Neonatal systemic juvenile Xanthogranuloma with Hydrops diagnosed by Purpura skin biopsy: a case report and literature review.

BACKGROUND: Systemic juvenile xanthogranuloma is a very rare disease typically presents as skin lesions with yellow papules or nodules and is sometimes fatal. We report a case of congenital neonatal systemic juvenile xanthogranuloma with atypical skin appearance that made the diagnosis difficult. CASE PRESENTATION: A preterm Japanese female neonate with prenatally diagnosed fetal hydrops in-utero was born with purpuric lesions involving the trunk and face. Since birth, she had hypoxemic respiratory failure, splenomegaly, anemia, thrombocytopenia, coagulopathy, and was transfusion dependent for red blood cells, fresh frozen plasma, and platelets. Multiple cystic lesions in her liver, part of them with vascular, were detected by ultrasound. A liver biopsy was inconclusive. A skin lesion on her face similar to purpura gradually changed to a firm and solid enlarged non-yellow nodule. Technically, the typical finding on skin biopsy would have been histiocytic infiltration (without Touton Giant cells) and immunohistochemistry results which then would be consistent with a diagnosis of systemic juvenile xanthogranuloma, and chemotherapy improved her general condition. CONCLUSIONS: This case report shows that skin biopsies are necessary to detect neonatal systemic juvenile xanthogranuloma when there are organ symptoms and skin eruption, even if the skin lesion does not have a typical appearance of yellow papules or nodules.

Chylothorax Associated with Congenital Complete Atrioventricular Block.

Introduction Congenital complete atrioventricular block (CCAVB) associated with congenital chylothorax is a rare finding that has been reported in only one case in the literature. We report here the case of an infant with CCAVB complicated by congenital chylothorax. Patient Report We present the case of a male neonate with a birth weight of 2114 g. Fetal bradycardia and right pleural effusion were detected at gestational age of 22 weeks. Maternal serum levels of anti-Sjögren's-syndrome-related antigen A autoantibody were high (4840 U/mL). The neonate was delivered at gestational age of 33 weeks; a temporary external pacemaker was placed immediately after birth that resulted in an improved cardiac output. Milk-colored pleural effusion increased in volume together with the initiation of breast milk feeding. Lymphocytosis and high triglyceride levels in the pleural fluid led to the diagnosis of chylothorax. The pleural effusion resolved in response to prednisolone, octreotide, and total parenteral nutrition. Discussion The causal relationship between CCAVB and congenital chylothorax can be explained by considering the damage to the lymphatic vessels secondary to inflammation due to maternal autoantibodies and venous congestion due to bradycardia. Conclusion In any case of CCAVB associated with atypical pleural effusion, one must consider the possibility of congenital chylothorax.

Neurodevelopmental impairment at 3 years of age after fetoscopic laser surgery for twin-to-twin transfusion syndrome.

BACKGROUND: Data on neurodevelopmental outcomes of children surviving after fetoscopic laser surgery (FLS) for twin-to-twin transfusion syndrome (TTTS) are scarce. METHODS: We retrospectively investigated children surviving after FLS for TTTS at 16 to 26 weeks' gestation between 2003 and 2014. Children were evaluated by standardized neurologic examinations using the Kyoto Scale 2001 at a corrected age of 3 years ± 6 months. Neurodevelopmental impairment (NDI) was defined as cerebral palsy (CP), bilateral blindness, bilateral deafness or a developmental quotient (DQ) < 70 points. Brain magnetic resonance imaging (MRI) was performed at term-equivalent age. RESULTS: A total of 188 children from 110 twin pregnancies were evaluated. NDI was detected in 16/188 (8.5%) children, including six cases of CP (3.2%). No children had bilateral blindness or deafness. An earlier gestational age at delivery was associated with a higher incidence of NDI (P < .001). Abnormal brain MRI findings were detected in 9/16 (56%) of children with NDI, including 6/6 (100%) with CP. CONCLUSION: The incidence of NDI in children following FLS at 3 years old was 8.5%. Prematurity is a strong risk factor for NDI. Brain MRI may predict the development of CP.

An extremely severe case of Aicardi-Goutières syndrome 7 with a novel variant in IFIH1.

We describe herein an extremely severe case of Aicardi-Goutières syndrome 7 (AGS7). The female patient was the daughter of nonconsanguineous parents and developed cardiomegaly, pericardial effusion, splenomegaly, and intracranial calcification during the fetal period. Because her cardiotocogram showed a non-reassuring fetal status, she was delivered at 29 weeks and 4 days of gestation by an emergency cesarean section. After birth, she suffered from respiratory distress, pulmonary hypertension, refractory fever, recurrent thrombocytopenia, and abdominal distention caused by hepatomegaly and ascites. She showed a lenticulostriate vasculopathy, which was compatible with the fetal intracranial calcification. Despite various intensive care procedures, she died of gradually progressive pulmonary hypertension at 3 months of age. After her death, whole exome sequencing on the patient and the parents was performed and revealed a novel, de novo, heterozygous mutation in the IFIH1 gene (IFIH1:NM_022168:exon12:c.2439A > T:p.Glu813Asp). On the basis of the mutation and the clinical features, the diagnosis was AGS7. Although AGS7 has been regarded as a relatively mild subtype of Aicardi-Goutières syndrome, this case indicates that the c.2439A > T variant of AGS7 can be fatal in early infancy.

Effect and Complications of Everolimus Use for Giant Cardiac Rhabdomyomas with Neonatal Tuberous Sclerosis.

Most cardiac rhabdomyomas with tuberous sclerosis (TS) are asymptomatic and spontaneously regress. However, some cases require surgical intervention due to arrhythmia and severe obstruction of cardiac inflow or outflow. We report herein a neonatal case of giant cardiac rhabdomyomas with TS and insufficient pulmonary blood flow from the right ventricle. Lipoprostaglandin E1 was necessary to maintain patency of the ductus arteriosus. We used everolimus, a mammalian target of rapamycin inhibitor, to diminish the cardiac rhabdomyomas. After treatment, the rhabdomyomas shrank rapidly, but the serum concentration of everolimus increased sharply (maximum serum trough level: 76.1 ng/mL) and induced complications including pulmonary hemorrhage, liver dysfunction, and acne. After the everolimus level decreased, the complications resolved. Everolimus may be a viable treatment option for rhabdomyomas, but its concentration requires close monitoring to circumvent complications associated with its use.

An investigation on clinical differences between congenital pulmonary airway malformation and bronchial atresia.

BACKGROUND/PURPOSE: Differences in clinical features between congenital pulmonary airway malformation (CPAM) and bronchial atresia (BA) have not yet been clearly described. METHODS: We retrospectively reviewed 112 patients with a pathological diagnosis of CPAM or BA. The clinical parameters were statistically analyzed between these diseases. RESULTS: Seventy-one patients received prenatal diagnosis and 41 received postnatal diagnosis. The percentage of prenatal diagnosis was significantly higher in CPAM patients (84% vs 50%, p < 0.001). Among patients with prenatal diagnosis, the backgrounds were not different between the two diseases except for the number of Caesarean sections (81% vs 9%, p < 0.0001). The numbers of patients that underwent fetal interventions and emergent neonatal surgery were higher in CPAM (51% vs 15%, p < 0.01 and 76% vs 12%, p < 0.0001), although there was no statistical difference in survival rate (86% vs 97%, p = 0.2). In patients receiving postnatal diagnosis, pneumonia was the primary symptom in most BA patients, whereas respiratory distress was the major symptom in patients with CPAM. Age at presentation of the primary symptom was significantly older in BA patients (4.2 years vs 1.2 years, p < 0.005). CONCLUSION: CPAM and BA have distinct clinical features in terms of therapeutic and natural history. Careful imaging evaluation and pathological analysis can lead to an accurate diagnosis of BA. TYPE OF STUDY: Prognostic study. LEVEL OF EVIDENCE: Level II. This study is categorized as a "Prognostic Study" with LEVEL III of Evidence.

11q23 deletion syndrome (Jacobsen syndrome) with severe bleeding: a case report.

BACKGROUND: 11q23 deletion syndrome, also known as Jacobsen syndrome, is characterized by growth retardation, psychomotor retardation, facial dysmorphism, multiple congenital abnormalities, and thrombocytopenia. In 11q23 deletion syndrome, it is often difficult to anticipate the severity of bleeding. We report a neonatal case of 11q23 deletion syndrome with bleeding that was more severe than predicted by the platelet count. CASE PRESENTATION: We report a case of 11q23 deletion syndrome in an Asian male newborn with severe bleeding just after birth. The diagnosis of 11q23 deletion syndrome was made prenatally by amniocentesis. An array comparative genomic hybridization analysis revealed a deletion of the 13.0 Mb regions ranging from 11q24.1 to the q terminus encoding FLI1. Our patient was delivered by cesarean section and exhibited skull deformities, facial asymmetry, low-set ears, inguinal hernia, flat feet, and crowded toes. He had a low platelet count (45,000/µL) and a coagulation abnormality with a prothrombin time-international normalized ratio of 1.92 and an activated partial thromboplastin time of 158.6 seconds. Bleeding at the site of a peripheral vessel puncture was more severe than expected with thrombocytopenia. The peripheral blood featured two different sizes of platelets containing large α-granules. As a result, he required eight platelet transfusions and two fresh frozen plasma transfusions within 13 days of birth. Massive bleeding was avoided, and cerebral magnetic resonance imaging indicated the occurrence of only petechial hemorrhage. CONCLUSIONS: Our patient with 11q deletion including FLI1 avoided massive bleeding and serious sequelae because of careful management after prenatal diagnosis. We suggest that prenatal diagnosis and vigilant perinatal care including a cesarean section are warranted for patients with 11q23 deletion syndrome.

Resolution of liver disease in transient abnormal myelopoiesis with fish oil emulsion.

Neonates with Down syndrome are at risk of developing transient abnormal myelopoiesis (TAM), which is characterized by transient clonal myeloproliferation of the blast cells. TAM can resolve spontaneously, but some patients die at an early age due to organ failure. Liver fibrosis in TAM is a life-threatening condition, but treatment options have not yet been established. Here, we report on the case of an infant with TAM complicated by liver disease, whose hyperbilirubinemia was successfully ameliorated with omega-3 fatty acid (ω3FA) lipid emulsion. Timely ω3FA lipid emulsion may be a feasible treatment for liver disease in TAM before serious liver damage develops.

The outcomes of 31 cases of trisomy 13 diagnosed in utero with various management options.

There are few reports on the prognosis of prenatally diagnosed trisomy 13 in relation to postnatal management. The aim of this study was to report on the prenatal and postnatal outcomes and postnatal management of trisomy 13 fetuses that were prenatally diagnosed at our center between 2003 and 2015. The data were retrospectively reviewed from medical records. Of the 31 cases of trisomy 13, 12 patients were diagnosed before 22 weeks of gestation, and 19 were diagnosed at or after 22 weeks of gestation. Nine families opted for termination of the pregnancy, 14 fetuses died, and 8 were born alive. Aggressive treatment was requested in two of the live births, with one patient achieving long-term survival (7 years). The other died during infancy (Day 61). One out of four who received palliative treatment is alive at two years of age with only nutrition supplementation. These three patients who achieved neonatal survival had few structural anomalies. Fetal death and early neonatal death are common in trisomy 13; however, fetuses that receive medical treatment for cases without major ultrasound abnormalities may achieve neonatal survival. Therefore, it is useful to provide comprehensive information, including precise ultrasound findings and treatment options, to parents with trisomy 13 fetuses during genetic counseling.

Bone fracture in severe small-for-gestational-age, extremely low birth weight infants: A single-center analysis.

INTRODUCTION: Bone fracture is a complication of extremely low birth weight infants (ELBWIs). This study aimed to analyze risk factors for bone fracture in a population of severe small-for-gestational-age (SGA) ELBWIs. METHODS: We retrospectively studied data from ELBWIs with a birth weight <1000g and <-2 standard deviations (SDs) born at the National Center for Child Health and Development, Japan, from 2013 to 2015. Infants were divided into fracture and control groups. Serum calcium (Ca) and phosphorus (P) levels, perinatal factors, and previously reported risk factors were analyzed. RESULTS: Of 25 cases of severe SGA ELBWIs, 5 cases of bone fracture were identified. Gestational age was 27.7±2.2, 29.1±2.6weeks (mean difference [MD] -1.4, 95% confidence interval [CI]: -4.0, -1.2, p=0.280), birth weight (BW) 448±105, 673±216g (MD -225, 95% CI: -433, -17, p=0.036) and BW-SD -4.1±0.1, -3.4±0.8 (MD -0.8, 95% CI: -1.5, -0.02, p=0.045) in the fracture and control groups, respectively. Minimums of serum Ca and P were 6.6±1.4, 8.1±0.8mg/dl (MD -1.5, 95% CI: -2.5, -0.6), p=0.003) and 2.3±0.6, 3.5±1.1mg/dl (MD -1.2, 95% CI: -2.2, -0.1, p=0.027) in the fracture and control groups, respectively. CONCLUSION: Lower BW and BW-SD were possible risk factors for bone fracture. Hypocalcemia and hypophosphatemia may also contribute to the condition.

A Case of Fatal Pulmonary Hypoplasia with Congenital Diaphragmatic Hernia, Thoracic Myelomeningocele, and Thoracic Dysplasia.

Background Congenital diaphragmatic hernia (CDH) is fatal in severe cases of pulmonary hypoplasia. We experienced a fatal case of pulmonary hypoplasia due to CDH, thoracic myelomeningocele (MMC), and thoracic dysplasia. This constellation of anomalies has not been previously reported. Case Report A male infant with a prenatal diagnosis of thoracic MMC with severe hydrocephalus and scoliosis was born at 36 weeks of gestation. CDH was found after birth and the patient died of respiratory failure due to pulmonary hypoplasia and persistent pulmonary hypertension of the newborn at 30 hours of age despite neonatal intensive care. An autopsy revealed a left CDH without herniation of the liver or stomach into the thoracic cavity, severe hydrocephalus, Chiari malformation type II, MMC with spina bifida from Th4 to Th12, hemivertebrae, fused ribs, deformities of the thoracic cage and legs, short trunk, and agenesis of the left kidney. Conclusion We speculate that two factors may be associated with the severe pulmonary hypoplasia: decreased thoracic space due to the herniation of visceral organs caused by CDH and thoracic dysplasia due to skeletal deformity and severe scoliosis.

The possible involvement of intestine-derived IgA1: a case of IgA nephropathy associated with Crohn's disease.

BACKGROUND: A link between IgA nephropathy and Crohn's disease has recently been reported. Other researchers hypothesize that intestine-derived IgA complexes deposit in glomerular mesangial cells, eliciting IgA nephropathy. Intestinal mucosal plasma cells mainly secrete IgA2. Nevertheless, IgA1 deposition is strongly implicated as being the primary cause of IgA nephropathy. CASE PRESENTATION: A 46-year-old Japanese man developed IgA nephropathy 29 years ago, following tonsillectomy. As a result, a normal urinalysis was obtained. The patient previously suffered Crohn's disease followed by urinary occult blood and proteinuria six years ago. Exacerbation of IgA nephropathy was highly suspected. Therefore a renal biopsy was performed. A diagnosis of exacerbation of IgA nephropathy with mesangial cell proliferation and fibrotic cellular crescent was based upon the pathological findings. The patient exhibited a positive clinical course and eventually achieved a remission with immunosuppressive therapy including prednisolone treatment. Immunostaining for the detection of IgA subtypes was performed on both of his kidney and excised ileum. The results revealed IgA1 and IgA2 deposition by submucosal cells in intestine. Furthermore, IgA1 deposition of mesangial areas in the patient's kidney, indicated an association of IgA1 with the exacerbation of IgA nephropathy. CONCLUSION: This case represents the possibility that the intestine-derived IgA1 can be the origin of galactose-deficient IgA which is known to cause IgA nephropathy exacerbation.

Hepatitis B virus surface antibody titers in babies administered hepatitis B immune globulin both intravenously and intramuscularly after birth.

OBJECTIVE: High rates of vertical transmission of hepatitis B virus (HBV) infection from carrier mothers to their babies are observed in hepatitis B e antigen (HBeAg)-positive mothers under the existing protocol. The current status suggests that the existing protocol may be insufficient for the prevention of mother-to-child transmission (MTCT) in HBeAg-positive mothers. To achieve complete prevention of HBV vertical transmission, we designed a protocol implementing intravenous administration along with ordinary intramuscular administration of HBV immune globulin (HBIG) to the baby after birth. METHODS: We compared the HBV surface antibody (HBsAb) titer in babies who were simultaneously administered HBIG both intravenously and intramuscularly after birth with that in babies who received HBIG only intramuscularly. RESULTS: The HBsAb titer rose rapidly after administration in the combined administration group, and the elevated titer was maintained for approximately 2 months. Although the antibody titer at the peak was nearly 6 times greater in the combined administration group than in the intramuscular administration group, the combined administration of HBIG did not have any effect on total IgG antibody levels in the bloodstream. CONCLUSION: The combined protocol was demonstrated to be safe and superior to the protocol of only intramuscular HBIG administration with respect to rapid elevation of HBsAb in the bloodstream. It could be an effective method for the prevention of MTCT in HBeAg-positive mothers.

Evaluation of two glucose meters and interference corrections for screening neonatal hypoglycemia.

BACKGROUND: Many neonatal intensive care and maternal units still use self-monitoring of blood glucose (SMBG) devices as a tool to aid diagnosis despite the introduction of point-of-care testing (POCT) devices, which are known to have higher accuracy. We evaluated the performance of two glucose meters, the StatStrip (Nova Biomedical), a POCT device, and the Medisafe Mini (Terumo), an SMBG device, to detect hypoglycemia in neonates. In addition, we evaluated the interference of hematocrit, acetaminophen and ascorbic acid. METHODS: Whole blood samples were drawn from neonates who were at risk of hypoglycemia and analyzed with the StatStrip and Medisafe Mini. The results were further confirmed with blood gas analyzers ABL825 and BM6050. To evaluate the interference of hematocrit, acetaminophen and ascorbic acid, concentrated solutions of glucose and interfering substances were gravimetrically prepared and analyzed. RESULTS: Among the 222 blood samples analyzed, results from the StatStrip were more closely aligned to those of the ABL825 at all levels of glucose than the Medisafe Mini. CONCLUSION: StatStrip appears to be unaffected by hematocrit, ascorbic acid or acetaminophen. We recommend its use in neonates in hospital. Further studies are required to identify other interference effects.

[Specific examinations for infants and children].

There are many diseases specific to childhood. Therefore, there are several specific examinations which are not performed in adults. In this article, we introduce some examinations specific to the neonatal period. Newborn mass-screening using tandem mass spectrometry is conducted to diagnose congenital metabolic error before onset early after birth and minimize the influence of disturbance. Tandem mass spectrometry is performed to detect amino acid metabolism disturbance, urea cycle disorder, organic acid metabolism disturbance, and fatty acid metabolism disturbance. Newborn auditory screening has commonly been conducted since the importance of early detection was proposed in the United States, making it possible to simply perform screening in a large number of patients using automatic analyzers. In Japan, the automated auditory brainstem response (Auto ABR) and otoacoustic emissions (OAE) have commonly been employed. Prenatal care consists of genetic and morphological tests. For morphological tests, screening is initially performed using ultrasonography. When an abnormality is suspected, closer echography and target organ/disease-based fetal MR/CT are used. With these examinations, cerebrospinal anomalies, congenital heart disease, occupying lesions, and bone diseases are diagnosed.

The landscape of somatic mutations in Down syndrome-related myeloid disorders.

Transient abnormal myelopoiesis (TAM) is a myeloid proliferation resembling acute megakaryoblastic leukemia (AMKL), mostly affecting perinatal infants with Down syndrome. Although self-limiting in a majority of cases, TAM may evolve as non-self-limiting AMKL after spontaneous remission (DS-AMKL). Pathogenesis of these Down syndrome-related myeloid disorders is poorly understood, except for GATA1 mutations found in most cases. Here we report genomic profiling of 41 TAM, 49 DS-AMKL and 19 non-DS-AMKL samples, including whole-genome and/or whole-exome sequencing of 15 TAM and 14 DS-AMKL samples. TAM appears to be caused by a single GATA1 mutation and constitutive trisomy 21. Subsequent AMKL evolves from a pre-existing TAM clone through the acquisition of additional mutations, with major mutational targets including multiple cohesin components (53%), CTCF (20%), and EZH2, KANSL1 and other epigenetic regulators (45%), as well as common signaling pathways, such as the JAK family kinases, MPL, SH2B3 (LNK) and multiple RAS pathway genes (47%).

Early-onset group B streptococcal disease following culture-based screening in Japan: a single center study.

AIM: We investigated trends in early-onset group B streptococcal disease (EOD) after the introduction of culture-based screening in Japan. MATERIAL AND METHODS: A retrospective cohort study examined EOD trends in 9506 pregnancies and 10 715 neonates at our center from 2002 to 2009. RESULTS: EOD occurred in four neonates (4/7332: 0.55/1000 live births). The EOD incidence among infants born to women positive for GBS by screening was 0.90 cases per 1000 live births (1/1107). In contrast, the EOD incidence among infants negative by GBS screening was 0.48 cases per 1000 live births (3/6225). Thus, of the four affected neonates, three had mothers who tested negative on antepartum GBS screening. Two neonates had symptoms of infection during labor and intrapartum antibiotic agents were administered. The other two neonates received no antibiotics because deliveries were uneventful and they were negative on GBS screening. CONCLUSION: The incidence of EOD is 0.90 cases per 1000 live births among GBS-positive women and 0.48 cases per 1000 live births among GBS-negative women. The results of our study implied that EOD can develop regardless of GBS screening and intrapartum clinical course, although the method of sample collection, indications for antibiotic prophylaxis, and the antibiotics regimen should be considered.

Persistent pulmonary hypertension of the newborn in twin-twin transfusion syndrome following fetoscopic laser surgery.

OBJECTIVE: We investigated persistent pulmonary hypertension of the newborn (PPHN) among monochorionic-diamniotic (MD) twins. METHODS: A retrospective cohort study examined MD twins from 195 deliveries and 373 live-born neonates at our center. RESULTS: PPHN occurred in three cases (3/373: 0.8%), all of which were recipients of twin-twin transfusion syndrome (TTTS), after fetoscopic laser surgery (FLS) (3/117: 2.6%). Although the clinical course of the three cases differed, all cardiothoracic area ratios exceeded 40%, and other cardiac parameters also worsened after FLS. CONCLUSIONS: The occurrence of PPHN in TTTS recipients should be noted, particularly when fetal cardiac function declines following FLS.