These authors contributed equally to this work. AUTHOR CONTRIBUTIONS The project was conceived and the experiments were planned by E.K. and B.W. We would like to note that Y.A. and K.E.B. had a comparable contribution to this study. The review of phenotypes and the sample collection were performed by B

The autosomal-recessive form of popliteal pterygium syndrome, also known as Bartsocas-Papas syndrome, is a rare, but frequently lethal disorder characterized by marked popliteal pterygium associated with multiple congenital malformations. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this malformation syndrome to chromosomal region 21q22.3. Direct sequencing of RIPK4 (receptor-interacting serine/threonine kinase protein 4) showed a homozygous transversion (c.362T>A) that causes substitution of a conserved isoleucine with asparagine at amino acid position 121 (p.Ile121Asn) in the serine/threonine kinase domain of the protein. Additional pathogenic mutations-a homozygous transition (c.551C>T) that leads to a missense substitution (p.Thr184Ile) at a conserved position and a homozygous one base-pair insertion mutation (c.777_778insA) predicted to lead to a premature stop codon (p.Arg260ThrfsX14) within the kinase domain-were observed in two families. Molecular modeling of the kinase domain showed that both the Ile121 and Thr184 positions are critical for the protein's stability and kinase activity. Luciferase reporter assays also demonstrated that these mutations are critical for the catalytic activity of RIPK4. RIPK4 mediates activation of the nuclear factor-κB (NF-κB) signaling pathway and is required for keratinocyte differentiation and craniofacial and limb development. The phenotype of Ripk4(-/-) mice is consistent with the human phenotype presented herein. Additionally, the spectrum of malformations observed in the presented families is similar, but less severe than the conserved helix-loop-helix ubiquitous kinase (CHUK)-deficient human fetus phenotype; known as Cocoon syndrome; this similarity indicates that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth.

Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. MethodsWe did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. FindingsWe included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58•0%) were male. Median gestational age at birth was 38 weeks (IQR 36-39) and median bodyweight at presentation was 2•8 kg (2•3-3•3). Mortality among all patients was 37 (39•8%) of 93 in low-income countries, 583 (20•4%) of 2860 in middle-income countries, and 50 (5•6%) of 896 in high-income countries (p<0•0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90•0%] of ten in lowincome countries, 97 [31•9%] of 304 in middle-income countries, and two [1•4%] of 139 in high-income countries; p≤0•0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2•78 [95% CI 1•88-4•11], p<0•0001; middle-income vs high-income countries, 2•11 [1•59-2•79], p<0•0001), sepsis at presentation (1•20 [1•04-1•40], p=0•016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4-5 vs ASA 1-2, 1•82 [1•40-2•35], p<0•0001; ASA 3 vs ASA 1-2, 1•58, [1•30-1•92], p<0•0001]), surgical safety checklist not used (1•39 [1•02-1•90], p=0•035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1•96, [1•4...

AH occurs in the newborns with unexplained jaundice. Adrenal insufficiency is more frequent in preterm than in mature infants. Abdominal USG is required to determine AH in a newborn with swelling and bluish discoloration of the scrotum. Serial USG is the best modality for monitoring AH to prevent unnecessary surgery.

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Although UVC is a common and easy vascular access, this process is not without complications. UVC may be inappropriate position because the catheter is inserted by the pediatrician without imaging guidance and may occasionally be associated with complications. Inappropriate positioning of the catheter may observe during the follow-up and maintained care. Therefore, newborns particularly in premature and very low birth-weight newborn should be followed in terms of catheter complications during insertion, following and just after removing of the catheter.

We conclude that our results are important for CH screening regarding time-dependent changes of TSH and thyroid hormones besides diagnosis of thyroid hypoplasia or hyperplasia.

UTI should be investigated in neonates with hyperbilirubinemia of unknown etiology in the first two weeks of life.