system.

Inflammation aggravates heterogeneity of ventricular repolarization in children with Kawasaki disease.

Kawasaki disease complicates with myocarditis and vasculitis. Even if myocarditis is asymptomatic, heterogeneity of ventricular repolarization may be increased in the acute phase. We evaluated whether the change in repolarization characteristics can be used as a predictor for myocarditis and coronary lesions. Enrolled 34 children who were treated with intravenous immunoglobulin therapy. There were no sequelae in the recovery phase in any subjects, including those who had transient coronary artery lesion. QT and the interval from the Tpeak to Tend (Tp-e) were determined. The Tp-e/QT ratios were compared between the acute and recovery phases and correlations with CRP level and body temperature were evaluated. A retrospective evaluation of Tp-e/QT as predictors of coronary dilation was also performed. Tp-e/QT in the acute phase correlated positively with body temperature and CRP level. In a comparison of patients with and without transient coronary artery lesion, Tp-e/QT was significantly higher in those with dilation. In conclusion, Tp-e/QT was strongly related to transient coronary dilation, in comparison with inflammatory indicators including fever and CRP level.

Rotavirus Vaccination Can Be Performed Without Viral Dissemination in the Neonatal Intensive Care Unit

Background This study was conducted to assess the transmissibility of rotavirus vaccine strains after rotavirus vaccination in a neonatal intensive care unit (NICU). Methods Pentavalent (RV5) or monovalent (RV1) rotavirus vaccine was administered to infants admitted to the NICU. Nineteen vaccinated infants and 49 unvaccinated infants whose beds were located in close proximity to the vaccinated infants were enrolled in this study. Dissemination and fecal shedding of vaccine viruses within the NICU were examined using real-time reverse transcription-polymerase chain reaction. Results Shedding of the vaccine strain was detected in all 19 vaccinated infants. RV5 virus shedding started 1 day after the first vaccination and persisted for 8 days after the first vaccination, and viral shedding terminated by day 5 after administration of the second RV5 dose. The kinetics of RV1 virus shedding differed among vaccinated infants. The duration of RV1 virus shedding was longer after the first vaccination than after the second vaccination. In contrast to the vaccinated infants, no vaccine virus genomes were detected in any of the stool samples collected from the 49 unvaccinated infants. Conclusions This study is direct evidence of no transmission of rotavirus vaccine strains between vaccinated infants and unvaccinated infants in close proximity within a NICU.

Intragenic duplication in the PHKD1 gene in autosomal recessive polycystic kidney disease

BackgroundIn the present study, we report on a couple who underwent prenatal genetic diagnosis for autosomal recessive polycystic kidney disease (ARPKD).Case presentationThis healthy couple had previously had a healthy boy but had experienced two consecutive neonatal deaths due to respiratory distress resulting from pulmonary hypoplasia caused by oligohydramnios. The woman consulted our facility after she realized she was pregnant again. We promptly performed a carrier test for the PKHD1 gene by target exome sequencing of samples from the couple. A pathogenic mutation was identified only in the paternal allele (c.9008C>T, p.S3003F). The mutation was confirmed by Sanger sequencing of the DNA from formalin-fixed, paraffin-embedded, kidney tissue of the second neonate patient and was not found in the healthy sibling. We then performed haplotype analyses using microsatellite markers scattered throughout the PKHD1 gene. DNA from the amniocentesis was determined to belong to a carrier, and the couple decided to continue with the pregnancy, obtaining a healthy newborn. Subsequent detailed examination of the exome data suggested higher read depth at exons 45 and 46. Multiplex ligation-dependent probe amplification allowed identification of duplication of these two exons. This case suggests the potential usefulness of target exome sequencing in the prenatal diagnosis of the PKHD1 gene in ARPKD.ConclusionsThis is the first report of intragenic duplication in the PKHD1 gene in ARPKD.

Electrocardiographic RR and QT Interval Variability in Patients with Atrial Septal Defect and Healthy Children

Atrial septal defect is a common congenital heart disease. In patients with atrial septal defect, left-to-right shunting increases the right atrial and right ventricular preload. This pathological change affects sinus node automaticity and myocardial depolarization and repolarization, and has the potential to evoke arrhythmogenic substrates. We examined the effect of atrial septal defect on sinus node automaticity and myocardial repolarization by investigating the variability in the repolarization interval, namely the QT variability index (QTVI) and variability ratio (VR). This retrospective study included 38 patients (mean age, 2.2 ± 1.9 years; mean left-to-right shunt ratio, 2.1 ± 0.70) and 40 age-matched healthy control subjects evaluated from 2008 to 2015. QTVI was calculated using the ratio of the repolarization parameter variance to heart rate variance, and VR was calculated as the ratio of the standard deviation (SD) of QT intervals to the SD of RR intervals on electrocardiography. There was a significant difference in the SD of all normal RR intervals, heart rate variance, VR, and QTVI of control subjects or patients with low shunt ratio compared with patients with high shunt ratio (all P < 0.05). Linear regression analysis revealed strong positive correlations between the left-to-right shunt ratio and VR (r = 0.662, P < 0.0001) or QTVI (r = 0.808, P < 0.0001). These repolarization indices provide information on alteration of sinus node autonomic control and the pathophysiology of myocardial repolarization, and could be used as a noninvasive indicator of the shunt ratio in children with atrial septal defect.

Relationship between QT and JT peak interval variability in prepubertal children

The QT variability index (QTVI) is a noninvasive index of repolarization lability that has been applied to subjects with cardiovascular disease. QTVI provides a ratio of normalized QT variability to normalized heart rate variability, and therefore includes an assessment of autonomic nervous activity. However, measurement of QT time is particularly difficult in children, who exhibit physiologically high heart rates compared with adults. In this study, we developed a set of standard values of J‐point to Tpeak interval (JTp) for infants by age, and assessed the correlation of QTVI with the JTp variability index (JTpVI).

A Family With Craniofrontonasal Syndrome: The First Report of Familial Cases of Craniofrontonasal Syndrome With Bilateral Cleft Lip and Palate

Craniofrontonasal syndrome (CFNS) is a very rare genetic disorder, the common physical malformations of which include coronal synostosis, widely spaced eyes, clefting of the nasal tip, and various skeletal anomalies. Mutations of EFNB1, which encodes a member of the ephrin family of transmembrane ligands for Eph receptor tyrosine kinases, is the cause of CFNS. Although familial CFNS cases have been reported, no studies in the literature describe familial cases of CFNS expressing bilateral cleft lip and palate. Here, we describe a Japanese family with three cases of CFNS expressing bilateral cleft lip and palate.

Maturation of the QT Variability Index is Impaired in Preterm Infants

Reduced heart rate (HR) variability in preterm infants compared with full-term infants suggests that autonomic cardiac control is developmentally delayed. However, the association between developmental changes in myocardial repolarization and gestational age remains unknown. This study investigated the association between the myocardial repolarization lability index, namely the QT variability index (QTVI) = log10 [(QTv/QTm2)/(HRv/HRm2)], and the perinatal profile of healthy 1-month-old infants. We included 209 infants (143 boys and 87 girls; mean gestational weeks at birth, 38.6 ± 1.7) who were born in university hospitals between 2014 and 2015 without apparent cardiac disease. We compared the ECG variability indices in 28 infants born before 37 gestational weeks (mean gestational weeks at birth, 35.6 ± 1.1 as preterm) and 181 infants born at the average number of gestational weeks (mean gestational weeks at birth, 38.8 ± 1.1 as controls). There was a negative correlation between the QTVI and gestational weeks (r = − 0.460, p = 0.035). QTVI values in preterm infants were larger than those in the controls (0.01 ± 0.50 vs. −0.26 ± 0.48, p = 0.023). In conclusion, the QTVI is negatively correlated with gestational age. The QTVI can serve as an index of the maturity of the cardiac autonomic nervous system and myocardial depolarization.