Tadamune Kinjo

SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7

Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.

Paediatric presentation and outcome of congenital protein C deficiency in Japan

Severe heritable protein C (PC) deficiency is quite rare, although heterozygous PROC mutation is the second leading cause of genetic predisposition to thrombosis in Japanese adults. The aim of the study was to search the optimal management, the paediatric onset and outcomes of PC deficiency were characterized in Japan. The genetic study, postmarketing survey of activated PC (aPC) concentrate (Anact®C) and intensive review in Japan for 20 years enabled the analysis of the disease onset, genotype, treatment and prognosis. Symptomatic PC deficiency was determined in 27 Japanese children. All but two patients presented within 16 days after birth (three prenatal and six neonatal onsets). Postnatal‐onset cases had normal growth at full‐term delivery. Of the 27 patients, 19 suffered intracranial thrombosis or haemorrhage (ICTH) (three foetal hydrocephalies), 16 developed purpura fulminans (PF) and 10 had both at the first presentation. ICTH preceded PF in both affected cases. Low PC activities of 18 mothers and/or 12 fathers indicated 20 inherited PC deficiencies (2 homozygotes, 11 compound heterozygotes and 7 heterozygotes) and seven unidentified causes of PC deficiency. Nine of 11 patients studied had PROC mutations. Four unrelated patients (50%) carried PC nagoya (1362delG). No PC‐deficient parents had experienced thromboembolism. Of the 18 patients with aPC therapy, two died and eight evaluable survivors had neurological sequelae. This first comprehensive study of paediatric PC deficiency suggested that perinatal ICTH was the major presentation, occurring earlier than neonatal PF. PC nagoya was prevalent in paediatric, but not adult, patients in Japan. Early maternal screening and optimal PC therapy are required for newborns at risk of PC deficiency.

Survival and Neurodevelopmental Outcome of Preterm Infants Born at 22-24 Weeks of Gestational Age

Background: The limits of viability in extremely premature infants are challenging for any neonatologists in developed countries. The neurological development and growth of extremely preterm infants have come to be the emerging issue following the management in the neonatal intensive care unit. Objective: To assess potential associations between changes in practice and survival/neurodevelopmental outcome, and clinical outcomes of extremely preterm infants born at the limit of viability studied in a tertiary center. Study Design: A retrospective study enrolled 51 infants who had no congenital disorders, and were born at 22-24 weeks of gestational age (GA) in 2000-2009 in our institution. Clinical variables and interventions were studied with regard to one-year survival and developmental quotient (DQ) at 3 years of age. Results: The one-year survival rate of 24 preterm infants born in 2005-2009 (79%) was higher than that of the 27 infants born in 2000-2004 (52%, p = 0.04). Infants born after 2005 underwent less tocolysis (54 vs. 94%, p < 0.01) and more frequently antenatal steroid therapy (32 vs. 6%, p = 0.01) than those born before 2004. The post-2005 survivors (n = 19) received more frequently indomethacin therapy (89 vs. 50%, p = 0.03) and early parenteral nutrition (95 vs. 36%, p < 0.01) than the pre-2004 survivors (n = 14). There were no differences in the proportion of infants who attained a DQ of >50 at 3 years of age between pre-2004 (9/13, 69%) and post-2005 groups (10/17, 59%). Multivariate analysis indicated that extremely premature birth at GA <24 weeks was the sole critical factor for a DQ of >50 in survivors. Conclusions: The perinatal care after 2005 improved the overall survival rate, but not the neurological outcome of preterm survivors at the limit of viability. Neurodevelopmental impairments were associated with extremely premature birth at GA <24 weeks.

Serum neutrophil gelatinase-associated lipocalin as a predictor of the development of bronchopulmonary dysplasia in preterm infants.

BACKGROUND Bronchopulmonary dysplasia (BPD) is a chronic lung disease mostly occurring in preterm infants. The pathogenesis of BPD involves early inflammation and remodeling of the premature lung. AIM To search for the novel predictive marker of BPD development, we studied serum levels of neutrophil gelatinase-associated lipocalin (NGAL), an innate immune mediator, in preterm infants. METHODS Serum NGAL concentrations at birth were measured by enzyme-linked immunosorbent assay. The reference levels were determined in 52 infants having no anomalies or inherited diseases. The levels and clinical variables were assessed in association with BPD. RESULTS Geometric means (95%CI) of serum NGAL levels at birth of infants having no underlying diseases were 32.4 (22.1-47.5), 58.6 (47.9-71.8), and 126.2 (99.0-168.7) ng/mL for <31, 31-36 and >36 gestational weeks (GW), respectively (p<0.001). These levels positively correlated with neutrophil (p<0.0001) or monocyte counts (p<0.0001). The median NGAL levels (307.8 ng/mL) and neutrophil counts (4141/μL) at birth of 16 preterm infants (<31 GW) who developed BPD were higher than those (42.9 ng/mL and 1357/μL) of 20 infants (<31 GW) who did not (p<0.0001 and p=0.012), respectively. In multivariable analysis for 36 infants born less than 31 GW, higher NGAL levels (≥ 82 ng/mL) but not neutrophil counts at birth had a significant association with developing BPD (gestational-age adjusted odds ratio [OR]=37.45 [3.08-455.49], p<0.01). CONCLUSIONS High serum levels of NGAL at birth could be an early sensitive marker for BPD in preterm infants, because their levels were physiologically low.

Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome.

Sotos syndrome (OMIM #117550) is a congenital syndrome characterized by overgrowth with advanced bone age, macrocephaly, and learning difficulties. Endocrine complications of this syndrome have not yet been fully described in previous reports. We here investigated the clinical manifestations of Sotos syndrome in Japanese patients who presented with hyperinsulinemic hypoglycemia of infancy. We recruited patients diagnosed as having Sotos syndrome who presented with the complication of hyperinsulinemia during the neonatal period using a survey of the abstracts of Pediatric Meetings in domestic areas of Japan from 2007 to 2011. As a result, five patients (four females and one male) were recruited to evaluate the clinical presentation of Sotos syndrome by reference to the clinical record of each patient. A 5q35 deletion including the NSD1 gene was detected in all patients. Major anomalies in the central nervous, cardiovascular, and genito‐urinary systems were frequently found. Hypoglycemia occurred between 0.5 and 3 hr after birth and high levels of insulin were initially found within 3 days of birth. The patients were treated with intravenous glucose infusion at a maximum rate of 4.6–11.0 mg/kg/min for 12–49 days. Three of the five patients required nasal tube feeding. One patient received medical treatment with diazoxide. This study shows that patients with Sotos syndrome may present with transient hyperinsulinemic hypoglycemia in the neonatal period.

Differential Transmission and Postnatal Outcomes in Triplets with Intrauterine Cytomegalovirus Infection

We present a case of triplets with intrauterine cytomegalovirus (CMV) infection, each of whom showed differential transmission, placental pathology, and postnatal outcome. The first- and second-born infants were both vigorous and asymptomatic at birth, although the first-, but not the second-born, triplet had a high copy number of CMV DNA in the peripheral blood (1.2 × 103 copy/mL). The third-born triplet suffered from symptomatic CMV infection with a high viral load (6.0 × 106 copy/mL). The triamniotic-trichorionic placentas were not fused to each other. The histopathologic analysis showed that CMV-positive cells were frequently found in the decidua, villi, and amnion of the third-born triplets placenta but were limited and scattered in the decidua or villi but not amnion of the other 2 placentas. The third-born triplet underwent ganciclovir therapy. None of the infants had physical or auditory problems at 4 years of age, whereas the third-born triplet had been diagnosed with an autistic disorder. This observation exemplifies the preventive roles of the individual placentas of triplets with regard to virus infection, thus suggesting that developing CMV disease largely depends on the placental function.

Circulating PCSK9 levels correlate with the serum LDL cholesterol level in newborn infants

BACKGROUND AND AIMS Protein convertase subtilisin/Kexin type-9 (PCSK9) is a substantial player in lipoprotein metabolism. This study was designed to elucidate the role of PCSK9 in the regulation of lipoprotein during the fetal period. STUDY DESIGN AND SUBJECTS This study was a cross-sectional study. Eighty-one neonates (45 males, 36 females) who were admitted to the neonatal intensive care unit were enrolled in the study. The median age in gestational weeks and weight at birth were 37.1 weeks and 2493 g, respectively. There were no gender differences, but the proportion of infants who were small-for-gestational age (SGA) was significantly higher among females than males. The prefed serum PCSK9 level was assayed with ELISA kits. RESULTS The median PCSK9 concentration in male newborns was significantly lower than that in females (148.2 ng/ml vs. 171.4 ng/ml, respectively, p<0.001). Circulating serum PCSK9 levels were positively correlated with total cholesterol (r=0.281, p<0.05) and low-density lipoprotein cholesterol (LDL-C; r=0.272, p<0.05). However, there were no correlations between PCSK9 levels and birth weight, gestational age or SGA. Multivariate forward stepwise linear regression analysis revealed that gestational age and circulating PCSK9 levels were independent predictors of the serum LDL-C levels in newborn infants. CONCLUSION Our first quantitative analysis of neonatal serum PCSK9 levels at birth showed that circulating PCSK9 levels show gender-based differences and are significantly correlated with LDL-C. These results suggest that PCSK9 could play an important role in regulating LDL-C levels during the fetal period.

Serum chemokine levels and developmental outcome in preterm infants

BACKGROUND Cytokines and chemokines during perinatal period may involve the neurological development of newborns. AIMS We investigated the association of circulating chemokines during neonatal period with the outcome of premature infants. STUDY DESIGN The prospective study enrolled 29 very low birth weight (<1500 g) and appropriate-for-date infants having no underlying diseases. Serum concentrations of chemokines (CXCL8, CXCL9, CXCL10 and CCL2) and cytokines at birth and 4 weeks postnatal age were measured. Developmental quotients (DQ) at 3 years of age by the Kyoto Scale of Psychological Development were studied for the association with chemokine/cytokine levels and clinical variables including chorioamnionitis, Apgar scores, ventilator treatment and supplemental oxygen. RESULTS CXCL8 levels at birth and days of ventilator treatment were negatively, CCL2 levels at 4 weeks after birth and 5-minute Apgar scores were positively correlated with the DQ of postural-motor [P-M] area at 3 years of age, respectively (CXCL8: correlation coefficient [CC]=-0.394, p=0.037, ventilation: CC=-0.518, p=0.006, CCL2: CC=0.528, p=0.013, and Apgar score: CC=0.521, p=0.005). Infants showing both ≥50 pg/ml of CXCL8 at birth and <250 pg/ml of CCL2 4 weeks after birth had lower DQ of P-M than those who did not (p<0.001). Multivariate analyses indicated that CCL2 levels at 4 weeks of age were higher in infants who attained normal DQ of P-M (≥85) (adjusted mean, 338.4 [95% confidence interval, 225.5-507.8]) than in those who did not (<85) (159.0, [108.2-233.7]) (p=0.019). CONCLUSION Circulating patterns of CXCL8 (IL-8) and CCL2 (MCP-1) during the neonatal period might affect the neurological development of preterm infants.

Risk of respiratory syncytial virus in survivors with severe congenital diaphragmatic hernia

Background: During the follow‐up period in surviving patients with severe congenital diaphragmatic hernia (CDH), respiratory complications, such as recurrence of CDH or chronic lung disease, have been reported to occur as a late complication. Although some risk factors for deterioration of respiratory condition have been reported in CDH, the risk of respiratory syncytial virus (RSV) in postoperative CDH patients has not as yet been reported upon.

Neonatal asphyxia and renal failure as the presentation of non-inherited protein C deficiency

Inherited or acquired protein C (PC) deficiency leads to thromboembolic events. Plasma PC activity in infancy is physiologically lower than in adults. We describe a case of neonatal asphyxia and acute renal failure associated with isolated PC deficiency. A full-term male infant was born to a healthy mother by caesarean section because of fetal distress. The small-for-gestational age infant showed 2 and 7 of Apgar scores at 1 and 5 minutes, respectively. Hypercoagulability required repeated infusions of fresh frozen plasma. Coagulation study revealed PC activity, 6%, protein S activity, 61%, and high D-dimer levels, along with normal factor VII activity and absent vitamin K deficiency. Anticoagulant and activated PC therapy improved coagulopathy and nephropathy. Imaging analyses indicated no visceral infarctions. Renal function and PC activity have been slowly normalized until 6 months of age. He had no PROC mutation or PC-deficient parents. Selective PC deficiency may occur as an acquired cause of hypercoagulable crisis in the stressed newborn.