Changes in branched-chain amino acids in an infant with maple syrup urine disease during perioperative pediatric liver transplant: A case report.

An 11-month-old female infant diagnosed with classic subtype IB maple syrup urine disease underwent living donor liver transplantation. Blood samples for plasma amino acid analysis were collected during the three phases of the operation. Despite the perioperative prophylactic administration of 12.5% hypertonic dextrose solution with insulin and a 20% intralipid emulsion, the blood levels of the branched-chain amino acids increased dramatically during surgery, consistent with an acute intraoperative metabolic decompensation. However, these blood levels normalized soon after liver transplantation with an excellent outcome. We suggest that the occurrence of an intraoperative metabolic crisis during liver transplantation is not necessarily a sign of graft failure.

Genetic, metabolic and clinical delineation of an MRPS23-associated mitochondrial disorder.

MRPS23 is a nuclear gene encoding a mitochondrial ribosomal protein. A patient with a mitochondrial disorder was found to carry a variant in MRPS23. More cases are necessary to establish MRPS23 as a mitochondrial disease gene. Of 5134 exomes performed in our center, we identified five independent patients who had similar clinical manifestations and were homozygous for the same germline variant c.119C>T; p.P40L in MRPS23. Detailed clinical findings, mitochondrial enzyme activity assays from cultured skin fibroblasts, PCR-Sanger-sequencing, and variant age estimation were performed. Their available family members were also studied. Eight members homozygous for the MRPS23 p.P40L were identified. All were from Hmong hilltribe. Seven presented with alteration of consciousness and recurrent vomiting, while the eighth who was a younger brother of a proband was found pre-symptomatically. Patients showed delayed growth and development, hearing impairment, hypoglycemia, lactic acidosis, and liver dysfunction. In vitro assays of cultured fibroblasts showed combined respiratory chain complex deficiency with low activities of complexes I and IV. PCR-Sanger-sequencing confirmed the variant, which was estimated to have occurred 1550 years ago. These results establish the MRPS23-associated mitochondrial disorder inherited in an autosomal recessive pattern and provide insight into its clinical and metabolic features.

Can knowledgeable experts assess costs and outcomes as if they were ignorant? An experiment within precision medicine evaluation.

OBJECTIVES: The purpose of this study is to evaluate the validity of the standard approach in expert judgment for evaluating precision medicines, in which experts are required to estimate outcomes as if they did not have access to diagnostic information, whereas in fact, they do. METHODS: Fourteen clinicians participated in an expert judgment task to estimate the cost and medical outcomes of the use of exome sequencing in pediatric patients with intractable epilepsy in Thailand. Experts were randomly assigned to either an "unblind" or "blind" group; the former was provided with the exome sequencing results for each patient case prior to the judgment task, whereas the latter was not provided with the exome sequencing results. Both groups were asked to estimate the outcomes for the counterfactual scenario, in which patients had not been tested by exome sequencing. RESULTS: Our study did not show significant results, possibly due to the small sample size of both participants and case studies. CONCLUSIONS: A comparison of the unblind and blind approach did not show conclusive evidence that there is a difference in outcomes. However, until further evidence suggests otherwise, we recommend the blind approach as preferable when using expert judgment to evaluate precision medicines because this approach is more representative of the counterfactual scenario than the unblind approach.

AI-based diagnosis in mandibulofacial dysostosis with microcephaly using external ear shapes.

Introduction: Mandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia, microcephaly, and ear abnormalities. Here, we aimed at describing the external ear phenotype of MFDM patients, and train an Artificial Intelligence (AI)-based model to differentiate MFDM ears from non-syndromic control ears (binary classification), and from ears of the main differential diagnoses of this condition (multi-class classification): Treacher Collins (TC), Nager (NAFD) and CHARGE syndromes. Methods: The training set contained 1,592 ear photographs, corresponding to 550 patients. We extracted 48 patients completely independent of the training set, with only one photograph per ear per patient. After a CNN-(Convolutional Neural Network) based ear detection, the images were automatically landmarked. Generalized Procrustes Analysis was then performed, along with a dimension reduction using PCA (Principal Component Analysis). The principal components were used as inputs in an eXtreme Gradient Boosting (XGBoost) model, optimized using a 5-fold cross-validation. Finally, the model was tested on an independent validation set. Results: We trained the model on 1,592 ear photographs, corresponding to 1,296 control ears, 105 MFDM, 33 NAFD, 70 TC and 88 CHARGE syndrome ears. The model detected MFDM with an accuracy of 0.969 [0.838-0.999] (p < 0.001) and an AUC (Area Under the Curve) of 0.975 within controls (binary classification). Balanced accuracies were 0.811 [0.648-0.920] (p = 0.002) in a first multiclass design (MFDM vs. controls and differential diagnoses) and 0.813 [0.544-0.960] (p = 0.003) in a second multiclass design (MFDM vs. differential diagnoses). Conclusion: This is the first AI-based syndrome detection model in dysmorphology based on the external ear, opening promising clinical applications both for local care and referral, and for expert centers.

Case report: Severe nonketotic hyperglycinemia in a neonate without apparent seizures but concomitant cleft palate and cerebral sinovenous thrombosis.

Nonketotic hyperglycinemia (NKH) is in most cases a fatal inborn error of metabolism which usually presents during the neonatal period as encephalopathy and refractory seizures. The reported congenital anomalies associated with NKH included corpus callosal agenesis, club foot, cleft palate, and congenital heart disease. Here, we report a newborn who presented with encephalopathy without overt seizures, cerebral venous sinus thrombosis, and cleft palate. Electroencephalography showed a burst suppression pattern, which suggests the etiology could be due to a metabolic or genetic disorder. The amino acid analysis of plasma and cerebrospinal fluid showed elevated glycine. Whole exome sequencing identified a heterozygous c.492C > G; p.Tyr164Ter variant in exon 4 of the GLDC gene inherited from the patient's father. Further long-read whole genome sequencing revealed an exon 1-2 deletion in the GLDC gene inherited from the patient's mother. Additional analyses revealed no pathogenic variants of the cleft palate-related genes. The cleft palate may be an associated congenital anomaly in NKH. Regarding cerebral venous sinus thrombosis, we found a heterozygous variant (p.Arg189Trp) of the PROC gene, which is a common cause of thrombophilia among Thai newborns. A neonate with NKH could present with severe encephalopathy without seizures. A close follow up for clinical changes and further next generation sequencing are crucial for definite diagnosis in neonates with encephalopathy of unclear cause.

Using an experiment among clinical experts to determine the cost and clinical impact of rapid whole exome sequencing in acute pediatric settings.

Objective: Evaluate the cost and clinical impacts of rapid whole-exome sequencing (rWES) for managing pediatric patients with unknown etiologies of critical illnesses through an expert elicitation experiment. Method: Physicians in the intervention group (n = 10) could order rWES to complete three real-world case studies, while physicians in the control group (n = 8) could not. Costs and health outcomes between and within groups were compared. Results: The cost incurred in the intervention group was consistently higher than the control by 60,000-70,000 THB. Fewer other investigation costs were incurred when rWES could provide a diagnosis. Less cost was incurred when an rWES that could lead to a change in management was ordered earlier. Diagnostic accuracy and the quality of non-pharmaceutical interventions were superior when rWES was available. Conclusion: In acute pediatric settings, rWES offered clinical benefits at the average cost of 60,000-70,000 THB. Whether this test is cost-effective warrants further investigations. Several challenges, including cost and ethical concerns for assessing high-cost technology for rare diseases in resource-limited settings, were potentially overcome by our study design using expert elicitation methods.

Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants.

Mutations in KCNQ2 encoding for voltage-gated K channel subunits underlying the neuronal M-current have been associated with infantile-onset epileptic disorders. The clinical spectrum ranges from self-limited neonatal seizures to epileptic encephalopathy and delayed development. Mutations in KCNQ2 could be either gain- or loss-of-function which require different therapeutic approaches. To better understand genotype-phenotype correlation, more reports of patients and their mutations with elucidated molecular mechanism are needed. We studied 104 patients with infantile-onset pharmacoresistant epilepsy who underwent exome or genome sequencing. Nine patients with neonatal-onset seizures from unrelated families were found to harbor pathogenic or likely pathogenic variants in the KCNQ2 gene. The p.(N258K) was recently reported, and p. (G279D) has never been previously reported. Functional effect of p.(N258K) and p.(G279D) has never been previously studied. The cellular localization study demonstrated that the surface membrane expression of Kv7.2 carrying either variant was decreased. Whole-cell patch-clamp analyses revealed that both variants significantly impaired Kv7.2 M-current amplitude and density, conductance depolarizing shift in voltage dependence of activation, membrane resistance, and membrane time constant (Tau), indicating a loss-of-function in both the homotetrameric and heterotetrameric with Kv7.3 channels. In addition, both variants exerted dominant-negative effects in heterotetrameric with Kv7.3 channels. This study expands the mutational spectrum of KCNQ2- related epilepsy and their functional consequences provide insights into their pathomechanism.

Exome sequencing as first-tier genetic testing in infantile-onset pharmacoresistant epilepsy: diagnostic yield and treatment impact.

Pharmacoresistant epilepsy presenting during infancy poses both diagnostic and therapeutic challenges. We aim to identify diagnostic yield and treatment implications of exome sequencing (ES) as first-tier genetic testing for infantile-onset pharmacoresistant epilepsy. From June 2016 to December 2020, we enrolled patients with infantile-onset (age ≤ 12 months) pharmacoresistant epilepsy. 103 unrelated patients underwent ES. Clinical characteristics and changes in management due to the molecular diagnosis were studied. 42% (43/103) had epilepsy onset within the first month of life. After ES as first-tier genetic testing, 62% (64/103) of the cases were solved. Two partially solved cases (2%; 2/103) with heterozygous variants identified in ALDH7A1 known to cause autosomal recessive pyridoxine dependent epilepsy underwent genome sequencing (GS). Two novel large deletions in ALDH7A1 were detected in both cases. ES identified 66 pathogenic and likely pathogenic single nucleotide variants (SNVs) in 27 genes. 19 variants have not been previously reported. GS identified two additional copy number variations (CNVs). The most common disease-causing genes are SCN1A (13%; 13/103) and KCNQ2 (8%; 8/103). Eight percent (8/103) of the patients had treatable disorders and specific treatments were provided resulting in seizure freedom. Pyridoxine dependent epilepsy was the most common treatable epilepsy (6%; 6/103). Furthermore, 35% (36/103) had genetic defects which guided gene-specific treatments. Altogether, the diagnostic yield is 64%. Molecular diagnoses change management in 43% of the cases. This study substantiates the use of next generation sequencing (NGS) as the first-tier genetic investigation in infantile-onset pharmacoresistant epilepsy.

Novel Variants and Phenotypes in NEUROG3-Associated Syndrome.

CONTEXT: Biallelic pathogenic variants in the NEUROG3 gene cause malabsorptive diarrhea, insulin-dependent diabetes mellitus (IDDM), and rarely hypogonadotropic hypogonadism. With only 17 reported cases, the clinical and mutational spectra of this disease are far from complete. OBJECTIVE: To identify the underlying genetic etiology in 3 unrelated Thai patients who presented with early-onset malabsorptive diarrhea, endocrine abnormalities, and renal defects and to determine the pathogenicity of the newly identified pathogenic variants using luciferase reporter assays and western blot. METHODS: Three unrelated patients with congenital diarrhea were recruited. Detailed clinical and endocrinological features were obtained. Exome sequencing was performed to identify mutations and in vitro functional experiments including luciferase reporter assay were studied to validate their pathogenicity. RESULTS: In addition to malabsorptive diarrhea due to enteric anendocrinosis, IDDM, short stature, and delayed puberty, our patients also exhibited pituitary gland hypoplasia with multiple pituitary hormone deficiencies (Patient 1, 2, 3) and proximal renal tubulopathy (Patient 2, 3) that have not previously reported. Exome sequencing revealed that Patient 1 was homozygous for c.371C > G (p.Thr124Arg) while the other 2 patients were homozygous for c.284G > C (p.Arg95Pro) in NEUROG3. Both variants have never been previously reported. Luciferase reporter assay demonstrated that these 2 variants impaired transcriptional activity of NEUROG3. CONCLUSIONS: This study reported pituitary gland hypoplasia with multiple pituitary hormone deficiencies and proximal renal tubulopathy and 2 newly identified NEUROG3 loss-of-function variants in the patients with NEUROG3-associated syndrome.

A LILRB1 variant with a decreased ability to phosphorylate SHP-1 leads to autoimmune diseases.

Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a receptor on leukocytes playing a role in regulating immune responses. No phenotypes have been reported to be caused by germline mutations in LILRB1. We aimed to identify the causative variant in a three-generation family with nine members suffering from one of the three autoimmune diseases-Graves' disease, Hashimoto's thyroiditis, or systemic lupus erythematosus. Whole-genome linkage study revealed a locus on chromosome 19q13.4 with the maximum LOD score of 2.71. Whole-exome sequencing identified a heterozygous missense variant, c.479G > A (p. G160E) in LILRB1, located within the chromosomal-linked region, in all nine affected members. The variant has never been previously reported. Jurkat cells transfected with the mutant LILRB1, compared with those with the wild-type LILRB1, showed decreased phosphorylation of both LILRB1 and its downstream protein, SHP-1. Flow cytometry was used to study immunophenotype and revealed that LILRB1 was significantly lower on the surface of activated regulatory T lymphocytes (Treg) cells of patients. Single-cell RNA sequencing showed substantially increased M1-like monocytes in peripheral blood mononuclear cells of affected individuals. This study, for the first time, implicates LILRB1 as a new disease gene for autoimmunity.

Cleidocranial dysplasia and novel RUNX2 variants: dental, craniofacial, and osseous manifestations.

OBJECTIVES: Cleidocranial dysplasia (CCD) is a skeletal disorder affecting cranial sutures, teeth, and clavicles, and is associated with the RUNX2 mutations. Although numerous patients have been described, a direct genotype-phenotype correlation for RUNX2 has been difficult to establish. Further cases must be studied to understand the clinical and genetic spectra of CCD. To characterize detailed phenotypes and identify variants causing CCD in five unrelated patients and their family members. METHODOLOGY: Clinical and radiographic examinations were performed. Genetic variants were identified by exome and Sanger sequencing, data were analyzed by bioinformatics tools. RESULTS: Three cases were sporadic and two were familial. Exome sequencing successfully detected the heterozygous pathogenic RUNX2 variants in all affected individuals. Three were novel, comprising a frameshift c.739delA (p.(Ser247Valfs*)) in exon 6 (Patient-1), a nonsense c.901C>T (p.(Gln301*)) in exon 7 (Patient-2 and affected mother), and a nonsense c.1081C>T (p.(Gln361*)) in exon 8 (Patient-3). Two previously reported variants were missense: the c.673C>T (p.(Arg225Trp)) (Patient-4) and c.674G>A (p.(Arg225Gln)) (Patient-5) in exon 5 within the Runt homology domain. Patient-1, Patient-2, and Patient-4 with permanent dentition had thirty, nineteen, and twenty unerupted teeth, respectively; whereas Patient-3 and Patient-5, with deciduous dentition, had normally developed teeth. All patients exhibited typical CCD features, but the following uncommon/unreported phenotypes were observed: left fourth ray brachymetatarsia (Patient-1), normal clavicles (Patient-2 and affected mother), phalangeal malformations (Patient-3), and normal primary dentition (Patient-3, Patient-5). CONCLUSIONS: The study shows that exome sequencing is effective to detect mutation across ethnics. The two p.Arg225 variants confirm that the Runt homology domain is vital for RUNX2 function. Here, we report a new CCD feature, unilateral brachymetatarsia, and three novel truncating variants, expanding the phenotypic and genotypic spectra of RUNX2 , as well as show that the CCD patients can have normal deciduous teeth, but must be monitored for permanent teeth anomalies.

Cleidocranial dysplasia and novel RUNX2 variants: dental, craniofacial, and osseous manifestations

Abstract Cleidocranial dysplasia (CCD) is a skeletal disorder affecting cranial sutures, teeth, and clavicles, and is associated with the RUNX2 mutations. Although numerous patients have been described, a direct genotype-phenotype correlation for RUNX2 has been difficult to establish. Further cases must be studied to understand the clinical and genetic spectra of CCD. Objectives To characterize detailed phenotypes and identify variants causing CCD in five unrelated patients and their family members. Methodology Clinical and radiographic examinations were performed. Genetic variants were identified by exome and Sanger sequencing, data were analyzed by bioinformatics tools. Results Three cases were sporadic and two were familial. Exome sequencing successfully detected the heterozygous pathogenic RUNX2 variants in all affected individuals. Three were novel, comprising a frameshift c.739delA (p.(Ser247Valfs*)) in exon 6 (Patient-1), a nonsense c.901C>T (p.(Gln301*)) in exon 7 (Patient-2 and affected mother), and a nonsense c.1081C>T (p.(Gln361*)) in exon 8 (Patient-3). Two previously reported variants were missense: the c.673C>T (p.(Arg225Trp)) (Patient-4) and c.674G>A (p.(Arg225Gln)) (Patient-5) in exon 5 within the Runt homology domain. Patient-1, Patient-2, and Patient-4 with permanent dentition had thirty, nineteen, and twenty unerupted teeth, respectively; whereas Patient-3 and Patient-5, with deciduous dentition, had normally developed teeth. All patients exhibited typical CCD features, but the following uncommon/unreported phenotypes were observed: left fourth ray brachymetatarsia (Patient-1), normal clavicles (Patient-2 and affected mother), phalangeal malformations (Patient-3), and normal primary dentition (Patient-3, Patient-5). Conclusions The study shows that exome sequencing is effective to detect mutation across ethnics. The two p.Arg225 variants confirm that the Runt homology domain is vital for RUNX2 function. Here, we report a new CCD feature, unilateral brachymetatarsia, and three novel truncating variants, expanding the phenotypic and genotypic spectra of RUNX2 , as well as show that the CCD patients can have normal deciduous teeth, but must be monitored for permanent teeth anomalies.

Rapid exome sequencing as the first-tier investigation for diagnosis of acutely and severely ill children and adults in Thailand.

The use of rapid DNA sequencing technology in severely ill children in developed countries can accurately identify diagnoses and positively impact patient outcomes. This study sought to evaluate the outcome of Thai children and adults with unknown etiologies of critical illnesses with the deployment of rapid whole exome sequencing (rWES) in Thailand. We recruited 54 unrelated patients from 11 hospitals throughout Thailand. The median age was 3 months (range, 2 days-55 years) including 47 children and 7 adults with 52% males. The median time from obtaining blood samples to issuing the rWES report was 12 days (range, 5-27 days). A molecular diagnosis was established in 25 patients (46%), resulting in a change in clinical management for 24 patients (44%) resulting in improved clinical outcomes in 16 patients (30%). Four out of seven adult patients (57%) received the molecular diagnosis which led to a change in management. The 25 diagnoses comprised 23 different diseases. Of the 34 identified variants, 15 had never been previously reported. This study suggests that use of rWES as a first-tier investigation tool can provide tremendous benefits in critically ill patients with unknown etiology across age groups in Thailand.

Expanding phenotypic and mutational spectra of mitochondrial HMG-CoA synthase deficiency.

Mitochondrial 3-hydroxy-3 methylglutaryl-CoA synthase-2 deficiency (HMGCS2D) is a rare autosomal recessive inborn error of hepatic ketogenesis, caused by mutations in HMGCS2. As its clinical and laboratory manifestations resemble many other metabolic disorders, HMGCS2D definite diagnosis presents a challenge, frequently requiring molecular tests. Only 26 patients with HMGCS2 mutations have been previously described, and this study reports the first two unrelated Thai patients, a 9-month-old male and an 8-month-old female, with HMGCS2D. During acute episodes, steatorrhea and dyslipidemia occurred, both previously unreported. Increased serum levels of triglycerides, very low density lipoproteins (VLDL), and low density lipoproteins (LDL), along with a decreased serum level of HDL were found. Both patients had hypophosphatemic encephalopathy, and the female had metabolic acidosis without hypoglycemia. Trio whole-exome sequencing (WES) revealed that the male harbored two HMGCS2 mutations, a novel c.1480C>T (p.Arg494*) and a previously reported c.1502G>C (p.Arg501Pro), while the female was compound heterozygous for the c.1502G>C (p.Arg501Pro) and a previously reported mutation, c.520T>C (p.Phe174Leu). Interestingly, c.1502G>C (p.Arg501Pro) was not only found in both of our patients but also detected heterozygously in 9 out of 1081 unrelated individuals (allele frequency of 9/2162; 0.42%) in our in-house Thai exome database. Discovery of this common mutation suggests there could be about 14 babies with HMGCS2D within 800,000 newborns in Thailand annually. Therefore, awareness of HMGCS2D among medical personnel in Thailand should be raised.

Severe craniofrontonasal syndrome in a male patient mosaic for a novel nonsense mutation in EFNB1.

Craniofrontonasal syndrome (CFNS) is an X-linked disorder caused by mutations in EFNB1. Uncommonly and paradoxically, female patients with CFNS exhibit significantly more severe symptoms than male patients. This is explained by "cellular interference". Nevertheless, there have been a few reports of male patients severely affected with CFNS due to postzygotic mosaicism. Here, we demonstrated a male patient with severe CFNS. Whole exome sequencing showed that he harbored both wild type and nonsense mutation, c.253C > T (p.Gln85Ter), in the EFNB1 gene. Sanger sequencing of his leukocytes, buccal swab, and hair root revealed a variable level of mosaicism. This nonsense mutation is absent in his parents and has never been previously reported. Our findings expand the mutational spectrum of EFNB1 and substantiates that males with severely affected CFNS are mosaic.

Risk factor analysis of pneumothorax associated with persistent pulmonary hypertension of the newborn in Thai neonates.

Objective: To determine the risk factors and outcomes of persistent pulmonary hypertension of the newborn (PPHN)-associated pneumothorax (PTX).Study design: The medical records of infants diagnosed with PPHN with or without PTX from January 2012 to July 2017 were retrospectively reviewed.Results: Of the 102 included PPHN infants, PTX was found in 32 (31.4%) infants with 43.8% (14/32) mortality. PTX was significantly associated with increased mortality with an odds ratio (OR) of 5.27 (95% confidence interval [CI] 1.96-14.17). Unilateral PTX was more common than bilateral PTX (53.1 versus 46.9%, respectively). Multivariate logistic regression analysis indicated that a 1-minute Apgar score of ≤7 was associated with an increased risk for PTX (adjusted OR = 2.67 [95% CI 1.14-6.25]). In subgroup analysis, each increase of maximum peak inspiratory pressure (PIP) of 1 cmH2O significantly increased the odds of PTX by 1.46 (95% CI 1.02-2.07), while each 1 mmHg increase in arterial partial pressure of oxygen (PaO2) decreased the odds of PTX (adjusted OR = by 0.98 [95% CI 0.97-0.99]).Conclusions: PTX was significantly associated with higher mortality in PPHN infants. Lower Apgar score and increasing PIP in conventional mechanical ventilation were risk factors for PTX. Higher PaO2 was associated with a decreased rate of PTX.

Widespread and debilitating hemangiomas in a patient with enchondromatosis and D-2-hydroxyglutaric aciduria.

Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) (OMIM 614875) is a severe chondrodysplasia combined with a urinary excretion of D-2-hydroxyglutaric acid. Here, we reported the tenth case of this disease. A 15-year-old boy had symmetric radiolulencies in the metaphyses of the long bones suggesting enchondromatosis and platyspondyly. Remarkably, he manifested widespread cavernous hemangiomas including scalp, lips, tongue, larynx, and prepuce, with the onset of 3 years of age. Hemangiomas at the larynx had caused dyspnea and those in the oral cavity led to recurrent bleeding, requiring several surgical removals. These multiple and debilitating hemangiomas have never been previously reported in patients with MC-HGA. Mutation analyses including Sanger sequencing of genes involving in enchondromatosis and the metabolic pathway of D-2-hydroxyglutarate including PTHR1, D2HGDH, HOT, and IDH1, as well as whole-exome sequencing for proband-parent trio analysis and paired blood versus hemangioma studies showed no pathogenic variants. In summary, we reported the tenth patient with MC-HGA who manifested widespread and debilitating hemangiomas in several organs, expanding the clinical spectrum of MC-HGA.

Factors and Outcomes of Persistent Pulmonary Hypertension of the Newborn Associated with Acute Kidney Injury in Thai Neonates.

OBJECTIVE: This study aims to determine the risk factors and outcome of persistent pulmonary hypertension of the newborn (PPHN)-associated acute kidney injury (AKI). STUDY DESIGN: Infants diagnosed with PPHN at Hat Yai Hospital from January 2012 to December 2016 were retrospectively reviewed. RESULTS: Of the 109 included PPHN infants, 28.4% (31/109) died, and AKI was found in 28.4% following neonatal KDIGO classification. Of the 31, 19 who died (61.3%) reached stage 1, 3 (9.7%) reached stage 2, and 9 (29.0%) reached stage 3. AKI (all stages combined) was significantly associated with increased mortality with an odds ratio (OR) of 8.71 (95% confidence interval [CI], 3.37-22.49). Multivariate logistic regression analysis indicated that male gender (adjusted OR = 8.56; 95% CI = 0.84-85.09) and urine output of < 1 mL/kg/h in 12 hours of admission (adjusted OR = 15.57; 95% CI = 2.58-93.98) were the main factors associated with an increased risk for AKI, while birth by cesarean delivery was associated with reduced risk of AKI (adjusted OR = 0.10; 95% CI = 0.16-0.68). CONCLUSION: The incidence of AKI in PPHN was high in this study, and this complication was also significantly associated with higher mortality. In PPHN neonates, AKI should be especially closely monitored in males and infants who have a urine output of < 1 mL/kg/h in the first 12 hours of admission.

Fatal Vernix Caseosa Aspiration Associated With Persistent Pulmonary Hypertension of the Newborn.

Vernix caseosa aspiration is an extremely rare condition resulting in high mortality if complicated by persistent hypertension of the newborn (PPHN). Herein we offer the first case report of PPHN due to massive vernix caseosa aspiration documented by histopathological examination. This case report is presented to provide a synopsis of the pathoetiology of PPHN related to vernix caseosa aspiration syndrome as likely to be encountered by neonatologists and general pediatricians involved with neonatal care.