A case of inherited glycosylphosphatidylinositol deficiency caused by PGAP3 variant with uniparental isodisomy on chromosome 17.

BACKGROUND: Inherited glycosylphosphatidylinositol (GPI) deficiency is an autosomal recessive disease and a set of syndromes caused by different genes involved in the biosynthesis of phosphatidylinositol characterized by severe cognitive disability, elevated serum alkaline phosphatase (ALP) levels, and distinct facial features. This report presents a patient with inherited GPI deficiency caused by a homozygous frameshift variant of PGAP3 due to uniparental isodisomy (UPiD) on chromosome 17. METHOD: Clinical characteristics of the patient were collected. Microarray analysis followed by adaptive sampling sequencing targeting chromosome 17 was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. RESULTS: The patient was born at 38 weeks of gestation with a birthweight of 3893 g. He had a distinctive facial appearance with hypertelorism, wide nasal bridge, and cleft soft palate. Postnatal head magnetic resonance imaging revealed a Blake's pouch cyst. The serum ALP level was 940 IU/L at birth and increased to 1781 IU/L at 28 days of age. Microarray analysis revealed region of homozygosity in nearly the entire region of chromosome 17, leading to the diagnosis of UPiD. Adaptive sampling sequencing targeting chromosome 17 confirmed the homozygous variant NM_033419:c.778dupG (p.Val260Glyfs*14) in the PGAP3 gene, resulting in a diagnosis of inherited GPI deficiency. CONCLUSION: This is the first report of inherited GPI deficiency caused by UPiD. Inherited GPI deficiency must be considered in patients with unexplained hyperphosphatasemia.

Host-derived protein profiles of human neonatal meconium across gestational ages.

Meconium, a non-invasive biomaterial reflecting prenatal substance accumulation, could provide valuable insights into neonatal health. However, the comprehensive protein profile of meconium across gestational ages remains unclear. Here, we conducted an extensive proteomic analysis of first meconium from 259 newborns across varied gestational ages to delineate protein composition and elucidate its relevance to neonatal diseases. The first meconium samples were collected, with the majority obtained before feeding, and the mean time for the first meconium passage from the anus was 11.9 ± 9.47 h. Our analysis revealed 5370 host-derived meconium proteins, which varied depending on sex and gestational age. Specifically, meconium from preterm infants exhibited elevated concentrations of proteins associated with the extracellular matrix. Additionally, the protein profiles of meconium also exhibited unique variations depending on both specific diseases, including gastrointestinal diseases, congenital heart diseases, and maternal conditions. Furthermore, we developed a machine learning model to predict gestational ages using meconium proteins. Our model suggests that newborns with gastrointestinal diseases and congenital heart diseases may have immature gastrointestinal systems. These findings highlight the intricate relationship between clinical parameters and meconium protein composition, offering potential for a novel approach to assess neonatal gastrointestinal health.

Congenital cytomegalovirus infection in a preterm infant with 22q11.2 deletion syndrome and immunological abnormalities.

The 22q11.2 deletion syndrome has many complications; one of them is immunodeficiency. However, the time of onset and the degree of immunodeficiency can vary. We report a case of a preterm infant with congenital cytomegalovirus infection complicated with 22q11.2 deletion syndrome and immunological abnormalities. Ultrasonography revealed pulmonary atresia, ventricular septal defect, major aortopulmonary collateral artery, and thymic hypoplasia. His serum chemistry tests on admission revealed immunoglobulin G, A, and M levels of 1,547 mg/dL, 70 mg/dL, and 274 mg/dL, respectively. A surface antigen analysis of the peripheral lymphocytes using flow cytometry revealed the following: relatively low CD4-positive T-cell levels (18.1%; 1,767/µL), very high CD8-positive T-cell levels (58.9%; 5,751/µL), and CD4/CD8 ratio of 0.31. The level of T-cell receptor excision circles was relatively low at 17.5 copies/µL. After birth, the CD8-positive T-cell level began to gradually decrease, whereas the CD4/CD8 ratio began to increase. Thrombocytopenia, neutropenia, and skin petechiae were observed on admission. However, the condition improved. Treatment for congenital cytomegalovirus infection was not provided due to the absence of viremia. Unfortunately, the patient died suddenly on the 158th day of life, and the cause of death was unknown. To the best of our knowledge, no association between 22q11 deletion syndrome and cCMV has been described in the recent medical literature. According to the calculation, around one newborn infant who have both 22q11 deletion syndrome and cCMV infection will be born each year in Japan. Healthcare providers should pay more attention to this medical situation in the future.

The importance of designing a protector for a preterm and low birth weight infant with ectopia cordis.

Ectopia cordis is a rare condition with expected low survival rate based on past studies. We encountered a case of a preterm and low birth weight infant with ectopia cordis. When the infant cried, the prolapse of the heart, liver, and intestinal tract worsened. A pressure-applying protector was used to protect the organs and reduce the prolapse. Upon application, the infant's tachypnea and desaturation worsened. Fluoroscopic examination suggested that the pressure from the prolapsed regions was impeding pulmonary expansion and negatively affecting circulation. It is essential to carefully design a protector that accommodates the infant's growth.

Treatments and outcomes of neonatal disseminated intravascular coagulation with and without neonatal asphyxia: A retrospective study using nationwide data in Japan.

BACKGROUND: Although neonatal disseminated intravascular coagulation (DIC) is associated with high mortality and severe complications, few studies have reported its clinical course. We aimed to describe the characteristics, treatments, and outcomes of neonatal DIC by using a national inpatient database. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified 5533 patients with neonatal DIC who were admitted to neonatal intensive care units between July 2010 and March 2020. We categorized the patients into those with asphyxia (n = 2911) and those without asphyxia (n = 2622). We investigated the patient characteristics, treatments, and outcomes. We further categorized neonates with asphyxia according to its severity. RESULTS: The gestational age of neonates with asphyxia was significantly lower than that of neonates without asphyxia (P < 0.001). Antithrombin was most commonly used for DIC (40%). Neonates with asphyxia were more likely to receive antithrombin (43% vs. 38%; P < 0.001), recombinant human soluble thrombomodulin (28% vs. 20%; P < 0.001), and fresh frozen plasma transfusion (68% vs. 51%; P < 0.001) than those without asphyxia. Neonates with asphyxia had higher in-hospital mortality (17% vs. 10%; P < 0.001), severe bleeding (11% vs. 6.8%; P < 0.001), and hospitalization costs than those without asphyxia. Additionally, neonates with severe asphyxia were more likely to receive several DIC therapies (such as recombinant human soluble thrombomodulin [30% vs. 24%]) and had higher in-hospital mortality (19% vs. 11%) and hospitalization costs than those with mild asphyxia. CONCLUSIONS: In this large retrospective study of neonatal DIC, patients with asphyxia received several treatments and demonstrated unfavorable outcomes when compared to those without asphyxia.

Effects of Milrinone on Neonates after Patent Ductus Arteriosus Ligation: A Retrospective Nationwide Database Study.

INTRODUCTION: Milrinone is administered after patent ductus arteriosus (PDA) ligation to prevent and treat postoperative hemodynamic instability (i.e., postligation cardiac syndrome). We aimed to explore the effectiveness of milrinone on in-hospital outcomes in infants who underwent PDA ligation using a nationwide inpatient database in Japan. METHODS: Using the Japanese Diagnosis Procedure Combination database, we identified patients who received milrinone after PDA ligation (n = 428) in neonatal intensive care units between July 2010 and March 2021 and those who did not (n = 3,392). We conducted a 1:4 propensity score-matched analysis with adjustment for background characteristics (e.g., gestational age, birth weight, comorbidities, preoperative treatments, and hospital background) to compare morbidities (bronchopulmonary dysplasia, intraventricular hemorrhage, necrotizing enterocolitis, and retinopathy of prematurity), mortality, total hospitalization costs, and other outcomes. For sensitivity analysis, we performed an overlap propensity score-weighted analysis. RESULTS: In-hospital morbidity, bronchopulmonary dysplasia, intraventricular hemorrhage, and necrotizing enterocolitis occurred in 58%, 48%, 9.5%, and 7.1% of patients, respectively; the in-hospital mortality was 5.4%. After 1:4 propensity score matching, no significant difference was observed regarding mortality (7.1 vs. 5.7%), in-hospital morbidity (55 vs. 50%), bronchopulmonary dysplasia (44 vs. 41%), intraventricular hemorrhage (7.8 vs. 9.1%), necrotizing enterocolitis (8.5 vs. 8.9%), retinopathy of prematurity (21 vs. 22%), or total hospitalization costs (median: approximately 86,000 vs. 82,000 US dollars) between milrinone users (n = 425) and nonusers (n = 1,698). Sensitivity analyses yielded consistent results. CONCLUSIONS: Milrinone use after PDA ligation was not associated with improved in-hospital outcomes, such as mortality and morbidity.

Risk factors for anemia of prematurity among 30-35-week preterm infants.

BACKGROUND: The risk factors for anemia of prematurity (AOP) among late preterm infants are unelucidated. We identified risk factors for declining hemoglobin (Hb) concentration and triggering factors for AOP treatment in infants born at 30-35 gestational weeks. METHODS: From 2012 to 2020, we conducted a single-center retrospective study of infants born at 30-35 weeks of gestation without congenital anomalies or severe hemorrhage. The primary outcome was AOP development, defined by initiation of treatments including red blood cell transfusion, subcutaneous injections of erythropoietin, and iron supplementation. A multivariable logistic regression model was used to investigate potential risk factors for AOP. RESULTS: A total of 358 infants were included. Lower gestational age (odds ratio, 0.19; 95% confidence interval 0.11-0.32), small for gestational age (SGA; 7.17, 2.15-23.9), low maternal Hb level before birth (0.66, 0.49-0.87), low Hb at birth (0.71, 0.57-0.89), and multiple large blood samplings (1.79; 1.40-2.29) showed significantly higher odds for AOP development. CONCLUSIONS: Gestational age, SGA, low maternal Hb before birth, Hb at birth, and high number of large blood samplings were positively associated with AOP development in infants born at 30-35 gestational weeks.

Case report: A case of fetal umbilical vein varix presenting disseminated intravascular coagulation, polycythemia, and neonatal hepatitis in an extremely low birth weight infant.

Reports on the clinical course of fetal umbilical vein varix in premature infants are limited. We report a case of an extremely low body weight infant with intra-abdominal umbilical vein varix who developed disseminated intravascular coagulation, polycythemia, and hyperbilirubinemia after birth; late-onset neonatal hepatitis; and fetal thrombotic vasculopathy confirmed by placental histopathology. Ultrasonography after birth showed a dilated portion of the umbilical vein at the hepatic hilum with thrombi inside. We speculate that the umbilical vein varix caused the fetal thrombotic vasculopathy, and the presence of umbilical vein varix and fetal thrombotic vasculopathy in combination with prematurity caused coagulopathy, polycythemia, hyperbilirubinemia, and hepatitis. Despite the favorable outcomes reported in the literature, premature infants with umbilical vein varix may require careful observation and management for coagulopathy and late-onset hepatitis. Furthermore, placental histopathology could aid in the understanding of various clinical outcomes in infants with umbilical vein varices.

Case Report: Treatment of Extremely Preterm Infants With Birthweight Below 300 g: Case Series.

Reports on the birth of infants weighing <300 g are quite rare and little is known about the best practices in treating such micropreemies. Therefore, we report here on three cases of low birthweight infants weighing <300 g, of whom two infants survived. The birthweights and gestational ages were ranging 279-293 g and 22 + 6/7 - 23 + 6/7 weeks, respectively. All the infants had severe fetal growth restriction and prematurity. The infant in case 1 died of hepatic rupture, perhaps due to birth trauma, which emphasized the need for less invasive obstetric procedures including en caul delivery. The infant in case 2 managed to survive through severe prematurity secondary to hydrops fetalis. However, complications followed soon as tracheal granulation tissue was formed with neurodevelopmental impairment. The infant in case 3 was born recently and her clinical course was less remarkable without severe complications, despite having the least gestational age and birthweight among the three patients. The improved care protocols for extremely low birthweight infants over these years through experiential learning including that with cases 1 and 2 may have ensured the better outcome of case 3. Accumulating evidence and recording the experience of such cases with continuous constructive discussion can contribute to better outcomes and appropriate parental counseling for extremely small babies in the future.

Identification of epigenetic memory candidates associated with gestational age at birth through analysis of methylome and transcriptional data.

Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23-41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin.

A male preterm infant with cow's milk allergy to human milk fortifier showing only severe respiratory symptoms.

We report a male infant with a birthweight of 1,400 g at 29 weeks 2 days gestation diagnosed as having cow's milk allergy (CMA) due to human milk fortifier, who developed severe respiratory symptoms. The infant had no gastrointestinal symptoms; rather, the initial symptoms were apnea attacks and wheezing with a prolonged expiratory phase that progressed to severe ventilatory insufficiency requiring mechanical ventilation. Aggravation of his general condition, which appeared to be due to sepsis, was improved by temporary starvation and respiratory care, but he relapsed on the resumption of enteral feeding of his mother's milk with a human milk fortifier. As a result, this event was interpreted as a positive oral food challenge test. The infant resumed complete breastfeeding without the fortifier and has not relapsed since. Examination of his serial cytokine profiles from residual serum revealed that although interleukin-5 was not increased, interferon (IFN)-γ was increased, suggesting some relation between the time course of IFN-γ and the infant's eosinophil count. These findings may indicate that the involvement of IFN-γ is one cause of the onset of this disease.

Neonatal Leukemoid Reaction with Fetal Inflammatory Response Syndrome Is Associated with Elevated Serum Granulocyte Colony Stimulating Factor and Interleukin-6.

Leukemoid reaction (LR) is a reactive disease that exhibits abnormal blood values similar to leukemia, but not due to leukemia. One report showed that neonatal LR (NLR) was associated with elevated serum granulocyte colony stimulating factor (G-CSF) in only 30% of the study neonates. NLR is not always associated with the elevation of serum G-CSF. NLR was defined as a white blood cell count of ≥ 40 × 103/µL and/or blast cell concentration of > 2%. We have focused on NLR with fetal inflammatory response syndrome (FIRS), defined as a fetal systemic inflammatory reaction triggered by intrauterine infection. FIRS was diagnosed based on a cord serum interleukin-6 (IL-6) concentration ≥ 17.5 pg/mL and histopathological chorioamnionitis. Because NLR is highly associated with FIRS, we have hypothesized that NLR is associated with the elevation of both G-CSF and IL-6. This is the first report to measure multiple cytokines in NLR at the same time. The study comprised 19 preterm infants with FIRS: 8 with NLR (study group) and 11 without NLR (control group). Serum G-CSF and IL-6 concentrations were significantly higher in the study group than the control group. There was a positive correlation between G-CSF and IL-6 levels in the study group but not in the control group. These results suggest that elevated serum G-CSF and IL-6 may underlie NLR. Thus, G-CSF and IL-6 concentrations may be predictive of the onset of NLR. Measuring these cytokines is useful for judging the prognosis of preterm infants and for their post-natal clinical management.