Bilateral severe microphthalmia in a neonate with trisomy 8 mosaicism: A new finding.

Mosaic Trisomy 8 is a rare chromosomal abnormality estimated to occur one in 30,000 newborns. The phenotype is highly variable and the severity does not appear to be correlated with the proportion of cells that contain the additional chromosome. Ocular involvement in Trisomy 8 mosaicism has previously been described to include corneal opacities, retinal dystrophy, coloboma, and unilateral microphthalmia. We report a case of severe bilateral microphthalmia in a neonate with Trisomy 8 mosaicism, a previously unrecognized ophthalmic manifestation.

Zellweger spectrum disorder patient-derived fibroblasts with the PEX1-Gly843Asp allele recover peroxisome functions in response to flavonoids.

Zellweger spectrum disorder (ZSD) results from biallelic mutations in PEX genes required for peroxisome biogenesis. PEX1-G843D is a common hypomorphic allele in the patient population that is associated with milder disease. In prior work using a PEX1-G843D/null patient fibroblast line expressing a green fluorescent protein (GFP) reporter with a peroxisome-targeting signal (GFP-PTS1), we demonstrated that treatments with the chemical chaperone betaine and flavonoid acacetin diacetate recovered peroxisome functions. To identify more effective compounds for preclinical investigation, we evaluated 54 flavonoids using this cell-based phenotype assay. Diosmetin showed the most promising combination of potency and efficacy (EC50 2.5 µM). All active 5',7'-dihydroxyflavones showed greater average efficacy than their corresponding flavonols, whereas the corresponding flavanones, isoflavones, and chalcones tested were inactive. Additional treatment with the proteostasis regulator bortezomib increased the percentage of import-rescued cells over treatment with flavonoids alone. Cotreatments of diosmetin and betaine showed the most robust additive effects, as confirmed by three independent functional assays in primary PEX1-G843D patient cells, but neither agent was active alone or in combination in patient cells homozygous for the PEX1 c.2097_2098insT null allele. Moreover, diosmetin treatment increased PEX1, PEX6, and PEX5 protein levels in PEX1-G843D patient cells, but none of these proteins increased in PEX1 null cells. We propose that diosmetin acts as a pharmacological chaperone that improves the stability, conformation, and functions of PEX1/PEX6 exportomer complexes required for peroxisome assembly. We suggest that diosmetin, in clinical use for chronic venous disease, and related flavonoids warrant further preclinical investigation for the treatment of PEX1-G843D-associated ZSD.

Report of the proceedings of a UK skin safety advisory group.

Moisture-associated skin damage, especially incontinence-associated dermatitis, continues to present significant health challenges and requires multidisciplinary input to provide effective prevention and treatment. In the absence of mandatory reporting such damage is under- or wrongfully reported, resulting in a lack of accurate data on prevalence and costs of associated care. In March this year, a multidisciplinary team of experts met in the UK to seek to determine measures to improve patient skin care. They aimed to identify activities to increase awareness and education, collect data, and improve prevention and treatment regimes. This article describes that discussion and the conclusions made by the group, such as the key actions required to effect policy changes.

Medications to manage infant pain, distress and end-of-life symptoms in the immediate postpartum period.

INTRODUCTION: Perinatal palliative care (PnPC) is a growing field where healthcare providers from multiple disciplines are supporting families and providing holistic care for their babies with life-limiting illnesses. It is important to have an approach that includes the standardized management of end-of-life symptoms that are anticipated around the time of birth. AREAS COVERED: A need was identified to develop medication orders for the initial pharmacological management of symptoms at end-of-life for infants with life-limiting conditions intended for use outside of an intensive care setting. The choice of medications was based on a review of the literature, discussion with content experts and guided by their ease of use, accessibility and noninvasive route of delivery. The recommendations can be used as a guide for the initial management of common symptoms encountered in perinatal palliative care. EXPERT OPINION: There are studies looking at many qualitative aspects of perinatal palliative care including perceptions of care, decision-making, and bereavement; however, few specifically focus on symptom management in the delivery room and postpartum ward settings. There is a need for standardization of the medical management of infants born with life-limiting conditions whose parents choose to pursue palliative care.

Caudal catheter placement for repeated epidural morphine doses after neonatal upper abdominal surgery.

Effective pain control after major surgery in neonates presents many challenges. Parenteral opioids (and co-analgesics) are often used but inadequate analgesia and oversedation are not uncommon. Although continuous thoracic epidural analgesia is highly effective and opioid-sparing, its associated risks and the need for staff with specialised skills and/or neonatal intensive care unit staff buy-in may preclude this option even in many academic centres. We present the case of a six-day-old infant who underwent upper abdominal surgery and received intermittent morphine doses via a tunnelled caudal epidural catheter, which provided satisfactory analgesia and facilitated early extubation.

Congenital Chylothorax and Hydrops Fetalis: A Novel Neonatal Presentation of RASA1 Mutation.

Mutations in the RASA1 gene are known to cause arteriovenous malformations (AVMs), with evidence of associated lymphatic malformations. We report for the first time, to the best of our knowledge, an infant with RASA1 mutation presenting with hydrops fetalis and chylothorax, but without an associated AVM. Previously, researchers studying rodents have found chylothorax associated with RASA1 mutations, and, in previous case reports, researchers have reported on infants with RASA1 mutations born with hydrops fetalis and AVMs. In this report, we describe the case of a "late preterm" female infant born with nonimmune hydrops fetalis and congenital chylothorax who was detected to have a RASA1 deletion on genetic workup. Although classically described phenotypes of RASA1 mutations present with venous malformations, no such malformations were found in this infant on extensive imaging. This combination is a novel and nonclassic presentation of RASA1 mutation. In cases of congenital chylothorax, especially with nonimmune hydrops fetalis, RASA1 mutations should be considered as part of the differential diagnosis and genetic testing should be included as part of a complete workup to allow for screening for associated vascular anomalies.

Comparisons between umbilical cord biomarkers for newborn hypoxic-ischemic encephalopathy.

BACKGROUND: Cord blood umbilical artery (Ua) pH, base deficit (BD), and pH eucapnic Blickstein/Green-50 may mislead clinicians to identify newborns at risk for hypoxic-ischemic encephalopathy. Neonatal eucapnic pH (pH euc-n Racinet-54) may be a comprehensive alternative. The goal of the study is to compare the predictive performance of these four biomarkers for the combined primary outcome of hypoxic-ischemic encephalopathy/death. METHODS: This retrospective cohort study includes newborns ≥35 weeks gestational age. Receiver operating characteristics curves analysis was performed for Ua cord pH, BD, pH euc-n Racinet-54, and pH eucapnic Blickstein/Green-50 for the global cohort and for two subgroups of newborns with Ua cord pH ≤ 7.15. Cutoff values were derived for all four markers. RESULTS: From the original cohort of 61,037 newborns born between 1 January 2007 and 31 December 2016, we excluded cases with major congenital malformations and missing/incomplete data. The global cohort includes 51,286 newborns and 60 newborns afflicted with hypoxic-ischemic encephalopathy (HIE)/death. The area under the curves (AUC) derived from the global cohort were comparable between Ua cord pH (0.95; 95%CI = 0.94-0.95), BD (0.93; 95%CI = 0.93-0.93), pH euc-n Racinet-54 (0.93; 95% CI = 0.93-0.93), and lower for pH Blickstein/Green-50 (0.78; 95% CI = 0.77-0.78) (p < .05). Within newborn with severe acidemia (pH ≤ 7.00) and moderate acidemia (7.00 ≤ pH ≤ 7.15), pH euc-n Racinet-54 had the largest AUC and best positive likelihood ratios especially for sensitivity ≥ 0.80 to minimize false negative cases. CONCLUSION: In this large retrospective study, predictive performance for Ua cord pH, BD, and pH euc-n Racinet-54 are comparable when applied to the global group. For newborns with Ua cord pH ≤ 7.00 and Ua cord 7.00 ≤ pH ≤ 7.15, pH euc-n Racinet-54 appears better to identify those with HIE/death, especially when the target is sensitivity > 80%. Prospective studies will confirm if pH euc-n Racinet-54 is a better alternative to Ua cord pH and BD to evaluate newborn acid-base physiology.

Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives.

The peroxisome biogenesis disorders (PBD) are a heterogeneous group of autosomal recessive disorders in which peroxisome assembly is impaired, leading to multiple peroxisome enzyme deficiencies, complex developmental sequelae and progressive disabilities. Mammalian peroxisome assembly involves the protein products of 16 PEX genes; defects in 14 of these have been shown to cause PBD. Three broad phenotypic groups are described on a spectrum of severity: Zellweger syndrome is the most severe, neonatal adrenoleukodystrophy is intermediate and infantile Refsum disease is less severe. Another group is Rhizomelic chondrodysplasia punctata spectrum. Recently, atypical phenotypes have been described, indicating that the full spectrum of these disorders remains to be identified. For most patients, there is a correlation between clinical severity and effect of the mutation on PEX protein function. Diagnosis relies on biochemical measurements of peroxisome functions and PEX gene sequencing. There are no targeted therapies, although management protocols have been suggested and research endeavors continue. In this review we will discuss peroxisome biology and PBD, and research contributions to pathophysiology and treatment.