Pulmonary hypertension with bronchopulmonary dysplasia: Aichi cohort study.

BACKGROUND: The incidence of pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD) has not been investigated in regional cohorts. The aim of this study was to clarify the incidence of PH associated with BPD in all very low birthweight infants (VLBWIs) born during the study period in Aichi Prefecture, Japan. METHODS: We conducted a retrospective observational cohort study of all VLBWIs born in Aichi Prefecture. The inclusion criteria were VLB, birth between 1 January 2015 and 31 December 2015, and admission to any neonatal intensive care unit in Aichi Prefecture. BPD28d and BPD36w were defined as the need for supplemental oxygen or any respiratory support at 28 days of age or 36 weeks of postmenstrual age (PMA). The primary outcome was the incidence of PH after 36 weeks' PMA (PH36w) in VLBWIs with BPD28d and BPD36w. The secondary outcomes were the clinical factors related to PH36w in BPD36w patients. Mann-Whitney U-test and Fisher's exact test were used for univariate analysis. Differences were considered statistically significant at P < 0.05. Risk ratio (RR) and 95% confidence interval (CI) were also evaluated. RESULTS: A total of 441 patients were analyzed. A total of 217 and 131 patients met the definition of BPD28d and BPD36w, respectively. Nine patients were diagnosed with PH36w (4.2% and 6.9% of the BPD28d and BPD36w patients, respectively). The presence of oligohydramnios (RR, 2.71; 95% CI: 1.55-4.73, P = 0.014) and sepsis (RR, 3.62; 95% CI: 1.51-8.63, P = 0.025) was significant in the PH36w patients. CONCLUSIONS: The incidence of PH36w was 4.2% and 6.9% in the BPD28d and BPD36w patients, respectively. Oligohydramnios and sepsis were significantly associated with PH36w in VLBWIs.

A Novel α-Spectrin Pathogenic Variant in Trans to α-Spectrin LELY Causing Neonatal Jaundice With Hemolytic Anemia From Hereditary Pyropoikilocytosis Coexisting With Gilbert Syndrome.

Hereditary pyropoikilocytosis is a subtype of hereditary elliptocytosis because of biallelic mutations of SPTA1, SPTB, and EPB41. The authors present a proband with neonatal jaundice and hemolytic anemia, with poikilocytosis in the blood film. Targeted next-generation sequencing identified Q267del trans to the αLELY allele in SPTA1. In addition, the proband presented coexisting Gilbert syndrome as determined by homozygous mutation of UGT1A1. Investigation of 13 relatives and his sibling revealed that only his sibling showed the same phenotype and genotype as the proband. This is the first report of molecular confirmation of coexisting hereditary pyropoikilocytosis and Gilbert syndrome and a novel mutation in SPTA1.

Prognostic factors of hydrops fetalis with pleural effusion.

BACKGROUND: Hydrops fetalis (HF) has a low survival rate, particularly in the case of preterm birth. In addition, the severity index of HF has not been fully investigated yet. The aim of this study was to clarify the prognostic factors of HF with pleural effusion. METHODS: All live-born HF patients with pleural effusion, except for chromosomal abnormality or complex congenital heart disease, born from 2009 to 2013 in Aichi Prefecture in Japan were included. Prenatal, perinatal, and postnatal information was obtained from the medical records and was retrospectively analyzed. RESULTS: Forty-one HF patients with pleural effusion were included, and 28 patients (68%) survived. On multivariate logistic stepwise analysis, gestational birth week (OR, 0.71; 95% CI: 0.52-0.96, P = 0.027) and standard deviation (SD) score of the birthweight (OR, 1.74; 95% CI: 1.01-2.99, P = 0.045) were significant factors for postnatal death. All patients with both ≥32 gestational weeks and <3.0 birthweight SD score survived. CONCLUSIONS: Combined with the gestational weeks data, birthweight SD score may be useful to estimate the prognosis of HF with pleural effusion.

Single nucleotide polymorphisms in AGTR1, TFAP2B, and TRAF1 are not associated with the incidence of patent ductus arteriosus in Japanese preterm infants.

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 <32 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. RESULTS: 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). CONCLUSIONS: 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.

Risk factors for early death in transient myeloproliferative disorder without phenotypic features of Down syndrome: a case report and literature review.

Not only in newborns with Down syndrome, but newborns without phenotypic features of Down syndrome also develop transient myeloproliferative disorder (TMD). In these cases, trisomy 21 and related chromosomal abnormalities are either constitutionally mosaic or limited to blood cells. Risk factors for early death of these patients are unknown so far. We here report a fatal case of TMD without phenotypic features of Down syndrome and review literature to identify risk factors associated with early death. Not only are gestational age and white blood cell count risk factors for early death in TMD with Down syndrome, but they also appear to be risk factors in TMD without Down syndrome.

Effects of exchange transfusion on cytokine profiles in necrotizing enterocolitis.

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.

Cytokine profiles before and after exchange transfusion in a neonate with transient myeloproliferative disorder and hepatic fibrosis.

SUMMARY: 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.

Neonatal MRI in preterm infants with periventricular leukomalacia and mild disability.

BACKGROUND: The aim of the present study was to describe the neonatal magnetic resonance imaging (MRI) findings of preterm infants with periventricular leukomalacia and mild neurological disability. METHODS: MRI findings at term equivalent were retrospectively investigated in eight preterm infants with mild disability and periventricular leukomalacia diagnosed on MRI in infancy. RESULTS: Linear, spotted, or macular areas of hyperintensity on T1-weighted imaging and hypointensity on T2-weighted imaging were identified in all subjects in the white matter lateral to the body of the lateral ventricle. No cystic lesions were seen. These findings were more widespread and more clearly visualized on T2-weighted imaging than T1-weighted imaging. CONCLUSIONS: Linear, spotted, or macular lesions that are hyperintense on T1-weighted imaging and hypointense on T2-weighted imaging are possibly compatible with periventricular leukomalacia.

Echovirus Type 7 Virus-Associated Hemophagocytic Syndrome in a Neonate Successfully Treated With Intravenous Immunoglobulin Therapy: A Case Report.

Virus-associated hemophagocytic syndrome (VAHS) in the neonatal period has a high mortality. Although clear diagnostic criteria and treatment methods have not been established, early diagnosis and treatment are critical. However, treatments for VAHS have potentially serious side effects, especially during the neonatal period. Echovirus type 7 can cause maternal infection around parturition and be vertically transmitted to the neonate and induce VAHS. Intravenous immunoglobulin (IVIG) therapy could be a first-line therapy for neonatal VAHS, so that treatments with potentially serious side effects, including cyclosporine A and etoposide, could be avoided. A case of VAHS associated with echovirus type 7 that was successfully treated with IVIG therapy is reported.

Natural histories of patients with Wolf-Hirschhorn syndrome derived from variable chromosomal abnormalities.

Wolf-Hirschhorn syndrome (WHS) is a subtelomeric deletion syndrome affecting the short arm of chromosome 4. The main clinical features are a typical craniofacial appearance, growth deficiency, developmental delays, and seizures. Previous genotype-phenotype correlation analyses showed some candidate regions for each clinical finding. The WHS critical region has been narrowed into the region 2 Mb from the telomere, which includes LETM1 and WHSC1; however, this region is insufficient to cause "typical WHS facial appearance". In this study, we identified 10 patients with a deletion involving 4p16.3. Five patients showed pure terminal deletions and three showed unbalanced translocations. The remaining patients showed an interstitial deletion and a suspected inverted-duplication-deletion. Among 10 patients, one patient did not show "typical WHS facial appearance" although his interstitial deletion included LETM1 and WHSC1. On the other hand, another patient exhibited "typical WHS facial appearance" although her small deletion did not include LETM1 and WHSC1. Instead, FGFRL1 was considered as the candidate for this finding. The largest deletion of 34.7 Mb was identified in a patient with the most severe phenotype of WHS.

Neurodevelopmental outcomes at 3 years old for infants with birth weights under 500 g.

BACKGROUND: Marked improvements have been achieved in the survival of extremely low birth weight infants, but survival rates and prognoses of extremely small infants with birth weights ≤500 g remain poor. The aim of this study was to clarify long-term outcomes for surviving infants with birth weights ≤500 g. METHODS: The study population comprised fetuses of gestational age ≥22 weeks, expected live- or stillbirth weight ≤500 g, and birth date between 2003 and 2012. Developmental assessments were performed prospectively at 3 years old. RESULTS: Data were obtained for 21 fetuses, including 10 live births and 11 stillbirths. Of the 10 live births, median gestational age was 25.2 weeks (range, 22.4-27.1 weeks), median birth weight was 426 g (range, 370-483 g), and two neonates died before discharge. One infant with severe asphyxia died within 12 h and another infant with Down syndrome died at 34 days. The survival rate was thus 80%. All surviving infants were small for gestational age. Seven of the 8 surviving infants (88%) weighed less than 2500 g at a corrected age of 40 weeks. Seven infants were available for developmental assessments at 3 years old. One infant could not be followed. Two of those seven infants (29%) showed normal development, three infants (42%) showed mild neurodevelopmental disability, and two infants (29%) showed severe neurodevelopmental disability. One infant had periventricular leukomalacia and cerebral palsy. Two of the seven infants (29%) had short stature (<3 SD) at 3 years old. CONCLUSION: Although the survival rate among live births was good (80%) in this study, neurodevelopmental outcomes remained poor in infants with birth weights ≤500 g. Further large studies are needed to assess long-term outcomes for extremely small infants.

Hypoxic ischemic encephalopathy in a case of intranuclear rod myopathy without any prenatal sentinel event.

Intranuclear rod myopathy (IRM), a variant of nemaline myopathy, is characterized by the presence of nemaline bodies in myonuclei. We report a case of IRM presenting with hypoxic ischemic encephalopathy (HIE). There were no prenatal complications caused by fetal brain injury. Although no nemaline bodies were observed in the cytoplasm, intranuclear rods were observed in some fibers under light and electron microscopy. Molecular analysis identified a heterozygous variant, c.449C>T (p.Thr150Ile), in ACTA1. On magnetic resonance imaging at 9days of age, injuries to the basal ganglia, thalamus, and brainstem consistent with perinatal HIE were seen. Respiratory insufficiency at birth was strongly suspected to be the cause of HIE. Our case highlights that a patient with a congenital neuromuscular disorder who presents with severe respiratory dysfunction requiring substantial resuscitative efforts at birth can be complicated by HIE without any prenatal sentinel event. Prenatal detection of neuromuscular disorders, careful management of delivery, and neonatal resuscitation and adequate respiratory management are important in preventing irreversible brain injury in these patients.

Nemaline myopathy with KLHL40 mutation presenting as congenital totally locked-in state.

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.

Spontaneous movements in the supine position of preterm infants with intellectual disability.

OBJECTIVE: Spontaneous movements at 2 months of corrected age in preterm infants with intellectual disability (ID) were investigated by assessing individual motor elements separated from movements involving the entire body. METHODS: Video recordings of 20 preterm infants with ID (16 males, 4 females; median gestational age 26 weeks; median birth weight 810 g) were analyzed and were compared with those of 21 normal preterm infants (8 males, 13 females; median gestational age 30 weeks; median birth weight 1216 g). RESULTS: In the preterm infants with ID at 2 months corrected age, startle response, lateral decumbent position, predominant shoulder rotation, and maintaining hip adduction were more frequently observed and hand sucking, maintaining shoulder abduction, to-and-fro shoulder abduction, to-and-fro elbow flexion, isolated hip adduction, to-and-fro hip abduction, and leg lift were less frequently seen than in the normal preterm infants (Fisher's exact test, p<0.05). CONCLUSION: Abnormal spontaneous movements at 2 months of age in preterm infants with ID result from persistent immature movements and non-emergence of mature movements.

Spontaneous movements in the supine position of healthy term infants and preterm infants with or without periventricular leukomalacia.

AIM: The individual motor elements presumed to be essential for motor development were determined from spontaneous movements involving the entire body of normal term and preterm infants. Then, diagnostic items for motor abnormality in infants with periventricular leukomalacia (PVL) were investigated. METHODS: Video recordings of 24 healthy term infants, 21 normal preterm infants (8 males, 13 females; median gestational age 30 weeks; median birth weight 1216g) and 14 preterm infants with PVL (6 males, 8 females; median gestational age 30 weeks; median birth weight 1360g) were analyzed. RESULTS: In healthy term infants, predominant shoulder rotation was noticed until 1 month of age. After 2 months of age, isolated movements of the shoulder, elbow, hip, knee, and ankle frequently emerged. In preterm infants with PVL at the corrected age of 2 months, startle response and predominant shoulder rotation were more frequently seen and isolated neck, shoulder, elbow, hip, knee, and ankle movements were less frequently seen than in the normal preterm infants (Fisher's exact test, p<0.025). INTERPRETATION: At 2 months of age, isolated movements evolve, and their failure to occur is suggested to be a useful sign for the diagnosis of cerebral motor disorders.

Magnetic resonance imaging in neonates with total asphyxia.

Magnetic resonance (MR) findings in cases of total asphyxia, whose lesions are mainly in the brainstem and deep nuclei, have not been clarified. In this study, we investigated MR images in neonates with total asphyxia. MR images of six infants (three males and three females; gestational age, 35-39 weeks; birth weights, 1880-3572 g) with total asphyxia were examined. In all subjects, neonatal cortical MR lesions were limited to the hippocampus with highlighting on T1-weighted imaging (T1-WI). The neonatal MR lesions of the cerebral white matter were limited to the white matter between the insula and putamen in four infants, and were diffusely involved in two infants. The ventral lateral nucleus of the thalamus was hyperintense on T1-WI in all of the subjects. Other nuclei in the thalamus, the globus pallidus and the putamen were involved in neonatal MR images of all subjects. High intensity areas on T2- weighted imaging were observed at the dorsal areas in the midbrain, pons and medulla oblongata in all or most of the subjects at the neonatal period. Also, high intensity areas on T1-WI were observed in the tegmentum of the pons and the midbrain in five cases. Neonates with total asphyxia had lesions mainly in the tegmentem of the brainstem, thalamus, putamen and globus palludus. Some of the infants had extensive lesions of the white matter.

Neurodevelopmental outcomes at 18 months' corrected age of infants born at 22 weeks of gestation.

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 22(3/7)-22(6/7) 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.

A case of systemic aplasia cutis congenita: a newly recognized 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.