Truncating and zinc-finger variants in GLI2 are associated with hypopituitarism.

Variants in transcription factor GLI2 have been associated with hypopituitarism and structural brain abnormalities, occasionally including holoprosencephaly (HPE). Substantial phenotypic variability and nonpenetrance have been described, posing difficulties in the counseling of affected families. We present three individuals with novel likely pathogenic GLI2 variants, two with truncating and one with a de novo missense variant p.(Ser548Leu), and review the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2. We show that most of the 31 missense variants previously reported as pathogenic are likely benign or, at most, low-risk variants. Four Zn-finger variants: p.(Arg479Gly), p.(Arg516Pro), p.(Gly518Lys), and p.(Tyr575His) were classified as likely pathogenic, and three other variants as possibly pathogenic: p.(Pro253Ser), p.(Ala593Val), and p.(Pro1243Leu). We analyze the phenotypic descriptions of 60 individuals with pathogenic GLI2 variants and evidence a morbidity spectrum that includes hypopituitarism (58%), HPE (6%) or other brain structure abnormalities (15%), orofacial clefting (17%) and dysmorphic facial features (35%). We establish that truncating and Zn-finger variants in GLI2 are associated with a high risk of hypopituitarism, and that a solitary median maxillary central incisor is part of the GLI2-related phenotypic variability. The most prevalent phenotypic feature is post-axial polydactyly (65%) which is also the mildest phenotypic expression of the condition, reported in many parents of individuals with systemic findings. Our approach clarifies clinical risks and the important messages to discuss in counseling for a pathogenic GLI2 variant.

Increased referrals for congenital hyperinsulinism genetic testing in children with trisomy 21 reflects the high burden of non-genetic risk factors in this group.

BACKGROUND: Hyperinsulinism results from inappropriate insulin secretion during hypoglycaemia. Down syndrome is causally linked to a number of endocrine disorders including Type 1 diabetes and neonatal diabetes. We noted a high number of individuals with Down syndrome referred for hyperinsulinism genetic testing, and therefore aimed to investigate whether the prevalence of Down syndrome was increased in our hyperinsulinism cohort compared to the population. METHODS: We identified individuals with Down syndrome referred for hyperinsulinism genetic testing to the Exeter Genomics Laboratory between 2008 and 2020. We sequenced the known hyperinsulinism genes in all individuals and investigated their clinical features. RESULTS: We identified 11 individuals with Down syndrome in a cohort of 2011 patients referred for genetic testing for hyperinsulinism. This represents an increased prevalence compared to the population (2.5/2011 expected vs. 11/2011 observed, p = 6.8 × 10-5 ). A pathogenic ABCC8 mutation was identified in one of the 11 individuals. Of the remaining 10 individuals, five had non-genetic risk factors for hyperinsulinism resulting from the Down syndrome phenotype: intrauterine growth restriction, prematurity, gastric/oesophageal surgery, and asparaginase treatment for leukaemia. For five individuals no risk factors for hypoglycaemia were reported although two of these individuals had transient hyperinsulinism and one was lost to follow-up. CONCLUSIONS: Down syndrome is more common in patients with hyperinsulinism than in the population. This is likely due to an increased burden of non-genetic risk factors resulting from the Down syndrome phenotype. Down syndrome should not preclude genetic testing as coincidental monogenic hyperinsulinism and Down syndrome is possible.

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

A prospective evaluation of high- and low-power holmium laser settings for transurethral lithotripsy in the management of adults with large bladder calculi.

PURPOSE: To prospectively investigate the efficacy and safety of high-power (100 W) vs low-power (20 W) laser settings for transurethral laser lithotripsy in the management large vesical calculi (> 4 cm). METHODS: All patients with vesical calculi > 4 cm in the maximum dimension and scheduled for transurethral holmium laser lithotripsy were invited to participate in the study. Every alternate patient was treated with either the low- or high-power laser settings. We used a continuous irrigation resectoscope with laser bridge or a laser working element (Karl Storz) for laser lithotripsy of bladder stones. We compared the operative time, intra-operative/post-operative complications (up to 1 year), and stone-free rates between the treatment groups using IBM SPSS Statistics 24 software. Comparisons between treatment groups for continuous variables were assessed using the Welch test, while categorical variables were compared with either the Chi-square or Fisher's exact test. A p value < 0.05 was considered statistically significant. RESULTS: Twenty patients with ten in each cohort were recruited. Preoperative data and mean bladder stone size were comparable in both groups. The duration of surgery was significantly reduced from 70.80 ± 25.28 min in low-power cohort to 40.90 ± 15.01 min in the high-power group (p = 0.005). There were no significant intra-operative complications in either group. All patients were stone-free following the procedure. CONCLUSION: High-power laser setting of up to 100 W results in a significant reduction in duration of surgery without any increase in the complication rate for treatment of large bladder stones.

Robotic intracorporeal orthotopic neobladder in the supine Trendelenburg position: a stepwise approach.

Robotic radical cystectomy with urinary diversion has become increasingly utilized for the surgical management of bladder cancer. Orthotopic neobladder reconstruction is still performed worldwide primarily via an extracorporeal approach because of the difficulty associated with robotic intracorporeal reconstruction. The objective of this article is to demonstrate a stepwise approach for robotic intracorporeal neobladder in a standardized manner that adheres to the principles of open surgery.

Clustering of Hypoglycemia Events in Patients With Hyperinsulinism: Extension of the Digital Phenotype Through Retrospective Data Analysis.

BACKGROUND: Hyperinsulinism (HI) due to excess and dysregulated insulin secretion is the most common cause of severe and recurrent hypoglycemia in childhood. High cerebral glucose use in the early hours results in a high risk of hypoglycemia in people with diabetes and carries a significant risk of brain injury. Prevention of hypoglycemia is the cornerstone of the management of HI, but the risk of hypoglycemia at night or the timing of hypoglycemia in children with HI has not been studied; thus, the digital phenotype remains incomplete and management suboptimal. OBJECTIVE: This study aims to quantify the timing of hypoglycemia in patients with HI to describe glycemic variability and to extend the digital phenotype. This will facilitate future work using computational modeling to enable behavior change and reduce exposure of patients with HI to injurious hypoglycemic events. METHODS: Patients underwent continuous glucose monitoring (CGM) with a Dexcom G4 or G6 CGM device as part of their clinical assessment for either HI (N=23) or idiopathic ketotic hypoglycemia (IKH; N=24). The CGM data were analyzed for temporal trends. Hypoglycemia was defined as glucose levels <3.5 mmol/L. RESULTS: A total of 449 hypoglycemic events totaling 15,610 minutes were captured over 237 days from 47 patients (29 males; mean age 70 months, SD 53). The mean length of hypoglycemic events was 35 minutes. There was a clear tendency for hypoglycemia in the early hours (3-7 AM), particularly for patients with HI older than 10 months who experienced hypoglycemia 7.6% (1480/19,370 minutes) of time in this period compared with 2.6% (2405/92,840 minutes) of time outside this period (P<.001). This tendency was less pronounced in patients with HI who were younger than 10 months, patients with a negative genetic test result, and patients with IKH. Despite real-time CGM, there were 42 hypoglycemic events from 13 separate patients with HI lasting >30 minutes. CONCLUSIONS: This is the first study to have taken the first step in extending the digital phenotype of HI by describing the glycemic trends and identifying the timing of hypoglycemia measured by CGM. We have identified the early hours as a time of high hypoglycemia risk for patients with HI and demonstrated that simple provision of CGM data to patients is not sufficient to eliminate hypoglycemia. Future work in HI should concentrate on the early hours as a period of high risk for hypoglycemia and must target personalized hypoglycemia predictions. Focus must move to the human-computer interaction as an aspect of the digital phenotype that is susceptible to change rather than simple mathematical modeling to produce small improvements in hypoglycemia prediction accuracy.

An eHealth Framework for Managing Pediatric Growth Disorders and Growth Hormone Therapy.

BACKGROUND: The use of technology to support health and health care has grown rapidly in the last decade across all ages and medical specialties. Newly developed eHealth tools are being implemented in long-term management of growth failure in children, a low prevalence pediatric endocrine disorder. OBJECTIVE: Our objective was to create a framework that can guide future implementation and research on the use of eHealth tools to support patients with growth disorders who require growth hormone therapy. METHODS: A total of 12 pediatric endocrinologists with experience in eHealth, from a wide geographical distribution, participated in a series of online discussions. We summarized the discussions of 3 workshops, conducted during 2020, on the use of eHealth in the management of growth disorders, which were structured to provide insights on existing challenges, opportunities, and solutions for the implementation of eHealth tools across the patient journey, from referral to the end of pediatric therapy. RESULTS: A total of 815 responses were collected from 2 questionnaire-based activities covering referral and diagnosis of growth disorders, and subsequent growth hormone therapy stages of the patient pathway, relating to physicians, nurses, and patients, parents, or caregivers. We mapped the feedback from those discussions into a framework that we developed as a guide to integration of eHealth tools across the patient journey. Responses focused on improved clinical management, such as growth monitoring and automation of referral for early detection of growth disorders, which could trigger rapid evaluation and diagnosis. Patient support included the use of eHealth for enhanced patient and caregiver communication, better access to educational opportunities, and enhanced medical and psychological support during growth hormone therapy management. Given the potential availability of patient data from connected devices, artificial intelligence can be used to predict adherence and personalize patient support. Providing evidence to demonstrate the value and utility of eHealth tools will ensure that these tools are widely accepted, trusted, and used in clinical practice, but implementation issues (eg, adaptation to specific clinical settings) must be addressed. CONCLUSIONS: The use of eHealth in growth hormone therapy has major potential to improve the management of growth disorders along the patient journey. Combining objective clinical information and patient adherence data is vital in supporting decision-making and the development of new eHealth tools. Involvement of clinicians and patients in the process of integrating such technologies into clinical practice is essential for implementation and developing evidence that eHealth tools can provide value across the patient pathway.

Complexities in the medical management of hypoglycaemia due to congenital hyperinsulinism.

Congenital Hyperinsulinism (CHI) is a rare disease of hypoglycaemia but is the most common form of recurrent and severe hypoglycaemia causing brain injury and neurodisability in children. The management of CHI is complex due to the limited choice of medications, all with a limited therapeutic window, often lacking efficacy and associated with serious side effects. The therapeutic strategy in CHI is to recognize and treat hypoglycaemia promptly, thereby optimizing long-term neurological outcomes; this should be achieved through individualized treatment plans that deliver glycaemic stability while minimizing side effects. Further, such a strategy should consider the likelihood of reduction in disease severity over time, with dose adjustments and medication withdrawal as indicated to optimize both safety and tolerability. The option for pancreatic surgery should also be considered in specific circumstances as appropriate for the patient's best long-term interests.

Continuous glucose monitoring for hypoglycaemia in children: Perspectives in 2020.

Hypoglycaemia in children is a major risk factor for adverse neurodevelopment with rates as high as 50% in hyperinsulinaemic hypoglycaemia (HH). A key part of management relies upon timely identification and treatment of hypoglycaemia. The current standard of care for glucose monitoring is by infrequent fingerprick plasma glucose testing but this carries a high risk of missed hypoglycaemia identification. High-frequency Continuous Glucose Monitoring (CGM) offers an attractive alternative for glucose trend monitoring and glycaemic phenotyping but its utility remains largely unestablished in disorders of hypoglycaemia. Attempts to determine accuracy through correlation with plasma glucose measurements using conventional methods such as Mean Absolute Relative Difference (MARD) overestimate accuracy at hypoglycaemia. The inaccuracy of CGM in true hypoglycaemia is amplified by calibration algorithms that prioritize hyperglycaemia over hypoglycaemia with minimal objective evidence of efficacy in HH. Conversely, alternative algorithm design has significant potential for predicting hypoglycaemia to prevent neuroglycopaenia and consequent brain dysfunction in childhood disorders. Delays in the detection of hypoglycaemia, alarm fatigue, device calibration and current high cost are all barriers to the wider adoption of CGM in disorders of hypoglycaemia. However, machine learning, artificial intelligence and other computer-generated algorithms now offer significant potential for further improvement in CGM device technology and widespread application in childhood hypoglycaemia.

Diazoxide-induced pulmonary hypertension in hyperinsulinaemic hypoglycaemia: Recommendations from a multicentre study in the United Kingdom.

OBJECTIVE: Diazoxide is first-line treatment for hyperinsulinaemic hypoglycaemia (HH) but diazoxide-induced pulmonary hypertension (PH) can occur. We aim to characterize the incidence and risk factors of diazoxide-induced PH in a large HH cohort to provide recommendations for anticipating and preventing PH in diazoxide-treated patients with HH. DESIGN AND PATIENTS: Retrospective cohort study involving four UK regional HH centres; review of case notes of HH patients on diazoxide. MEASUREMENTS: The diagnosis of PH was based on clinical and echocardiography evidence. Patient and treatment-related risk factors were analysed for association. RESULTS: Thirteen (6 men) of 177 HH diazoxide-treated patients developed PH, an incidence of 7%. In the PH group, HH was diagnosed at median (range) of 9 (1,180) days, with diazoxide commenced 4 (0,76) days from diagnosis and reaching a maximum dose of 7 (2.5,20) mg/kg/d. The majority (8 of 13 patients) developed PH within 2 weeks of diazoxide. Complete diazoxide withdrawal, but not dose reduction, led to PH resolution at 41 (3,959) days. In three patients, PH continued beyond 12 months. Risk factors for the development of PH included the presence of congenital heart disease (CHD) (P = .008), and total fluid volume exceeding 130 mL/kg/d in the immediate 24 hours preceding diazoxide (P = .019). CONCLUSION: Pulmonary hypertension can occur in 7% of diazoxide-treated HH patients. Risk factors include the presence of congenital heart disease and fluid overload. Recommendations include echocardiography and fluid restriction to 130 mL/kg/d prior to diazoxide treatment and immediate discontinuation of diazoxide if PH develops.

Focal Congenital Hyperinsulinism as a Cause for Sudden Infant Death.

Congenital hyperinsulinism (CHI) is the commonest cause of persistent and severe hypoglycemia in infancy due to unregulated insulin secretion from pancreatic ß-cells. Prompt early diagnosis is important, as insulin reduces glucose supply to the brain, resulting in significant brain injury and risk of death. Histologically, CHI has focal and diffuse forms; in focal CHI, an inappropriate level of insulin is secreted from localized ß-cell hyperplasia. We report a 4-month-old male infant, who presented with sudden illness and collapse without a recognized cause and died. Postmortem examination revealed pancreatic histopathology compatible with focal CHI. Immunofluoresence staining showed limited expression of p57kip2 ß-cells reinforcing the diagnosis. Mutation testing for genes associated with CHI from DNA from the focal lesion was negative. This case highlights the recognition of focal CHI as a possible cause for sudden infant death. In children dying suddenly and unexpectedly, postmortem pancreatic sections should be carefully examined for focal CHI.

Next-generation sequencing reveals deep intronic cryptic ABCC8 and HADH splicing founder mutations causing hyperinsulinism by pseudoexon activation.

Next-generation sequencing (NGS) enables analysis of the human genome on a scale previously unachievable by Sanger sequencing. Exome sequencing of the coding regions and conserved splice sites has been very successful in the identification of disease-causing mutations, and targeting of these regions has extended clinical diagnostic testing from analysis of fewer than ten genes per phenotype to more than 100. Noncoding mutations have been less extensively studied despite evidence from mRNA analysis for the existence of deep intronic mutations in >20 genes. We investigated individuals with hyperinsulinaemic hypoglycaemia and biochemical or genetic evidence to suggest noncoding mutations by using NGS to analyze the entire genomic regions of ABCC8 (117 kb) and HADH (94 kb) from overlapping ~10 kb PCR amplicons. Two deep intronic mutations, c.1333-1013A>G in ABCC8 and c.636+471G>T HADH, were identified. Both are predicted to create a cryptic splice donor site and an out-of-frame pseudoexon. Sequence analysis of mRNA from affected individuals' fibroblasts or lymphoblastoid cells confirmed mutant transcripts with pseudoexon inclusion and premature termination codons. Testing of additional individuals showed that these are founder mutations in the Irish and Turkish populations, accounting for 14% of focal hyperinsulinism cases and 32% of subjects with HADH mutations in our cohort. The identification of deep intronic mutations has previously focused on the detection of aberrant mRNA transcripts in a subset of disorders for which RNA is readily obtained from the target tissue or ectopically expressed at sufficient levels. Our approach of using NGS to analyze the entire genomic DNA sequence is applicable to any disease.

Role of oral pentosan polysulphate in the reduction of local side effects of BCG therapy in patients with non-muscle-invasive bladder cancer: a pilot study.

OBJECTIVE: To assess the role of oral pentosan polysulphate (PPS) in the reduction of bacille Calmette-Guérin (BCG)-related local side effects in patients with high grade Ta/T1 non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A total of 32 symptomatic patients receiving BCG instillation were randomized into three groups: group A received placebo (vitamin B complex tablet) thrice daily; group B received PPS 100 mg thrice daily; and group C received PPS 100 mg once daily and placebo (vitamin B complex tablet) twice daily for 6 weeks. A visual analogue scale (VAS) score for bladder pain, Overactive Bladder-Validated 8 Question Screener (OAB-V8) scores and dysuria were evaluated in the three groups before and during each weekly visit for BCG instillation. RESULTS: The mean ± sd post-treatment VAS scores were significantly lower in groups B (4.4 ± 1.2) and C (5.8 ± 0.8) than in group A (8 ± 0.4). In addition, the post-treatment VAS score was significantly lower in group B than in group C (P<0.01). The mean post-treatment OAB-V8 score was significantly lower only in group B (decreased from 15.5 to 9.7). Dysuria decreased in groups B and C but persisted in group A. CONCLUSION: The present study shows that oral PPS (100 mg) thrice daily is effective in relieving BCG-related local side effects.

Increased plasma incretin concentrations identifies a subset of patients with persistent congenital hyperinsulinism without KATP channel gene defects.

Congenital hyperinsulinism causes profound hypoglycemia, which may persist or resolve spontaneously. Among 13 children with congenital hyperinsulinism, elevated incretin hormone concentrations were detected in 2 with atypical, persistent disease. We suggest that incretin biomarkers may identify these patients, and that elevated hormone levels may contribute to their pathophysiology.

Medicated Foley Catheters Do Not Prevent Catheter-Associated Urinary Tract Infection: A Systematic Review of Randomized Controlled Trials.

Infections of the urinary tract are among some of the most common infections treated in clinical practice. Numerous risk factors play an intrinsic role in the development of such infections, namely: age, sexual intercourse, prolonged use of feminine hygiene products, instrumentation, pregnancy, sexually transmitted infections, obstructive uropathy such as prostatic enlargement or urethral strictures, compromised immunity, and constipation. A major cause of urinary tract infections (UTIs) in hospitalized patients is catheter-associated urinary tract infections (CAUTIs). This systematic review aims to identify the causative agents and risk factors and to determine whether nitrofurazone, silver alloy, or zinc oxide-impregnated or coated/medicated Foley catheters, or non-medicated (standard) Foley catheters, can reduce the incidence of CAUTIs. A systematic review was conducted on the following databases: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Trip medical database, and Google Scholar. A combination of keywords and Boolean operators was used ((((urinary tract infections) OR (urinary catheterization)) OR (prevention AND control)) ) AND (catheter-associated infections) for data extraction. All the randomized controlled clinical trials (RCTs) completed and available between January 1, 2005, and June 30, 2024, which focused on the prevention of CAUTIs, were screened thoroughly and were included in this systematic review. The Cochrane risk-of-bias tool for randomized trials (RoB 2) tool was used for risk of bias assessment. The Robvis visualization tool (McGuinness, LA, Higgins, JPT. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res Syn Meth. 2020; 1-7) was used for development of traffic light plots and weighted bar plots for risk of bias. The literature search conducted produced 41,909 articles. Among these 19,076 were noted as duplicates and were excluded in the initial analysis; 22,833 manuscripts were thus screened after deduplication. Abstracts, case studies, reports, editorials, viewpoints, cross-sectional studies, cohort studies, case-control studies, case series, and letters to the editor/correspondence manuscripts (n = 22,745) were additionally excluded. A total of 88 full-text articles were assessed for eligibility. An in-depth evaluation and analysis further excluded 82 articles from the analysis quality assessment based on inclusion and exclusion criteria. Six RCTs were finally assessed regarding the prevention of CAUTIs and were ultimately included in the systematic review. The primary causative agents involved in the CAUTIs were found to be mainly Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Enterococcus faecalis. The risk factors noted for the development of these CAUTIs ranged from urethral trauma, overdistention of the bladder, prolonged catheterization, to improper handling of the urine bag. No significant advantage was noted between the use of medicated and non-medicated standard Foley catheters. The aseptic technique and indications followed for the catheterization play a vital role in the prevention of CAUTIs, and more cognizance thereof will aid in the reduction of the development of CAUTIs.

Congenital Hyperinsulinism - Notes for the General Pediatrician.

Congenital hyperinsulinism (CHI) is a rare condition but is a common cause of severe and persistent hypoglycemia in early life. Prompt recognition of CHI is critical to prevent the impact of neuroglycopenia and consequent lifelong neurodisability. It is important to be alert to the possibility of CHI in newborn babies with recurrent hypoglycemia associated with high glucose requirements. Pediatricians are advised to mitigate the risk of hypoglycemia by early treatment with high concentration dextrose and intravenous glucagon infusions. Specific medical therapies with diazoxide and/or somatostatin receptor analogues may be commenced after the finding of detectable insulin at hypoglycemia, a biochemical characteristic of CHI. Early exploration of genetic etiology is recommended, chiefly in the search for a focal form, amenable to limited pancreatic surgery. Genetic ascertainment is also useful to understand the basis of disease, variable responses to medical therapies and escalation of conservative treatment to subtotal pancreatectomy. CHI is a heterogeneous disorder with varying natural history. Many newborns and infants with CHI have severe and complex illness features; their long-term care is best achieved through review at specialist centers.

Brain magnetic resonance imaging review suggests unrecognised hypoglycaemia in childhood.

Introduction: Neonatal and early-life hypoglycaemia, is a frequent finding but is often non-specific and asymptomatic, making detection and diagnosis challenging. Hypoglycaemia-induced cerebral injury can be identified by magnetic resonance imaging (MRI) changes in cerebral white matter, occipital lobes, and posterior parietotemporal regions. It is unknown if children may have hypoglycaemic brain injury secondary to unrecognised hypoglycaemia in early life. We have examined retrospective radiological findings of likely brain injury by neuroimaging to investigate the existence of previous missed hypoglycaemic events. Methods: Retrospective MRI data in children in a single tertiary centre, over a ten-year period was reviewed to identify potential cases of unrecognised early-life hypoglycaemia. A detailed search from an electronic radiology repository involved the term "hypoglycaemia'' from text-based reports. The initial report was used for those who required serial scanning. Images specific to relevant reports were further reviewed by a designated paediatric neuroradiologist to confirm likely hypoglycaemia induced brain injury. Medical records of those children were subsequently reviewed to assess if the hypoglycaemia had been diagnosed prior to imaging. Results: A total of 107 MR imaging reports were identified for review, and 52 (48.5%) showed typical features strongly suggestive of hypoglycaemic brain injury. Medical note review confirmed no documented clinical information of hypoglycaemia prior to imaging in 22 (42%) patients, raising the likelihood of missed hypoglycaemic events resulting in brain injury. Conclusions: We have identified the existence of unrecognised childhood hypoglycaemia through neuroimaging review. This study highlights the need for heightened awareness of early life hypoglycaemia to prevent adverse neurological outcomes later in childhood.

Dasiglucagon for the Treatment of Congenital Hyperinsulinism: A Randomized Phase 3 Trial in Infants and Children.

CONTEXT: Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion causing hypoglycemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI. OBJECTIVE: To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycemia as add-on to standard of care (SoC). METHODS: In this open-label trial, patients were randomized 1:1 to SoC or SoC + dasiglucagon (10-70 µg/h) for 4 weeks. In the following 4 weeks, all patients received dasiglucagon + SoC. Hypoglycemia was assessed by self-monitored plasma glucose (SMPG) and blinded continuous glucose monitoring (CGM). Primary endpoint was average number of SMPG-detected hypoglycemia episodes/week (SMPG <3.9 mmol/L) during Weeks 2 to 4. RESULTS: Thirty-two patients (0.6-10.9 years) were randomly assigned to dasiglucagon + SoC (n = 16) or SoC (n = 16). The rate of SMPG-detected hypoglycemia decreased from baseline in both groups, but with no statistically significant difference during Weeks 2 to 4 (event rate ratio: 0.85 [0.54; 1.36], P = .5028). However, dasiglucagon administration resulted in a 43% reduction in CGM-detected hypoglycemia (<3.9 mmol/L) vs SoC alone during Weeks 2 to 4 (post hoc analysis; event rate ratio: 0.57 [0.39; 0.83], P = .0029). Dasiglucagon enabled reductions (of 37% to 61%) in all other measures of hypoglycemia assessed by CGM vs SoC alone including extent and percent time in hypoglycemia (post hoc analyses). Dasiglucagon appeared safe and well tolerated. Skin and gastrointestinal events were more frequent with dasiglucagon + SoC than SoC only. CONCLUSION: Clinically meaningful reductions in all CGM-recorded measures of hypoglycemia support using dasiglucagon as a potential treatment for CHI.

First Accuracy and User-Experience Evaluation of New Continuous Glucose Monitoring System for Hypoglycemia Due to Hyperinsulinism.

INTRODUCTION: Patients with congenital hyperinsulinism (HI) require constant glucose monitoring to detect and treat recurrent and severe hypoglycemia. Historically, this has been achieved with intermittent self-monitoring blood glucose (SMBG), but patients are increasingly using continuous glucose monitoring (CGM). Given the rapidity of CGM device development, and increasing calls for CGM use from HI families, it is vital that new devices are evaluated early. METHODS: We provided two months of supplies for the new Dexcom G7 CGM device to 10 patients with HI who had recently finished using the Dexcom G6. Self-monitoring blood glucose was performed concurrently with paired readings providing accuracy calculations. Patients and families completed questionnaires about device use at the end of the two-month study period. RESULTS: Compared to the G6, the G7 showed a significant reduction in mean absolute relative difference (25%-18%, P < .001) and in the over-read error (Bland Altman +1.96 SD; 3.54 mmol/L to 2.95 mmol/L). This resulted in an improvement in hypoglycemia detection from 42% to 62% (P < .001). Families reported an overall preference for the G7 but highlighted concerns about high sensor failure rates. DISCUSSION: The reduction in mean absolute relative difference and over-read error and the improvement in hypoglycemia detection implies that the G7 is a safer and more useful device in the management of hypoglycemia for patients with HI. Accuracy, while improved from previous devices, remains suboptimal with 40% of hypoglycemia episodes not detected.

Recognition of Hyperinsulinaemic Hypoglycaemia in Infants with Congenital Central Hypoventilation Syndrome.

INTRODUCTION: Congenital central hypoventilation syndrome [CCHS] is a rare autosomal dominant condition due to mutations in the transcription factor PHOX2B. It is characterized by alveolar hypoventilation with symptoms of autonomic nervous system dysfunction. Hyperinsulinaemic hypoglycaemia [HH] due to glucose dysregulation caused by anomalous insulin secretion has been reported as a feature of CCHS. However, HH and glycaemic outcomes in the context of CCHS have not been characterised in longitudinal follow-up. We describe the variable phenotype of glucose dysregulation and glycaemic outcomes in children with CCHS. Case presenatation: : We report 6 children with PHOX2B mutation-positive CCHS diagnosed with HH in a national cohort from two UK Congenital Hyperinsulinism specialist centres. We describe the initial presentation, the challenges in management and glycaemic outcomes in longitudinal follow-up. All patients were term infants diagnosed with CCHS in the neonatal period, due to PHOX2B mutations and required long-term ventilation by tracheostomy. HH was diagnosed at a median age 222 days [range 36-594] with post-prandial hypoglycaemia [4/6 patients] or fasting hypoglycaemia [2/6 patients]. Two patients were treated with diazoxide monotherapy; one with diazoxide and overnight continuous gastrostomy feeds; one with acarbose and two with dietary manifestations and use of continuous glucose monitoring sensor [CGMS]. Three patients who presented earlier in the observation period demonstrated a reduction in the severity of HH over time, leading to hypoglycaemia resolution at a median age of 4.8 years [range 4.45-5.5 years]. CONCLUSION: Patients with CCHS, due to PHOX2B mutations, may experience both fasting and postprandial hypoglycemia, necessitating treatment for HH. Clinicians should screen children with CCHS for hypoglycemia symptoms to quickly identify those affected by HH, initiate prompt treatment, and prevent potential brain injury from severe hypoglycemia. The severity of hypoglycemia due to HH tends to decrease over time, with glycemic resolution potentially being achieved over several years.