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Cholestasis is a rare but life-threatening complication of congenital syphilis. However, standard management methods for this disease have not been established. Here, we report a case of congenital syphilis presenting with progressively worsening cholestasis, and we review the clinical features and management practices. In these cases, differentiation from other diseases presenting with cholestasis during the neonatal period, such as biliary atresia, is critical. In this regard, operative cholangiogram and histopathological analysis of the liver are required. Moreover, comprehensive genetic analysis can be useful. Although there is no specific treatment for cholestasis associated with congenital syphilis, appropriate nutritional management and supplementation with fat-soluble vitamins, especially vitamin K, should be provided. The severity of liver fibrosis may affect the prognosis of cholestasis associated with congenital syphilis. Therefore, attention should be paid to liver fibrosis in these patients.

Mother-to-child transmission of the hepatitis B virus (HBV) is a major concern for infected mothers, especially after their first child has become an HBV carrier despite immunoprophylaxis. Eight mothers whose first child had become an HBV carrier despite immunoprophylaxis were referred for antiviral therapy during the subsequent pregnancy. All pregnant women were seropositive for both the hepatitis B surface antigen and hepatitis B e antigen. In the treatment group (three receiving lamivudine and two receiving tenofovir), mother-to-child transmission of the HBV was successfully prevented in all infants (5/5). On the other hand, two of three infants became HBV carriers in the untreated group. There were no significant adverse effects in either mothers or infants. Antiviral therapy using lamivudine and tenofovir during the second pregnancy successfully prevented mother-to-child transmission of the HBV for high-risk mothers.

Background: Phototherapy with radiation of 460–490 nm wavelengths provides the most potent therapeutic effect for neonatal jaundice. However, the efficacy of phototherapy has been estimated using single-wavelength detectors with sensitivity at approximately 460 nm. Cyclobilirubin formation capacity (CFC), which comprises the sum of the irradiance values from three wavelengths multiplied by their specific coefficients, has been proposed as an alternative marker to evaluate the efficacy of phototherapy. This study aimed to test whether two types of phototherapy devices with distinct spectral characteristics provide similar therapeutic effects on adjustment of device-to-patient distances to deliver similar CFCs. Methods: Using a three-wavelength spectroradiometer, CFCs and footprints of the light-emitting diode and fluorescent tube devices were assessed. Having determined the device-specific distances that ensured similar CFCs, 32 newborn infants, requiring phototherapy for hyperbilirubinemia, were randomized into the light-emitting diode and fluorescent tube groups. The total serum bilirubin levels before and after phototherapy were assessed. Results: The light-emitting diode and fluorescent tube devices had comparable CFCs at distances of 60 and 50 cm, respectively. Phototherapy reduced the total serum bilirubin levels from 18.1 to 14.6 mg/dL and from 19.1 to 15.1 mg/dL in the light-emitting diode and fluorescent tube groups, respectively. The two groups did not differ significantly with respect to the patients' clinical backgrounds, serum bilirubin levels, or changes before and after phototherapy. Conclusion: At similar CFCs, the two phototherapy devices reduced the total serum bilirubin levels by comparable amounts. Hence, determining CFCs may help predict phototherapy efficacy. This may ensure better safety and greater efficacy of the treatment for newborn infants. Key Words: bilirubin, cyclobilirubin, irradiance, light-emitting diode, spectroradiometer

The bile salt export pump is expressed at the canalicular membrane of hepatocytes and mediates biliary excretion of bile salts. 4-Phenylbutyrate (4 PB), a drug used to treat ornithine transcarbamylase deficiency, has been found to increase the hepatocanalicular expression of bile salt export pump. The beneficial effects of 4-phenylbutyrate therapy have been reported for patients with progressive familial intrahepatic cholestasis, an inherited autosomal recessive liver disease. This is the first study to show the therapeutic effect of 4 PB in a preterm infant with cholestasis and liver fibrosis. The preterm infant had severe cholestasis with jaundice and failure to thrive refractory to ursodeoxycholic acid. Histology indicated giant cell hepatitis, cholestasis, and severe fibrosis. Bile salt export pump immunostaining showed lower expression than in a control. Oral 4 PB was started at a daily dose of 200 mg/kg/day. After the start of 4 PB therapy, cholestasis improved.

Background Persistent patent ductus arteriosus (PDA) is a frequent complication in preterm infants. Single nucleotide polymorphisms (SNP) in several genes, including angiotensin II receptor, type 1 (AGTR1), transcription factor AP-2 beta (TFAP2B) and tumor necrosis factor receptor-associated factor 1 (TRAF1), have been reported to be associated with PDA in preterm infants. The aim of this study was to evaluate the relationships between PDA in preterm infants and polymorphisms in AGTR1, TFAP2B and TRAF1 in the Japanese population. Methods The subjects consisted of 107 preterm infants with gestational age

We report a case of nemaline myopathy with KLHL40 mutation, presenting as congenital totally locked-in state. At birth, a male patient developed hydrops fetalis, which was diagnosed based on the generalized edema and pleural effusion and could perform no significant spontaneous movements. His eyes were open, without blinking, and the eyeballs were locked in the midposition. He could not express his intentions by vocalization or moving his trunk, extremities, facial muscles, mouth, eyelids, or eyeballs in response to ambient events or personal interactions. Electrophysiological tests and neuroimaging revealed no evidence of visual or auditory impairment that might indicate a lack of sensory perception, and no evidence of impaired consciousness or intellectual disorder(s) that might prevent him from recognizing ambient events or expressing his intentions. He subsequently died at 4 years of age. Our case highlights the fact that severe congenital neuromuscular disorders can present as congenital totally locked-in state, and that special attention should be provided to these patients.

SUMMARY Objective To prevent neonatal alloimmune thrombocytopenia due to anti-group A antibody perinatal management was performed. Background We previously reported a case of severe intracranial haemorrhage associated with neonatal alloimmune thrombocytopenia due to anti-group A isoantibody. Material/Methods A 40-year-old Japanese woman, gravida 4 para 1, was pregnant with her second baby. The previous sibling developed severe thrombocytopenia and died 10 days after birth due to intracranial haemorrhage. He was diagnosed with neonatal alloimmune thrombocytopenia; the causative antibody was found to be the anti-group A antibody. Prednisone was started at 7 weeks' gestational age. Intravenous immunoglobulin 1 g kg−1 week−1 was started at 29 weeks' gestational age and continued to delivery. Serological studies and genotyping were performed. Results The second boy was delivered at 33 weeks' gestational age by caesarean section. He was discharged without intracranial haemorrhage or thrombocytopenia. The anti-group A antibody titre in the maternal serum was 2048–4096 (normal range: 4–64). The anti-group A antibody titre in the newborn's serum was 4. Cross-matching between the maternal serum and the paternal platelets was positive. Conclusion Owing to the history of neonatal alloimmune thrombocytopenia causing intracranial haemorrhage and death of the previous sibling, strict follow-up of the subsequent pregnancy was conducted.

Aim We evaluated combined genetic analyses with targeted next-generation sequencing (NGS), multiplex ligation probe amplification (MLPA) of Jagged1 (JAG1) genes and microarray comparative genomic hybridisation (CGH) in subjects with Alagille syndrome, incomplete clinical features of Alagille syndrome and biliary atresia. Methods Subjects recruited from April 2013 to December 2015 underwent a targeted NGS analysis, including JAG1 and Notch homolog 2 (NOTCH2). If no mutations were detected in JAG1 or NOTCH2, or if copy number variations were suggested by the NGS analysis, we performed an MLPA analysis of JAG1. We also performed a microarray CGH analysis with whole-exon deletion detected by the MLPA analysis. Results We analysed 30 subjects with Alagille syndrome, nine with incomplete Alagille syndrome and 17 with biliary atresia and detected pathogenic mutations in JAG1 or NOTCH2 in 24/30 subjects with Alagille syndrome and in 4/9 subjects with incomplete Alagille syndrome. No pathogenic mutations were detected in subjects with biliary atresia. The frequency of JAG1 mutations was: single nucleotide variants (51.9%), small insertion or deletion (29.6%) and gross deletion (18.5%). Conclusion Combined genetic analyses achieved efficient diagnostic yields for subjects with Alagille syndrome and incomplete Alagille syndrome. This article is protected by copyright. All rights reserved.

Tolvaptan is an oral vasopressin type 2 receptor antagonist that can be used for heart failure patients with hyponatremia or symptomatic congestion. Although the effects of tolvaptan in adults have been well documented, only limited information is available in children. The case of a neonate with congestive heart failure complicated with chylothorax after palliative surgery for transposition of the great arteries treated with tolvaptan is reported. Slow up-titration to 0.1 mg/kg successfully increased urine output and improved refractory congestive heart failure without hypernatremia. Subsequently, bodyweight and chylothorax decreased gradually. Moreover, the use of tolvaptan reduced the dosage of furosemide. Tolvaptan could be an alternative drug for neonates with congestive heart failure. Further large studies are needed to confirm the efficacy and identify the appropriate dose of tolvaptan in neonates.

Holoprosencephaly (HPE) is a rare brain abnormality characterized by an incomplete cleavage of the primitive prosencephalon of forebrain during early embryogenesis. To determine the clinical characteristics and outcome of fetuses with HPE, we retrospectively analyzed nine patients who were prenatally diagnosed as fetal HPE by ultrasounds. The mean diagnostic weeks were 20 weeks of gestation. Two cases died within one day after birth. The chromosomal examinations were performed in seven cases (trisomy 18: n = 2; trisomy 13: n = 2; 45,XX,der(18)t(18;21)(p10;p10)mat: n = 1; normal karyotype: n = 2). In our HPE cases, most cases had serious facial anomalies and poor prognosis. Our data suggested that the early prenatal diagnosis of HPE allowed time for parental counseling and delivery planning.

The aim of the present study was to identify predictive data on the short-term outcomes of fetuses with oligohydramnios.A retrospective study of all pregnancies diagnosed with oligohydramnios was performed.A total of 17 fetuses (seven males, seven females, and three unknown) with oligohydramnios were treated from 2004 to 2011. Oligohydramnios was first diagnosed at a 21.6 ± 4.2 weeks gestation. Terminations of pregnancy before 22 weeks were identified in five cases, and intrauterine fetal deaths occurred in two cases. Ten neonates were born alive, five cases survived over 28 days, and five cases died within 48 hours. Prognostic factors for survival included birth weight (2,457 ± 480 grams in survivors vs. 1973 ± 124 grams in non-survivors; p0.05) and the mean amniotic fluid index (AFI) (2.32 ± 1.19 cm in survivors vs. 0.46 ± 0.68 cm in non-survivors;p0.05).All patients who survived had a mean AFI1.0 cm.

Periventricular leukomalacia is recognized as the leading cause of cerebral palsy in preterm infants. To clarify the prevalence of periventricular leukomalacia and cerebral palsy in Japan, a nationwide survey was performed. The prevalence of periventricular leukomalacia in the group of surviving preterm infants of gestational ages less than 33 weeks born in 2007 was 2.7% (78/2883) on ultrasound diagnosis, and 3.3% (92/2824) on magnetic resonance imaging. The prevalence of cerebral palsy was 4.3% (125/2883) on clinical diagnosis. In our previous study, the prevalences of periventricular leukomalacia in 1990-1991, 1993-1994, 1996, and 1999 were 4.8%, 4.9%, 4.9%, and 5.3% on ultrasound, and 7.9%, 7.7%, 6.9%, and 7.3% on magnetic resonance imaging, respectively. The prevalence of periventricular leukomalacia has decreased significantly in Japan.

Aim: There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN-α2a monotherapy for children infected by chronic hepatitis C virus (HCV). Methods: From 2004–2006, we conducted a prospective, open-label, multicenter study of 22 patients aged 4–18 years, including eight with genotype 1 and 14 with genotype 2. None had previously received IFN. The patients were treated with s.c. PEG IFN-α2a at a dose of 3 µg/kg once a week for 48 weeks. Rapid virological response (RVR) was defined as: undetectable serum HCV RNA at week 4; early viral response (EVR) as a 2 or more log reduction or undetectable serum HCV RNA at week 12; and sustained viral response (SVR) as undetectable serum HCV RNA at 24 weeks after the cessation of treatment. Results: SVR was achieved in 10 (45%) of the 22 patients (three with genotype 1, seven with genotype 2). Retrospectively, the patients with SVR included five with RVR (one with genotype 1, four with genotype 2) and five with EVR (two with genotype 1, three with genotype 2). PEG IFN-α2a monotherapy was well tolerated, except in one patient in whom alanine aminotransferase activity flared (>500 IU/L) during treatment. Conclusion: The efficacy of PEG IFN-α2a monotherapy in children is similar to that for adults, while tolerability seems to be better in children than in adults.

Objective To clarify the clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome. Study design Ten patients with neonatal Dubin-Johnson syndrome were recruited from 6 pediatric centers in Japan between September 2013 and October 2016. Clinical and laboratory course, macroscopic and microscopic liver findings, and molecular genetic findings concerning ATP-binding cassette subfamily C member 2 (ABCC2) were retrospectively and prospectively examined. Results All neonates exhibited cholestasis, evident as prolonged jaundice with or without acholic stools and elevations of serum direct bilirubin as well as γ-glutamyltransferase or total bile acids. Only 38% (3 of 8) of patients who underwent liver biopsy showed a grossly black liver or melanin-like pigment deposits in hepatocytes; their biopsies were performed in early infancy. Immunohistochemically, all liver specimens showed no expression of multidrug resistance-associated protein 2 but increased expression of the bile salt export pump protein. Homozygous or compound heterozygous pathogenic variants of ABCC2 were identified in all patients, representing 11 distinct pathogenic variants including 2 not previously reported. Conclusions Immunohistochemical staining of the liver for multidrug resistance-associated protein 2 and molecular genetic analysis of ABCC2 are crucial for accurate diagnosis of neonatal Dubin-Johnson syndrome.

Aplasia cutis congenita, congenital absence of a localized area of skin, usually on the vertex of the scalp, occurs as an isolated defect, or with one or more other congenital anomalies as part of a syndrome, sequence or association. To date, more than 500 cases have been reported. A more severe and extensive form, almost complete absence of skin and subcutaneous tissue, was reported by Park et al. in 1998 [J Med Genet 35:609-611]. Until now, no other such lethal case has been reported. Here, we report the second case of systemic aplasia cutis congenita. The female was born without any skin at all, and with hypoplastic lungs, syndactyly, skull defect, esophageal atresia, intestinal malrotation, and calcifications of the hepatic capsule, as well as with other anomalies. She died about 12 hours after birth probably due to dehydration. On microscopic examination, the external surface of the body showed complete absence of the epidermis. Muscle fibers were thin. There was no evidence of skin appendages. The present case gives strong support to the suggestion that systemic aplasia cutis congenita is a newly recognized syndrome. More cases will have to be reported and studied in order to understand the etiology and establish diagnostic criteria. Thus, it is our conclusion that systemic aplasia cutis congenita might be a newly recognized syndrome.

Despite administration of vitamin K (VK), some infants show lower activity of VK-dependent coagulation factors and they could develop intracranial hemorrhage. For preventing VK deficiency bleeding (VKDB) in infants, oral administration of VK and a screening test for VK deficiency are carried out in Japan. For the screening, the total activity of VK-dependent coagulation factors is measured using a commercial product, Normotest. This study was undertaken to clarify the importance of the following genetic and environmental factors on the coagulation status in one-month-old infants: two polymorphisms in the factor VII gene, -323P0/10 (a 10-bp insertion in the promoter region at position -323) and R353Q (the replacement of arginine [R] with glutamine [Q] at residue 353) and sex, age, gestational age, birth weight, and feeding regimen. Two hundred Japanese infants (34.6 +/- 4.0 days old) were screened for VK-dependent coagulation activity with Normotest and were genotyped for the two polymorphisms. Among the subjects screened, 18 infants (9%) carried the P10 allele and 26 (13%) carried the R353Q allele. Multiple regression analysis showed that the 10-bp inserted (P10) allele or the Q allele was associated with the lower coagulation activities. The coagulation activities for the R/Q genotype were significantly lower than those for the R/R genotype and those for the P0/P10 genotype were significantly lower than those for the P0/P0 genotype. Therefore, infants who carry the P10 allele or the Q allele show lower activity of VK-dependent coagulation factors. These infants may have a higher risk of VKDB manifestation.

Persistent patent ductus arteriosus (PDA) is a frequent complication in preterm infants. Single nucleotide polymorphisms (SNP) in several genes, including angiotensin II receptor, type 1 (AGTR1), transcription factor AP-2 beta (TFAP2B) and tumor necrosis factor receptor-associated factor 1 (TRAF1), have been reported to be associated with PDA in preterm infants. The aim of this study was to evaluate the relationships between PDA in preterm infants and polymorphisms in AGTR1, TFAP2B and TRAF1 in the Japanese population.The subjects consisted of 107 preterm infants with gestational age32 weeks. Extremely low-birthweight infants were treated with prophylactic indomethacin during the first 24 h after birth. Five SNP, namely, rs5186 in AGTR1, rs987237 and rs6930924 in TFAP2B, and rs1056567 and rs10985070 in TRAF1, were genotyped using TaqMan SNP genotyping assays.There were no significant differences in the distributions of the genotypes and allele frequencies of all studied SNP between the PDA group (n = 46) and the non-PDA group (n = 61).There were no significant associations between the studied SNP and the incidence of PDA in Japanese preterm infants. These SNP may not be clinically important predisposing factors for PDA in Japanese preterm infants.

A 1-year-old girl had pancreaticobiliary maljunction, a choledochal cyst, and polycystic kidney. At the age of 4 years, she was treated by resection of the choledochal cyst and Roux-en-Y reconstruction because of the cyst's risk of cancer. She was diagnosed as having congenital hepatic fibrosis based on the histological findings. Postoperatively, she suffered recurrent fever of unknown origin, refractory to several antibiotics. At the age of 6 years, she underwent living donor liver transplantation from her father. Multi-drug-resistant Pseudomonas aeruginosa was cultured in the recipient's liver. After liver transplantation, she had no episodes of recurrent fever. Roux-en-Y reconstruction should be avoided for ductal plate malformations such as congenital hepatic fibrosis.

Recently, a novel deoxyribonucleic acid (DNA) virus, designated SEN virus (SENV), was discovered and strong associations between the two SENV variants (SENV-D and SENV-H) and non-A to E hepatitis were reported. To clarify the character of SENV infection in children, we investigated the detection rates of serum SENV DNA by polymerase chain reaction (PCR) among children with non-A to C hepatitis, with histories of transfusions, with neither histories of transfusions nor liver diseases (control), and among pregnant women. SENV-D was detected in 60% of fulminant hepatitis, 5% of acute hepatitis, 11% of chronic hepatitis, 13% of controls, and 15% of pregnant women. SENV-H was detected in none of fulminant hepatitis, 5% of acute hepatitis, none of chronic hepatitis, 2% of controls, and 12% of pregnant women. No significant difference was found for SENV-D between acute or chronic hepatitis and controls, however SENV-D detection rate in fulminant hepatitis was significantly higher than that in controls (P

To study the effect of exchange transfusion on cytokine profiles in a patient with necrotizing enterocolitis, the levels of 12 cytokines and serum calprotectin were measured among exchange transfusion. A male extremely low birth weight infant was in non-compensated shock and diagnosed stage 3 necrotizing enterocolitis. Exchange transfusion was performed for critical condition, refractory hypotension and disseminated intravascular coagulation. After exchange transfusion, the patient's blood pressure increased and stabilized. Then an enterostomy was performed and revealed necrosis of the ascending colon. Of the cytokines examined, interleukin-8 and serum calprotectin were high before exchange transfusion and decreased after exchange transfusion.

Holoprosencephaly (HPE) is a rare brain abnormality characterized by an incomplete cleavage of the primitive prosencephalon of forebrain during early embryogenesis. To determine the clinical characteristics and outcome of fetuses with HPE, we retrospectively analyzed nine patients who were prenatally diagnosed as fetal HPE by ultrasounds. The mean diagnostic weeks were 20 weeks of gestation. Two cases died within one day after birth. The chromosomal examinations were performed in seven cases (trisomy 18: n = 2; trisomy 13: n = 2; 45,XX,der(18)t(18;21)(p10;p10)mat: n = 1; normal karyotype: n = 2). In our HPE cases, most cases had serious facial anomalies and poor prognosis. Our data suggested that the early prenatal diagnosis of HPE allowed time for parental counseling and delivery planning.

Tolvaptan is an oral vasopressin type 2 receptor antagonist that can be used for heart failure patients with hyponatremia or symptomatic congestion. Although the effects of tolvaptan in adults have been well documented, only limited information is available in children. The case of a neonate with congestive heart failure complicated with chylothorax after palliative surgery for transposition of the great arteries treated with tolvaptan is reported. Slow up-titration to 0.1 mg/kg successfully increased urine output and improved refractory congestive heart failure without hypernatremia. Subsequently, bodyweight and chylothorax decreased gradually. Moreover, the use of tolvaptan reduced the dosage of furosemide. Tolvaptan could be an alternative drug for neonates with congestive heart failure. Further large studies are needed to confirm the efficacy and identify the appropriate dose of tolvaptan in neonates.

Introduction: Cytomegalovirus is the most common cause of intrauterine infection in developed countries. Between 10% and 15% of infants infected with congenital cytomegalovirus exhibits the clinically apparent or symptomatic form of the disease. Exchange transfusion is an established therapy for hyperbilirubinemia and severe anemia. However, to the best of our knowledge, the viral load of cytomegalovirus before and after exchange transfusion has not been previously reported. Case report: A Japanese female was delivered at 36 weeks of gestation to a 29-year-old gravida 3 para 3 by emergency Cesarean section because of non-reassuring fetal status. Hepatomegaly, splenomegaly, generalized petechiae, leptocephaly, and jaundice were noted at birth. On admission, her total bilirubin was 14.2 mg/dL, cytomegalovirus immunoglobulin M was positive (4.63 mg/dL), and her head ultrasound and computed tomography showed left intraventricular calcification and bilateral ventriculomegaly. Toxoplasma, rubella, and herpes simplex virus serologies were negative. The exchange transfusion was performed for the treatment of early onset hyperbilirubinemia, not for the treatment of congenital cytomegalovirus infection. The cytomegalovirus viral load before and after exchange transfusion was investigated by real-time polymerase chain reaction, and the plasma viral load of cytomegalovirus was not significantly decreased from before (8.7×105/mL) to after (4.3×105/mL) exchange transfusion. Conclusion: Exchange transfusion did not reduce the viral load of cytomegalovirus in severe congenital cytomegalovirus infection.

To study the effect of exchange transfusion on cytokine profiles in a patient with necrotizing enterocolitis, the levels of 12 cytokines and serum calprotectin were measured among exchange transfusion. A male extremely low birth weight infant was in non-compensated shock and diagnosed stage 3 necrotizing enterocolitis. Exchange transfusion was performed for critical condition, refractory hypotension and disseminated intravascular coagulation. After exchange transfusion, the patient's blood pressure increased and stabilized. Then an enterostomy was performed and revealed necrosis of the ascending colon. Of the cytokines examined, interleukin-8 and serum calprotectin were high before exchange transfusion and decreased after exchange transfusion.

Neonatal alloimmune thrombocytopenia (NAIT) is a rare but clinically important etiology of intracranial hemorrhage. There have been no reported cases of intracranial hemorrhage caused by anti-group A or anti-group B antibodies. A Japanese boy weighing 1550 g was born at 37 weeks. He suffered from refractory thrombocytopenia and developed severe intracranial hemorrhage on his second day. Despite repeated platelet, red-cell and fresh-frozen-plasma transfusions, he died at day 10 of life. Serological studies and genotyping of the patient and his parents were performed. There were no incompatible genotypes of platelet antigens between the patient and the mother. Serological studies revealed that the mother had extremely high-titer anti-group A immunoglobulin G(2) (4096-fold) that reacted strongly with the father's platelets. The reaction against the father's platelets disappeared when her serum was adsorbed with group A red blood cells. Maternal anti-group A antibody was associated with NAIT and severe bilateral intracranial hemorrhage.

Objectives To ascertain a molecular genetic diagnosis for subjects with neonatal/infantile intrahepatic cholestasis (NIIC) by the use of next-generation sequencing (NGS) and to perform a genotype-phenotype correlation. Study design We recruited Japanese subjects with NIIC who had no definitive molecular genetic diagnosis. We developed a diagnostic custom panel of 18 genes, and the amplicon library was sequenced via NGS. We then compared clinical data between the molecular genetically confirmed subjects with NIIC. Results We analyzed 109 patients with NIIC (“genetic cholestasis,” 31 subjects; “unknown with complications” such as prematurity, 46 subjects; “unknown without complications,” 32 subjects), and a molecular genetic diagnosis was made for 28 subjects (26%). The rate of positive molecular genetic diagnosis in each category was 22 of 31 (71%) for the “genetic cholestasis” group, 2 of 46 (4.3%) for the “unknown with complications” group, and 4 of 32 (12.5%) for the “unknown without complications” group. The grouping of the molecular diagnoses in the group with genetic cholestasis was as follows: 12 with Alagille syndrome, 5 with neonatal Dubin-Johnson syndrome, 5 with neonatal intrahepatic cholestasis caused by citrin deficiency, and 6 with progressive familial intrahepatic cholestasis or benign recurrent intrahepatic cholestasis with low gamma-glutamyl transpeptidase levels. Several clinical datasets, including age of onset, direct bilirubin, and aminotransferases, were significantly different between the disorders confirmed using molecular genetic diagnosis. Conclusion Targeted NGS can be used for molecular genetic diagnosis in subjects with NIIC. Clinical diagnosis should be accordingly redefined in the view of molecular genetic findings.

Purpose This retrospective case-control study aimed to examine the development of oxidative stress in asphyxiated infants delivered at more than 37 weeks of gestation. Material and Methods Thirty-seven neonates were stratified into 3 groups: the first group experienced hypothermia (n = 6); the second received hypothermia cooling cup treatment for 3 days, normothermia (n = 16); and the third was the control group (n = 15). Serum total hydroperoxide (TH), biological antioxidant potential, and oxidative stress index (OSI) (calculated as TH/biological antioxidant potential) were measured within 3 hours after birth. Results Serum TH and OSI levels gradually increased after birth in hypothermia and normothermia cases. At all time points, serum TH and OSI levels were higher in hypothermia and normothermia cases than in control cases. Serum TH and OSI levels were higher in normothermia cases than in hypothermia cases at days 3, 5, and 7. Conclusion This study demonstrated that hypothermia attenuated the development of systemic oxidative stress in asphyxiated newborns.

There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN-α2a monotherapy for children infected by chronic hepatitis C virus (HCV). From 2004-2006, we conducted a prospective, open-label, multicenter study of 22 patients aged 4-18 years, including eight with genotype 1 and 14 with genotype 2. None had previously received IFN. The patients were treated with s.c. PEG IFN-α2a at a dose of 3 µg/kg once a week for 48 weeks. Rapid virological response (RVR) was defined as: undetectable serum HCV RNA at week 4; early viral response (EVR) as a 2 or more log reduction or undetectable serum HCV RNA at week 12; and sustained viral response (SVR) as undetectable serum HCV RNA at 24 weeks after the cessation of treatment. SVR was achieved in 10 (45%) of the 22 patients (three with genotype 1, seven with genotype 2). Retrospectively, the patients with SVR included five with RVR (one with genotype 1, four with genotype 2) and five with EVR (two with genotype 1, three with genotype 2). PEG IFN-α2a monotherapy was well tolerated, except in one patient in whom alanine aminotransferase activity flared (500 IU/L) during treatment. The efficacy of PEG IFN-α2a monotherapy in children is similar to that for adults, while tolerability seems to be better in children than in adults.

Background: Increased survival rates for extremely low birth weight infants have been reported. However, survival rates and prognoses of extremely preterm infants, such as infants born at 22 weeks of gestation, are still poor. Objective: To investigate such infants’ long-term outcomes, developmental assessments were performed. Methods: Seven infants with gestational age of 22 weeks were delivered in our hospital from 2005 to 2008. One infant was a stillbirth despite resuscitation in the delivery room. Six infants, 4 boys and 2 girls, with a gestational age of 22 weeks (range 223/7–226/7 weeks), were admitted to the neonatal intensive care unit (NICU). Birth weights ranged from 514 to 710 g. None of the infants suffered from sepsis, necrotizing enterocolitis, or severe intraventricular hemorrhage. Results:The survival rate was 85.7% (6/7) as a percentage of deliveries and 100% (6/6) as a percentage of NICU admissions. None of the infants suffered from deafness, blindness, cerebral palsy, or epilepsy. Six infants were available for developmental assessments at 18 months’ corrected age. Three infants showed normal developmental quotients, and 3 infants showed developmental delay. Conclusion: In our study, all infants admitted to the NICU at a gestational age of 22 weeks were discharged from the hospital alive. This might suggest that infants after 22 weeks’ gestation be considered eligible for active treatment in Japan, though considering the size of the material, generalizibility of the results cannot be considered guaranteed.

Some oral antibiotics contain a pivalate ester, because molecules with a pivalate entity show enhanced absorption in the intestine. Upon absorption, such a "prodrug" is broken down into the active form of a given antibiotic and a pivalate molecule, the latter of which is converted to pivaloylcarnitine through pivaloyl-CoA and is excreted in the urine. Long-term administration of drugs containing pivalate decreases blood carnitine level and causes defects in fatty acid oxidation. Here, we used liquid chromatography tandem mass spectrometry to measure carnitine and pivaloylcarnitine levels in two patients (Patient 1: 16-month-old boy and Patient 2: 18-month-old boy) with secondary carnitine deficiency and hypoglycemic convulsions caused by pivalate-containing antibiotics. Both patients were administered excessive doses of pivalate for the long-term treatment of recurrent infection, and consequently, the serum free carnitine levels were very low (Patient 1: 1.0 micromol/L and Patient 2: 0.4 micromol/L), compared to normal range of 33.3-43.0 micromol/l, while the serum pivaloylcarnitine levels were elevated from normally undetectable level (Patient 1: 3.7 micromol/L and Patient 2: 1.6 micromol/L). Patient 1 recovered immediately after the glucose infusion, whereas Patient 2 remained symptomatic even after blood glucose level was normalized and fully recovered after carnitine supplementation. The urine pivaloylcarnitine level in Patient 2 was increased during carnitine supplementation (from 821.4 to 12,200 micromol/g creatinine) even after discontinuing the antibiotics, indicating that a considerable amount of pivalate was accumulated in the tissues. In conclusion, long-term administration of pivalate-containing antibiotics should be avoided particularly in children.

To study the effect of exchange transfusion on cytokine profiles in a patient with transient myeloproliferative disorder and hepatic fibrosis in which cytokines were measured before and after exchange transfusion. A newborn female was diagnosed with Down syndrome phenotypically and on karyotyping. Laboratory data showed a high leukocyte count with blast cells in the peripheral blood and liver dysfunction. Exchange transfusion was performed on day 1. However, respiratory distress and multiorgan failure progressed, and she died after 16 days. Of the cytokines examined, transforming growth factor-beta1 and interleukin-7 were extremely high before exchange transfusion, and decreased after exchange transfusion.

Easy screening and accurate diagnosis of congenital cytomegalovirus (CMV) infection are needed to predict and treat complications. We report the clinical course of two neonates with congenital CMV infection confirmed by real-time polymerase chain reaction (PCR) for CMV DNA in umbilical cord blood. A total of 1,010 neonates born at Yonaha Clinic from July 2005 to March 2007 were investigated. Umbilical cord blood was collected at birth, and DNA was extracted to screen for CMV DNA by real-time PCR. Head MRI and a developmental test were conducted for two cases (0.2%) in which CMV DNA was detected. Neither case showed clear abnormalities at birth, and head CT conducted at 1 month after birth revealed no abnormalities. Auditory brainstem responses were normal at both 1 and 12 months after birth in both cases. Head MRI at 12 months showed abnormalities in both cases. For both cases, development tests conducted at 12 months revealed mild developmental delays, particularly in posture and movement areas, which might have been caused by congenital CMV infection.

An 18-month-old boy was treated with an antibiotic containing pivalic acid for 6 months for intractable otitis media and then developed repeated convulsions and loss of consciousness. Laboratory data showed hypoglycemia and hypocarnitinemia. Intravenous administration of glucose was ineffective against the seizures and loss of consciousness. However, the patient regained consciousness and recovered soon after intravenous infusion of carnitine. To our knowledge, intravenous carnitine administration that contributed to marked improvements in neurologic deficit caused by administration of an antibiotic containing pivalic acid has not been reported previously. These findings indicate that long-term use of such antibiotics should be avoided.

Introduction: Hyperzincaemia and hypercalprotectinaemia with systemic inflammation, recurrent infections, hepatosplenomegaly, arthritis, anemia, cutaneous inflammation, and failure to thrive is an extremely rare disease and no therapy is reported. Aim: To evaluated the effects of cyclosporine A in hyperzincaemia and hypercalprotectinaemia in terms of serum cytokine level changes before and after treatment. Methods: A 10-year-old girl was admitted suffering from pyoderma gangrenosum, hepatosplenomegaly, anemia that was unresponsive to iron supplementation, persistent inflammation, arthritis, and increased serum zinc. The level of serum calprotectin was extremely high; therefore, we diagnosed hyperzincaemia and hypercalprotectinaemia and started cyclosporine A treatment. Twelve cytokines in serum were measured before and one year after treatment. Results: Cyclosporine A was very effective. Her skin lesion and joint pain were alleviated and quality of life was markedly improved. C-reactive protein had decreased and anemia had improved. While zinc levels had fallen, calprotectin remained at an extremely high level. Of the cytokines examined, interleukin -6 serum levels had fallen and interleukin -8 showed a marked reduction after treatment. Conclusion: Cyclosporine A is effective for hyperzincaemia and hypercalprotectinaemia. Serum interleukin -8 may be useful in assessing the therapeutic effects of cyclosporine A in hyperzincaemia and hypercalprotectinaemia.

Background: Recently, sporadic cases of acute hepatitis and fulminant hepatitis caused by hepatitis E virus (HEV) have been reported in Japan. However, few reports have addressed the issue of HEV infection during childhood. Methods: This study included 5 patients with fulminant hepatitis, 30 patients with acute hepatitis, and 309 patients without history of hepatic dysfunction or hepatitis in childhood as control. RNA was extracted from each serum sample, and HEV specific reverse-transcriptase polymerase chain reaction was performed. Anti-HEV immunoglobulin (Ig)M and IgG were measured by enzyme-linked immunoadsorbent assay. Results: HEV RNA, anti-HEV IgM, and anti-HEV IgG were not detected in the sera of any of the five patients with fulminant hepatitis. In the 30 patients with acute hepatitis, only one (3.3%) was positive for anti-HEV IgG, and all were negative for anti-HEV IgM and HEV RNA. Of the 309 control patients, 8 (2.6%) were positive for anti-HEV IgG, and 2 (0.6%) were positive for anti-HEV IgM, respectively. Conclusion: The result of patients with fulminant hepatitis suggests that HEV is an unlikely cause of fulminant hepatitis in children. However, the detection rate of anti-HEV IgG shows that a history of HEV infection is not so rare among children in Japan.

In Japan and many other industrialized countries, zinc is readily available as a nutritional supplement, for cosmetic purposes and for the treatment of atopic dermatitis. The potential risks associated with its use are not, however, fully recognized. As a reciprocal relationship exists between copper and zinc, excessive zinc can produce hypocupraemia, which can cause anaemia and neutropenia. We report on a male infant who presented with anaemia and neutropenia and showed signs of developmental delay after dietary restriction for food allergy and eating difficulties and zinc therapy administered for the treatment of atopic dermatitis at a dose nine times the daily dietary allowance for his age group. After 1 mo of zinc withdrawal, copper and ceruloplasmin concentrations had increased, and the blood cell count had improved, activity was increasing but verbal development remained limited. As development improved after withdrawal of zinc, we cannot rule out a relation between developmental delay and hyperzincaemia and/or hypocupraemia.Caution must be exercised in administering zinc to children during their neurological development.

Background: In recent years, progressive familial intrahepatic cholestasis has been classified into at least three types by genetic analysis: PFIC1, PFIC2, and MDR3. Liver transplantation is effective for treating patients with this intractable syndrome. Confirming the correct diagnosis is of paramount importance because prognosis after transplantation differs with the genetic type of the disease. Methods: Synthesis of cDNA was accomplished using RNA extracted from liver tissue of two Japanese patients with progressive familial intrahepatic cholestasis Polymerase chain reaction was performed using 13 primer sets designed for amplification of the bile salt export pump cDNA. Direct sequencing was undertaken, and identified sequences were compared with the sequence for bile salt export pump gene registered with GenBank. In addition, gene sequences for nonprogressive familial intrahepatic cholestasis patients were analyzed. Results: Genetic analysis of patient I revealed that substitutions in bile salt export pump protein sequences, namely R575X and E636G, might be the cause of the disease. In patient 2. V330X and R487H might fulfill the same role. Results of gene analysis in parents and cholestatic controls supported these conclusions. Conclusions: Absence or presence of bile salt export protein gene mutations was confirmed as representing a useful prognostic marker for clinical course after liver transplantation.