Takahide Yanagi

Bilirubin Uridine Diphosphate-Glucuronosyltransferase Variation Is a Genetic Basis of Breast Milk Jaundice

OBJECTIVE To evaluate the role of bilirubin UDP-glucuronosyltransferase family 1, polypeptide A1 (UGT1A1) gene variations on prolonged unconjugated hyperbilirubinemia associated with breast milk feeding (breast milk jaundice [BMJ]). STUDY DESIGN UGT1A1 gene allelic variation was analyzed in 170 Japanese infants with BMJ with polymerase chain reaction-direct sequencing, and their genotypes compared with serum bilirubin concentrations. In 62 of 170 infants, serum bilirubin concentration was followed after 4 months of life. Genotypes were examined in 55 infants without BMJ. RESULTS Of 170 infants with BMJ, 88 (51.8%) were homozygous UGT1A1*6. Serum bilirubin concentrations (21.8 ± 3.65 mg/dL) were significantly greater than in infants with other genotypes (P < .0001). The Gilbert UGT1A1*28 allele was not detected in infants with BMJ, except in an infant who was compound heterozygous with UGT1A1*6. At 4 months of age, serum bilirubin concentration improved to >1 mg/dL, except in 2 infants who were homozygous UGT1A1*7. Homozygous UGT1A1*6 was not detected in the control group. CONCLUSION One-half of the infants with BMJ were homozygous UGT1A1*6 and exhibited a serum bilirubin concentration significantly greater than other genotypes. This finding indicates that UGT1A1*6 is a major cause of BMJ in infants in East Asia. Previous finding have demonstrated that 5β-pregnane-3α,20β-diol present in breast milk inhibits p.G71R-UGT1A1 bilirubin glucuronidation activity. Thus, prolonged unconjugated hyperbilirubinemia may develop in infants with UGT1A1*6 who are fed breast milk.

Expression of megakaryocytic and myeloid markers in blasts of transient abnormal myelopoiesis in a stillbirth with Down syndrome: report of histopathological findings of an autopsy case.

Transient abnormal myelopoiesis in neonates with Down syndrome is an unusual leukemia that spontaneously regresses within several months of life and is thought to arise in the fetal liver. It is largely unknown how the leukemic blasts proliferate and differentiate in fetal tissues. We report the histopathological findings of an autopsy case of a stillbirth with transient abnormal myelopoiesis. Blood vessels in almost all organs were filled with immature leukemic cells, most of which expressed megakaryocyte antigen CD42b. In contrast, leukemic cells infiltrating the tissues, including the pericardium, expressed myeloperoxidase. These findings indicate that leukemic progenitors in transient abnormal myelopoiesis can differentiate along both megakaryocytic and myeloid lineages, which may be influenced by microenvironmental factors. Numerous dysplastic mature/immature megakaryocytes and blasts were present in the liver, whereas the bone marrow contained predominantly myeloid cells at various stages of differentiation, suggesting that the fetal liver is the major organ for proliferation of blasts in transient abnormal myelopoiesis.

Neonatal Meckel diverticulum: Obstruction due to a short mesodiverticular band

This is the first report of symptomatic Meckel diverticulum in a newborn, in which direct compression by a short mesodiverticular band (MDB) caused intestinal obstruction. A short MDB can cause intestinal obstruction due to direct compression. There are two mechanisms by which Meckel diverticulum with MDB can cause intestinal obstruction: internal hernia and direct compression. Onset of intestinal obstruction due to direct compression by a short MDB might be earlier than that for internal hernia with long MDB.

Bifidobacterium bifidum OLB6378 Simultaneously Enhances Systemic and Mucosal Humoral Immunity in Low Birth Weight Infants: A Non-Randomized Study

Probiotic supplementation has been part of the discussion on methods to enhance humoral immunity. Administration of Bifidobacterium bifidum OLB6378 (OLB6378) reduced the incidence of late-onset sepsis in infants. In this non-randomized study, we aimed to determine the effect of administration of live OLB6378 on infants’ humoral immunity. Secondly, we tried to elucidate whether similar effects would be observed with administration of non-live OLB6378. Low birth weight (LBW) infants weighing 1500–2500 g were divided into three groups: Group N (no intervention), Group L (administered live OLB6378 concentrate), and Group H (administered non-live OLB6378 concentrate). The interventions were started within 48 h after birth and continued until six months of age. Serum immunoglobulin G (IgG) levels (IgG at one month/IgG at birth) were significantly higher in Group L than in Group N (p < 0.01). Group H exhibited significantly higher serum IgG levels (p < 0.01) at one month of age and significantly higher intestinal secretory immunoglobulin A (SIgA) levels (p < 0.05) at one and two months of age than Group N. No difference was observed in the mortality or morbidity between groups. Thus, OLB6378 administration in LBW infants enhanced humoral immunity, and non-live OLB6378, which is more useful as a food ingredient, showed a more marked effect than the viable bacteria.

Possible Prevention of Neonatal Death: A Regional Population-Based Study in Japan

Purpose The neonatal mortality rate in Japan has currently been at the lowest level in the world. However, it is unclear whether there are still some potentially preventable neonatal deaths. We, therefore, aimed to examine the backgrounds of neonatal death and the possibilities of prevention in a region of Japan. Materials and Methods This is a population-based study of neonatal death in Shiga Prefecture of Japan. Results The 103 neonatal deaths in our prefecture between 2007 and 2011 were included. After reviewing by a peer-review team, we classified the backgrounds of these neonatal deaths and analyzed end-of-life care approaches associated with prenatal diagnosis. Furthermore, we evaluated the possibilities of preventable neonatal death, suggesting specific recommendations for its prevention. We analyzed 102 (99%) of the neonatal deaths. Congenital malformations and extreme prematurity were the first and the second most common causes of death, respectively. More than half of the congenital abnormalities (59%) including malformations and chromosome abnormality had been diagnosed before births. We had 22 neonates with non-intensive care including eighteen cases with congenital abnormality and four with extreme prematurity. Twenty three cases were judged to have had some possibility of prevention with one having had a strong possibility of prevention. Among specific recommendations of preventable neonatal death, more than half of them were for obstetricians. Conclusion There is room to reduce neonatal deaths in Japan. Prevention of neonatal death requires grater prenatal care by obstetricians before birth rather than improved neonatal care by neonatologists after birth.

Bilirubin Uridine Diphosphate-glucuronosyltransferase Polymorphism as a Risk Factor for Prolonged Hyperbilirubinemia in Japanese Preterm Infants

Objective To determine whether a variant of the bilirubin uridine diphosphate‐glucuronosyltransferase gene (UGT1A1*6) is a risk factor for prolonged hyperbilirubinemia in preterm infants. Study design UGT1A1 genotypes in 46 Japanese preterm infants (<37 weeks of gestation) were compared with UGT1A1 genotypes in 38 control infants, using polymerase chain reaction‐direct sequencing. Prolonged unconjugated hyperbilirubinemia was defined as serum total bilirubin concentration of >150 &mgr;mol/L (8.77 mg/dL) beyond 14 days of life. Results In the case group, 41 of 46 infants (89.1%) had a polymorphic variant, c.211G>A, p.G71R (UGT1A1*6). In the control group, 7 of 38 (18.4%) had UGT1A1*6. The allele frequency of UGT1A1*6 was 0.641 in the prolonged hyperbilirubinemia group, which was significantly higher than in the control group (0.092; P < .001). In total, 39 of 46 infants in the case group were breast fed, and only 10 infants in the control group were breast fed. Conclusions These data suggest that UGT1A1*6 is a risk factor for prolonged unconjugated hyperbilirubinemia in preterm infants in Japan. Given the different rate of breast feeding in this study, additional data are necessary for drawing a definitive conclusion.

Neonatal urethral polyps associated with Beckwith–Wiedemann syndrome

We report the first case of Beckwith–Wiedemann syndrome without urinary obstruction, but with a congenital urethral polyp as a tumor protruding from the external urinary meatus. The present case suggests a possible relation between Beckwith–Wiedemann and the onset of fibroepithelial polyps in the reno‐urinary system during the neonatal period.

Hallopeau-Siemens dystrophic epidermolysis bullosa due to homozygous 5818delC mutation in the COL7A gene.

Epidermolysis bullosa (EB) is a group of inherited mechanobullous skin disease. The dystrophic EB (DEB), one subtype of EB, is inherited in an autosomal dominant DEB or in an autosomal recessive (RDEB). DEB is caused by mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils. Over 300 pathogenic mutations have been detected within COL7A in DEB. Patients with the Hallopeau‐Siemens type (HS‐RDEB), most severe form of DEB, frequently have premature termination codon (PTC) mutations on both alleles. PTC mutations on both alleles result in depleted mRNA and α1 helix, and failure to form the triple helix structure characteristic of type VII collagen. As patients with HS‐RDEB usually have a pair of heterozygous PTC mutations, there have been rarely reported homozygous ones in HS‐RDEB. We report the first case of HS‐RDEB homozygous PTC mutations of 5818delC in both COL7A1 alleles. This case report suggests the positional effect of PTC mutations and vigilance against early infantile death in EB including HS‐RDEB.

Purpura fulminans in congenital protein C deficiency successfully treated with fresh frozen plasma and thrombomodulin

Dear Editor, A 5-day-old Japanese girl presented with ecchymosis (Fig. 1a), which occurred at 2 days after birth and gradually expanded. She was born by normal delivery at 41 weeks and 2 days with a birthweight of 2370 g. Physical examination at birth was normal. Maternal past medical history was insignificant except for a spontaneous abortion of the first pregnancy. The mother’s aunt and father’s grandmother had also experienced spontaneous abortions. Laboratory investigations showed elevated levels of D-dimer and fibrin degradation products and decreased levels of platelets and protein C (5%; normal range, 70–130%). Computerized tomography scan revealed cerebral hemorrhage at 5 days after birth. We identified compound heterozygous missense mutation of protein C gene in exon 7 (c.545C>T) and exon 9 (c.1015G>A). Therefore, we diagnosed her condition as purpura fulminans associated with congenital protein C deficiency. Her mother and father were found to be heterozygous in exons 7 and 9, respectively. We commenced fresh frozen plasma (FFP) infusion (20 mg 92/kg per day) for disseminated intravascular coagulation (DIC) and added thrombomodulin (380 U/kg per day) at 11 days after birth. As the DIC improved, expansion of the purpura also ceased. Then, we started oral warfarin at a prothrombin time international normalized ratio of 1.5–2.0. For the skin lesion, we performed debridement at 15–19 days (Fig. 1b) and applied prostaglandin ointment. The ulcer was almost epithelialized at 47 days (Fig. 1c). Protein C, protein S and antithrombin are the three major coagulation factors. Thrombin binding to thrombomodulin in vascular endothelial cells produces activated protein C, which binds to protein S and inactivates factor V and factor VIII in the coagulation cascade. When one of these coagulation factors is deficient, purpura fulminans will occur. Similarly, purpura fulminans may appear when coagulation factors are deficient due to infection, poisoning and side-effects of drugs. Cerebral hemorrhage was also observed in this case. Congenital protein C deficiency complicates cerebral hemorrhage or cerebral infarction at a high rate. There is a report reviewing 27 cases of congenital protein C deficiency, of which 16 cases have purpura fulminans and 19 cases have cerebral hemorrhage or cerebral infarction. We measured the level of protein C immediately after the onset of purpura and administrated FFP and thrombomodulin together. Thrombomodulin seemed to contribute to the resolution of DIC and cessation of expansion of the purpura. In the management of protein C deficiency in the acute phase, FFP, heparin and platelet concentrate are mainly used. To our knowledge, this is the first case of purpura fulminans in congenital protein C deficiency successfully treated with FFP and thrombomodulin. Because thrombomodulin has a significant effect on the treatment of DIC and anti-inflammatory actions in the presence of protein C, it is unknown how thrombomodulin improved DIC in this case. There are possibilities that thrombomodulin could have responded with a small amount of protein C produced by the neonate or with protein C contained in the FFP that was administrated at the same time. Although further investigation is needed, we propose the additional effect of thrombomodulin for the treatment of acute phase purpura fulminans associated with congenital protein C deficiency.

Suspected fetal onset of neonatal transient eosinophilic colitis and development of respiratory distress.

Neonatal transient eosinophilic colitis (NTEC) is a new disease concept within eosinophilic gastroenteritis, which was proposed by Ohtsuka et al. It causes hematochezia as a result of eosinophilia, in neonates who have not yet started to receive enteral nutrition, although the whole‐body status of the infant is in fact relatively good. To date, there have been no reports of this disease in which abnormalities were noted during gestation, and the clinical phenomena surrounding it, along with any complications, are not yet clear. We encountered a suspected case of NTEC causing respiratory distress with aspiration of hematochezia, in which dilated bowel was noted during gestation. This case indicates that NTEC may occur at the fetal stage and be complicated by respiratory distress.