Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome.

Context: Kabuki syndrome (KS) is associated with congenital hyperinsulinism (HI). Objective: To characterize the clinical and molecular features of HI in children with KS. Design: Retrospective cohort study of children with KS and HI evaluated between 1998 and 2023. Setting: The Congenital Hyperinsulinism Center of the Children's Hospital of Philadelphia. Patients: Thirty-three children with KS and HI. Main Outcome Measures: HI presentation, treatment, course, and genotype. Results: Hypoglycemia was recognized on the first day of life in 25 children (76%). Median age at HI diagnosis was 1.8 months (interquartile range [IQR], 0.6-6.1 months). Median age at KS diagnosis was 5 months (IQR, 2-14 months). Diagnosis of HI preceded KS diagnosis in 20 children (61%). Twenty-four children (73%) had a pathogenic variant in KMT2D, 5 children (15%) had a pathogenic variant in KDM6A, and 4 children (12%) had a clinical diagnosis of KS. Diazoxide trial was conducted in 25 children, 92% of whom were responsive. HI treatment was discontinued in 46% of the cohort at median age 2.8 years (IQR, 1.3-5.7 years). Conclusion: Hypoglycemia was recognized at birth in most children with KS and HI, but HI diagnosis was often delayed. HI was effectively managed with diazoxide in most children. In contrast to prior reports, the frequency of variants in KMT2D and KDM6A were similar to their overall prevalence in individuals with KS. Children diagnosed with KS should undergo evaluation for HI, and, because KS features may not be recognized in infancy, KMT2D and KDM6A should be included in the genetic evaluation of HI.

Novel Use of Dasiglucagon, a Soluble Glucagon Analog, for the Treatment of Hyperinsulinemic Hypoglycemia Secondary to Suspected Insulinoma: A Case Report.

INTRODUCTION: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. In adolescents and adults, hyperinsulinemic hypoglycemia is most frequently caused by an insulin-producing tumor. CASE PRESENTATION: A 17-year-old, previously healthy male presented with recurrent and severe episodes of hypoglycemia. Diagnostic evaluation was consistent with hyperinsulinemic hypoglycemia, and an insulinoma was suspected. Multiple imaging studies and surgical exploration failed to identify a lesion. Over the course of months, the patient was found to be refractory to conventional medical interventions. CONCLUSION: Upon approval from the US Food and Drug Administration and the Institutional Review Board, the patient was treated with dasiglucagon, a novel soluble glucagon analog, under a single-patient Investigational New Drug. The patient has tolerated the medication and has been able to achieve appropriate glycemic control.

Case report: Two unexpected cases of DGUOK-related mitochondrial DNA depletion syndrome presenting with hyperinsulinemic hypoglycemia.

Timely diagnosis of persistent neonatal hypoglycemia is critical to prevent neurological sequelae, but diagnosis is complicated by the heterogenicity of the causes. We discuss two cases at separate institutions in which clinical management was fundamentally altered by the results of molecular genetic testing. In both patients, critical samples demonstrated hypoketotic hypoglycemia and a partial glycemic response to glucagon stimulation, thereby suggesting hyperinsulinism (HI). However, due to rapid genetic testing, both patients were found to have deoxyguanosine kinase (DGUOK)-related mitochondrial DNA depletion syndrome, an unexpected diagnosis. Patients with this disease typically present with either hepatocerebral disease in the neonatal period or isolated hepatic failure in infancy. The characteristic features involved in the hepatocerebral form of the disease include lactic acidosis, hypoglycemia, cholestasis, progressive liver failure, and increasing neurologic dysfunction. Those with isolated liver involvement experience hepatomegaly, cholestasis, and liver failure. Although liver transplantation is considered, research has demonstrated that for patients with DGUOK-related mitochondrial DNA depletion syndrome and neurologic symptoms, early demise occurs. Our report advocates for the prompt initiation of genetic testing in patients presenting with persistent neonatal hypoglycemia and for the incorporation of mitochondrial DNA depletion syndromes in the differential diagnosis of HI.

Protocol-Driven Initiation and Weaning of High-Flow Nasal Cannula for Patients With Bronchiolitis: A Quality Improvement Initiative.

OBJECTIVES: Bronchiolitis is the most common cause for nonelective infant hospitalization in the United States with increasing utilization of high-flow nasal cannula (HFNC). We standardized initiation and weaning of HFNC for bronchiolitis and quantified the impact on outcomes. Our specific aim was to reduce hospital and ICU length of stay (LOS) by 10% between two bronchiolitis seasons after implementation. DESIGN: A quality improvement (QI) project using statistical process control methodology. SETTING: Tertiary-care children's hospital with 24 PICU and 48 acute care pediatric beds. PATIENTS: Children less than 24 months old with bronchiolitis without other respiratory diagnoses or underlying cardiac, respiratory, or neuromuscular disorders between December 2017 and November 2018 (baseline), and December 2018 and February 2020 (postintervention). INTERVENTIONS: Interventions included development of an HFNC protocol with initiation and weaning guidelines, modification of protocol and respiratory assessment classification, education, and QI rounds with a focus on efficient HFNC weaning, transfer, and/or discharge. MEASUREMENTS AND MAIN RESULTS: A total of 223 children were included (96 baseline and 127 postintervention). The primary outcome metric, average LOS per patient, decreased from 4.0 to 2.8 days, and the average ICU LOS per patient decreased from 2.8 to 1.9 days. The secondary outcome metric, average HFNC treatment hours per patient, decreased from 44.0 to 36.3 hours. The primary and secondary outcomes met criteria for special cause variation. Balancing measures included ICU readmission rates, 30-day readmission rates, and adverse events, which were not different between the two periods. CONCLUSIONS: A standardized protocol for HFNC management for patients with bronchiolitis was associated with decreased hospital and ICU LOS, less time on HFNC, and no difference in readmissions or adverse events.

Baccalaureate Nursing Program Admission Requirements and Predictors of Success.

ABSTRACT: This study aimed to determine if correlations existed between overall science prerequisite grade point average (GPA) and successful completion of pathophysiology and overall science GPA and the Test of Essential Academic Skills Version V (TEAS V) science subscore. The quantitative study design was used with 73 students who were conditionally admitted to the baccalaureate nursing program. No statistically significant correlation was found between overall science GPA and successful completion of pathophysiology; a weak low correlation was found between overall science GPA and TEAS V science subscore. These findings suggest that TEAS V science subscores used as a standalone assessment do not predict success in pathophysiology.

Case Report: Two Distinct Focal Congenital Hyperinsulinism Lesions Resulting From Separate Genetic Events.

Focal hyperinsulinism (HI) comprises nearly 50% of all surgically treated HI cases and is cured if the focal lesion can be completely resected. Pre-operative localization of the lesion is thus critical. Few cases of hyperinsulinism with multiple focal lesions have been reported, and assessment of the molecular mechanisms driving this rare occurrence has been limited. We present two cases of multifocal HI, each resulting from two independent, pancreatic focal lesions. 18Fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography detected both lesions preoperatively in one patient, whereas identification of the second lesion was an incidental finding during surgical exploration in the other. Complete resection of the focal lesions resulted in cure of the HI in both cases. In each patient, genetic testing of the individual focal lesions revealed different regions of loss of heterozygosity for the maternal 11p15 allele, confirming that each lesion arose from independent somatic events in the setting of a paternally inherited germline ABCC8 mutation. These cases highlight the importance of a multidisciplinary and personalized approach to the management of infants with HI.

Heterozygous recurrent HNF4A variant p.Arg85Trp causes Fanconi renotubular syndrome 4 with maturity onset diabetes of the young, an autosomal dominant phenocopy of Fanconi Bickel syndrome with colobomas.

Heterozygous pathogenic variants in HNF4A cause hyperinsulinism, maturity onset diabetes of the young type 1, and more rarely Fanconi renotubular syndrome. Specifically, the recurrent missense pathogenic variant c.253C>T (p.Arg85Trp) has been associated with a syndromic form of hyperinsulinism with additional features of macrosomia, renal tubular nephropathy, hypophosphatemic rickets, and liver involvement. We present an affected mother, who had been previously diagnosed clinically with the autosomal recessive Fanconi Bickel Syndrome, and her affected son. The son's presentation expands the clinical phenotype to include multiple congenital anomalies, including penile chordee with hypospadias and coloboma. This specific pathogenic variant should be considered in the differential diagnosis of Fanconi Bickel Syndrome when genetics are negative or the family history is suggestive of autosomal dominant inheritance. The inclusion of hyperinsulinism and maturity onset of the diabetes of the young changes the management of this syndrome and the recurrence risk is distinct. Additionally, this family also emphasizes the importance of genetic confirmation of clinical diagnoses, especially in adults who grew up in the premolecular era that are now coming to childbearing age. Finally, the expansion of the phenotype to include multiple congenital anomalies suggests that the full spectrum of HNF4A is likely unknown.

Interprofessional/interdisciplinary teamwork during the early COVID-19 pandemic: experience from a children's hospital within an academic health center.

The COVID-19 pandemic has created multiple, complex and intense demands on hospitals, including the need for surge planning in the many locations outside epicenters such as northern Italy or New York City. We here describe such surge planning in an Academic Health Center that encompasses a children's hospital. Interprofessional teams from every aspect of inpatient care and hospital operations worked to prepare for a COVID-19 surge. In so doing, they successfully innovated ways to integrate pediatric and adult care and maximize bed capacity. The success of this intense collaborative effort offers an opportunity for ongoing teamwork to enhance efficient, effective, and high-quality patient care.

Developing and Validating a Pediatric Potentially Avoidable Transfer Quality Metric.

This study aimed to evaluate a quality metric that identifies pediatric potentially avoidable transfers from diagnosis and procedure codes. Using physician medical record review as the gold standard, the following steps were used: (1) develop the initial metric definition, (2) estimate initial metric definition operating characteristics, (3) refine this definition to optimize the c-statistic, and (4) validate this optimized metric definition using a separate sample. The initial metric using Sample A patient transfers had a c-statistic of 0.63 (95% confidence interval = 0.53-0.73). Following 22 revisions, the optimized metric definition was a transfer discharged within 24 hours that did not receive any of a select list of 60 268 specialized diagnoses or procedures. The optimized metric on Sample B demonstrated a sensitivity of 80.6%, specificity of 85.7%, and c-statistic of 0.83 (95% confidence interval = 0.75-0.91). The quality metric developed and validated in this study demonstrated satisfactory operating characteristics, providing a feasible means to measure this important outcome.

You Don't Know What You Don't Know: Using Nominal Group Technique to Identify and Prioritize Education Topics for Regional Hospitals.

BACKGROUND: Our 121-bed children's hospital is a quaternary care referral center for a 33-county region. Referring hospitals asked for Pediatric Acute Care Education Sessions (PACES). To determine which topics to prioritize for these sessions, nominal group technique (NGT) methods were used to obtain stakeholder-prioritized consensus on education topics. METHODS: Five NGT sessions were conducted over 6 weeks at referring hospitals throughout central and northern California. Each session lasted ∼90 minutes and engaged a diverse multidisciplinary group of stakeholders. At these sessions, stakeholders answered the question "What are your top 5 clinical topics that should be prioritized by PACES?" NGT numeric ranking methods were used to determine prioritized topics. A thematic analysis was performed on the session transcripts. RESULTS: The 5 sessions had 43 total participants, including nurses, respiratory therapists, physicians, and administrators. The top 4 prioritized topics were sepsis, diabetic ketoacidosis, respiratory failure or support, and bronchiolitis and/or respiratory syncytial virus. Unique education needs for each hospital were also uncovered in the NGT discussion. Three qualitative themes emerged from the discussion: diverse educational needs, the need for guidelines on telemedicine and transfer, and relationship building. CONCLUSIONS: The use of NGT to engage multisite, multidisciplinary stakeholders helped to inform an education program. The use of NGT methods provided rich information that would not have been obtained through surveys alone and helped facilitate relationship building. The PACES group was able to identify and prioritize education topics of interest to referring community hospitals.

Aligning Career with Faith: Reflective Practice for Christian Nurse Educators.

Christian nurses are challenged by the process of incorporating faith and Christianity into their career. Nurse educators are particularly challenged to embed Christian principles into the tenure and promotion journey. Developing a God-inspired plan takes time and patience. Prayer, reflective practice, evaluation, decisions, and follow-through are areas that can be incorporated to infuse faith throughout the tenure and promotion process.

Glycemic control in youth with type 2 diabetes declines as early as two years after diagnosis.

OBJECTIVES: To determine the course of glycemic decline in a pediatric cohort with type 2 diabetes mellitus (T2DM) by defining longitudinal changes in hemoglobin A1c (HbA1c) and insulin requirement. We also followed markers of insulin reserve (fasting C-peptide and IGFBP-1) over time. STUDY DESIGN: Participants included two groups: (1) T2DM Nonacidotic (NA) (n = 46); and (2) T2DM diabetic ketoacidosis (n = 13). HbA1c, insulin dose, and fasting C-peptide and IGFBP-1 were obtained at baseline and every 6 months for 4 years. RESULTS: At baseline, Mann Whitney tests demonstrated that the diabetic ketoacidosis group had higher HbA1c (P = .002), required more insulin (P = .036), and had lower C-peptide (P = .003) than the NA group. Baseline insulin dose (Spearman r = -0.424, P = .009) and baseline IGFBP-1 (Spearman r = -0.349, P = .046) correlated negatively with C-peptide. Over time, HbA1c, insulin dose, and C-peptide changed significantly in a complex manner, with group differences. HbA1c reached a nadir at 6 to 12 months and began to rise after 1.5 years. Insulin requirements reached a nadir at 1 year and began to rise after 2 years. CONCLUSIONS: Unlike adults, children with T2DM require increasing insulin doses over a 4-year period, and diabetic ketoacidosis at diagnosis predicts greater ß-cell decline over time.

A mutation in the TMD0-L0 region of sulfonylurea receptor-1 (L225P) causes permanent neonatal diabetes mellitus (PNDM).

OBJECTIVE: We sought to examine the molecular mechanisms underlying permanenent neonatal diabetes mellitus (PNDM) in a patient with a heterozygous de novo L225P mutation in the L0 region of the sulfonylurea receptor (SUR)1, the regulatory subunit of the pancreatic ATP-sensitive K(+) channel (K(ATP) channel). RESEARCH DESIGN AND METHODS: The effects of L225P on the properties of recombinant K(ATP) channels in transfected COS cells were assessed by patch-clamp experiments on excised membrane patches and by macroscopic Rb-flux experiments in intact cells. RESULTS: L225P-containing K(ATP) channels were significantly more active in the intact cell than in wild-type channels. In excised membrane patches, L225P increased channel sensitivity to stimulatory Mg nucleotides without altering intrinsic gating or channel inhibition by ATP in the absence of Mg(2+). The effects of L225P were abolished by SUR1 mutations that prevent nucleotide hydrolysis at the nucleotide binding folds. L225P did not alter channel inhibition by sulfonylurea drugs, and, consistent with this, the patient responded to treatment with oral sulfonylureas. CONCLUSIONS: L225P underlies K(ATP) channel overactivity and PNDM by specifically increasing Mg-nucleotide stimulation of the channel, consistent with recent reports of mechanistically similar PNDM-causing mutations in SUR1. The mutation does not affect sulfonylurea sensitivity, and the patient is successfully treated with sulfonylureas.