Neonatal-onset pulmonary alveolar proteinosis is a phenotype associated with poor outcomes in surfactant protein-C disorder.

BACKGROUND: Surfactant protein C (SP-C) disorder is a major component of hereditary interstitial lung disease (HILD) among Japanese. The correlation between clinical outcomes and the phenotype/genotype of SP-C disorder has not been evaluated comprehensively. The current study aimed to evaluate the phenotype/genotype correlated with poor outcomes in patients with SP-C disorder. METHODS: Sequencing analysis of SFTPC in 291 candidates with HILD was performed. The phenotype and genotype correlated with poor outcomes were examined. The log-rank test was used to compare the probability of good outcomes between two patient groups. RESULTS: Twenty patients were diagnosed with SP-C disorder. Of nine patients with neonatal-onset disease, four and five presented with pulmonary alveolar proteinosis (PAP) and interstitial pneumonitis (IP), respectively. The remaining 11 patients with late-onset disease had IP. In total, four and 16 patients had PAP and IP phenotypes, respectively. Four of nine patients with neonatal-onset disease died, and one survived after lung transplant. Further, 1 of 11 patients with late-onset disease died. Four patients with neonatal-onset PAP had a significantly lower probability of good outcomes than the remaining patients. Two patients with neonatal-onset PAP had the p.Leu45Arg variant, one died and the another survived after lung transplant. Of eight patients with variants in the BRICHOS domain, one with frame shift variant located in exon 4, one with variant located at the splicing acceptor site of exon 4, and one with variant located at the splicing donor site of exon 4 died. CONCLUSION: Neonatal-onset PAP was a phenotype predicting poor outcomes in patients with SP-C disorder. The p.Leu45Arg variant and splicing disorder of exon 4 might be genotypes predicting poor outcomes in patients with SP-C disorder.

Distal arthrogryposis in a girl arising from a novel TNNI2 variant inherited from paternal somatic mosaicism.

TNNI2 at 11p15.5 encodes troponin I2, fast skeletal type, which is a member of the troponin I gene family and a component of the troponin complex. Distal arthrogryposis (DA) is characterized by congenital limb contractures without primary neurological or muscular effects. DA is inherited in an autosomal dominant fashion and is clinically and genetically heterogeneous. Exome sequencing identified a causative variant in TNNI2 [NM_003282.4:c.532T>C p.(Phe178Leu)] in a Japanese girl with typical DA2b. Interestingly, the familial study using Sanger sequencing suggested a mosaic variant in her healthy father. Subsequent targeted amplicon-based deep sequencing detected the TNNI2 variant with variant allele frequencies of 9.4-17.7% in genomic DNA derived from peripheral blood leukocytes, saliva, hair, and nails in the father. We confirmed a disease-causing variant in TNNI2 in the proband inherited from her asymptomatic father with its somatic variant. Our case demonstrates that careful clinical and genetic evaluation is required in DA.

Preterm toddlers have low nighttime sleep quality and high daytime activity.

A number of studies have been made on the sleep characteristics of children born preterm in an attempt to develop methods to address the sleep problems commonly observed among such children. However, the reported sleep characteristics from these studies vary depending on the observation methods used, i.e., actigraphy, polysomnography and questionnaire. In the current study, to obtain reliable data on the sleep characteristics of preterm-born children, we investigated the difference in sleep properties between 97 preterm and 97 term toddlers of approximately 1.5 years of age using actigraphy. Actigraphy units were attached to the toddlers' waists with an adjustable elastic belt for 7 consecutive days, and a child sleep diary was completed by their parents. In the study, we found that preterm toddlers had more nocturnal awakenings and more daytime activity, suggesting that preterm-born children may have a different process of sleep development in their early development.

Sleep maturation influences cognitive development of preterm toddlers.

Our recent study on full-term toddlers demonstrated that daytime nap properties affect the distribution ratio between nap and nighttime sleep duration in total sleep time but does not affect the overall total amount of daily sleep time. However, there is still no clear scientific consensus as to whether the ratio between naps and nighttime sleep or just daily total sleep duration itself is more important for healthy child development. In the current study, to gain an answer to this question, we examined the relationship between the sleep properties and the cognitive development of toddlers born prematurely using actigraphy and the Kyoto scale of psychological development (KSPD) test. 101 premature toddlers of approximately 1.5 years of age were recruited for the study. Actigraphy units were attached to their waist with an adjustable elastic belt for 7 consecutive days and a child sleep diary was completed by their parents. In the study, we found no significant correlation between either nap or nighttime sleep duration and cognitive development of the preterm toddlers. In contrast, we found that stable daily wake time was significantly associated with better cognitive development, suggesting that sleep regulation may contribute to the brain maturation of preterm toddlers.

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.

Influence of light exposure at nighttime on sleep development and body growth of preterm infants.

Previous studies have demonstrated that a light-dark cycle has promoted better sleep development and weight gain in preterm infants than constant light or constant darkness. However, it was unknown whether brief light exposure at night for medical treatment and nursing care would compromise the benefits brought about by such a light-dark cycle. To examine such possibility, we developed a special red LED light with a wavelength of >675 nm which preterm infants cannot perceive. Preterm infants born at <36 weeks' gestational age were randomly assigned for periodic exposure to either white or red LED light at night in a light-dark cycle after transfer from the Neonatal Intensive Care Unit to the Growing Care Unit, used for supporting infants as they mature. Activity, nighttime crying and body weight were continuously monitored from enrolment until discharge. No significant difference in rest-activity patterns, nighttime crying, or weight gain was observed between control and experimental groups. The data indicate that nursing care conducted at 3 to 4-hour intervals exposing infants to light for <15 minutes does not prevent the infants from developing circadian rest-activity patterns, or proper body growth as long as the infants are exposed to regular light-dark cycles.

Decreased baseline variability on fetal heart rate pattern in a fetus with heterotaxy syndrome.

In a fetus with suspected heterotaxy syndrome, a decreased/absent baseline variability of fetal heart rate pattern developed at gestational week 36(+5) and continued for 5 days until birth at gestational week 37(+2), while repeat biophysical profile scorings with ultrasound were consistently unremarkable. This neonate weighing 2404 g with Apgar scores of 7 (1-min) and 8 (5-min) and umbilical arterial cord blood pH of 7.28 with base deficit of 3.9 mmol/L, showed a heart rate of 120 b.p.m. for 3 h after birth, but subsequently developed sinus bradycardia (84 b.p.m.) unresponsive to crying. Isoproterenol initiated 9 h after birth was effective in the increase of heart rate to 120 b.p.m. in this neonate. Brain magnetic resonance imaging at 16 days of age was unremarkable. The decreased/absent baseline variability of fetal heart rate pattern was speculated to have been caused by sinus node dysfunction, and not by reduced fetal oxygenation in this case.

Outcomes of 83 fetuses exposed to angiotensin receptor blockers during the second or third trimesters: a literature review.

This literature review was conducted to provide better counsel to pregnant women who erroneously took angiotensin receptor blockers (ARBs) during the second and/or third trimesters regarding infant outcomes. Information was available on 83 fetuses in 34 literature reports, including one that we encountered recently. Fourteen pregnancies were terminated, and six were unknown regarding status of amniotic fluid volume (AFV). Fifty-eight and five fetuses did and did not show oligohydramnios, respectively, after being exposed to ARBs. Of the 58 fetuses that presented with oligohydramnios, 57 were exposed to ARBs at gestational week (GW) ⩾ 20, and 19 exhibited resolution of oligohydramnios 1-6 weeks after cessation of ARBs. The 24 mothers without oligohydramnios at delivery ceased taking ARBs earlier (GW of 26.8 ± 5.1 vs. 31.8 ± 4.0, respectively, P = 0.000) and had longer duration of gestation after cessation of ARBs (8.4 ± 5.2 vs. 0.7 ± 2.3 weeks, respectively, P = 0.000). The mothers without oligohydramnios also had better outcomes in terms of favorable infant outcomes (63% (15/24) vs. 15% (6/39), respectively, P = 0.000) and infant mortality rates (13% (3/24) vs. 56% (22/39), respectively, P = 0.001) than the 39 with oligohydramnios. Thus, a favorable outcome may be feasible if the fetuses are not indicated for prompt delivery at presentation and exhibit normal AFV or resolution of oligohydramnios after cessation of ARBs. Although the prevalence rate of oligohydramnios was high in this study, it may have been due to publication bias. A prospective study suggested a lower prevalence rate than that reported in the present study.

Exchange transfusion in patients with Down syndrome and severe transient leukemia.

BACKGROUND: Among neonates with Down syndrome (DS) and transient leukemia (TL), hyperleukocytosis (white blood cell [WBC] count >100 × 10(9) /L) is associated with increased blood viscosity, respiratory failure due to pulmonary hypertension, multiorgan failure, and increased risk of early death. There have been no previous studies focusing on the effects of exchange transfusion (ExT) on WBC count, respiratory status, and other parameters in TL patients with hyperleukocytosis. METHODS: An observational retrospective study was carried out at a single center of all five DS neonates with TL, GATA1 mutations, and hyperleukocytosis, born at a median gestational age of 34 weeks (range, 30-38 weeks) with birthweight 2556 g (range, 1756-3268 g) during a 24 month study period between September 2011 and August 2013. All five neonates underwent ExT at a median age of 2 days (range, 0-5 days) before initiation of other cytoreductive therapy with cytarabine, which was carried out in two patients. RESULTS: All patients required respiratory support before ExT. After ExT, respiration status improved in all five patients: WBC count (mean) decreased by 85% from 143 × 10(9) /L to 21 × 10(9) /L. None developed tumor lysis syndrome. Three survived and two died: one hydrops fetalis neonate born at gestational week 30 died at age 5 days, and another died eventually from acute gastroenteritis 40 days after leaving hospital at the age of 155 days with complete remission. Two of the three surviving neonates developed acute megakaryocytic leukemia at age 90 days and 222 days. CONCLUSION: ExT was very effective in improving hyperleukocytosis and may have had favorable effects on respiration.

Hereditary interstitial lung diseases manifesting in early childhood in Japan.

BACKGROUND: Genetic variations associated with interstitial lung diseases (ILD) have not been extensively studied in Japanese infants. METHODS: Forty-three infants with unexplained lung dysfunction were studied. All 43, 22, and 17 infants underwent analyses of surfactant protein (SP)-C gene (SFTPC) and ATP-binding cassette A3 gene (ABCA3), SP-B gene (SFTPB), and SP-B western blotting, respectively. Two and four underwent assessment of granulocyte macrophage colony-stimulating factor-stimulating phosphorylation of signal transducer and activator of transcription-5 (pSTAT-5) and analyses of FOXF1 gene (FOXF1), respectively. RESULTS: ILD were diagnosed clinically in nine infants: four, three, and two had interstitial pneumonitis, hereditary pulmonary alveolar proteinosis (hPAP), and alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), respectively. Genetic variations considered responsible were detected in six (67%) of the nine infants with ILD: three with hPAP (SFTPC p.Leu45Arg and p.Gln145fs, and ABCA3 p.Arg1583Trp/p.Val1495CysfsX21), two with interstitial pneumonitis (SFTPC p.Lys63Glu and p.Ser72Asn/p.Gly100Ala), and one with ACD/MPV (FOXF1 p.Leu300ArgfsX79). None showed SFTPB mutations or defects in pSTAT-5. The 17 bronchoalveolar lavage or tracheal aspirates contained enough SP-B protein. CONCLUSION: The SP-C abnormality was most prevalent, and SP-B deficiency was rare in Japanese infants with hereditary ILD.