IntroductionCongenital hyperinsulinism (HI) is a rare disorder characterized by severe, recurrent hypoglycemia. Subtotal pancreatectomy remains a treatment option for diffuse HI, but post-surgery quality of life is largely undescribed.MethodsThis mixed-methods study utilized quantitative data from the HI Global Registry, including individuals with diffuse HI and ≥75% pancreatectomy (n = 34). Of these, 13 (38%) completed qualitative interviews to capture the patient and caregiver perspectives. This is the first study to investigate long-term clinical and lived impacts of pancreatectomy for diffuse HI as reported by affected families.ResultsMost participants underwent subtotal pancreatectomy before two months of age (24, 71%). Only three (9%) had normal glucose status at discharge. At follow-up by median (range) age 9 (1.5-32) years, diabetes was reported in 15 (44%), pancreatic insufficiency in 14 (41%), and 24% reported ongoing medication use for hypoglycemia. Continuous glucose monitoring data demonstrated suboptimal time in range, regardless of diabetes status. Interviews revealed variability in surgical decision-making based on preoperative medical management, genetics, and imaging of the pancreas. Hospitalization and post-discharge periods were described as stressful and challenging to mental health for caregivers. At follow-up, children reported less perceived burden than caregivers. Of the six parents interviewed whose children have transitioned to diabetes, four stated that diabetes was easier to manage than HI, although hypoglycemia could still be frequent.DiscussionSubtotal pancreatectomy for diffuse HI may be necessary when medical therapy is not sufficient to prevent severe hypoglycemia. However, surgery was not curative and was associated with life-long consequences and management.

BACKGROUND:A substantial proportion of individuals with a well-defined monogenic disorder remain without a genetic diagnosis. Low-level mosaic pathogenic variants are recognised as an underappreciated cause of monogenic disease but are technically challenging to detect, particularly in organ-specific conditions when affected tissue is inaccessible. METHODS:We systematically investigated low-level mosaic variants in individuals with congenital hyperinsulinism (CHI: n = 1252) or neonatal diabetes (NDM: n = 312), two opposing pancreatic disorders of insulin secretion. We screened for established pathogenic variants with variant allele fraction (VAF) < 8% in dominant CHI (ABCC8, GCK, GLUD1, HK1) or dominant NDM (ABCC8, KCNJ11, INS) genes in targeted next-generation sequencing (tNGS) data using Mutect2. FINDINGS:This called 40 variants across the four genes in 39 individuals with CHI. No candidate variants were found in the NDM cohort. Orthogonal validation of 35 variants using TaqMan-based droplet digital PCR (ddPCR) confirmed 26/35 variants. The median VAF for confirmed variants was 3.6% (1.0-7.8%), while false positives (9/35) predominantly had a VAF <1% with some overlap in VAF with true positives. INTERPRETATION:This study shows that disease-causing low-level mosaic variants in dominant CHI genes can be detected in blood using tNGS but require orthogonal validation. These results provide a framework to improve diagnostic yield in organ-specific conditions where mosaic variants may represent an important missed cause of disease. FUNDING:This work was supported by a research grant from the University of Pennsylvania Orphan Disease Center in partnership with the Team CHIbra and Congenital Hyperinsulinism International [MDBR-23-020-CHI] and the Wellcome Trust [223187/Z/21/Z].

IntroductionCongenital hyperinsulinism [CHI] is a rare disorder characterised by hypoglycaemia secondary to excessive insulin secretion from the pancreas. The aim of management of CHI is to prevent severe and persistent hypoglycaemia which can lead to poor neurodevelopmental outcomes. Pancreatic surgery can play a role in the improvement of glycaemic safety in focal and diffuse CHI. Continuous glucose monitoring [CGM] is increasingly used in diabetes management, yet its application in CHI, particularly during perioperative settings, remains underexplored.ObjectiveThis study aimed to evaluate the utility and accuracy of CGM during pancreatic surgery in CHI patients.Research design and methodsA mixed methods observational study was conducted over three years involving 13 patients undergoing either focal lesionectomy or subtotal pancreatectomy. CGM was performed using the Dexcom G6 device, paired with point-of-care capillary blood glucose measurements to assess accuracy. Qualitative feedback from healthcare professionals and quantitative analysis of CGM data were collected.ResultsHyperglycaemia was observed in 8 patients, influenced by surgical stress and dextrose administration. CGM analysis revealed a median perioperative glucose level of 9.2 mmol/L, with a mean absolute relative difference [MARD] of 19.3% compared to capillary samples. The majority of professionals [94%] reported CGM as helpful in the perioperative period, highlighting its role in guiding prompt adjustment of dextrose infusions and reducing blood sampling frequency.ConclusionCGM demonstrates utility in monitoring glycaemic trends and managing hyperglycaemia during pancreatic surgery in CHI patients. The integration into perioperative care may further enhance surgical safety, extending the range of clinical applications of CGM.

Children affected by complex endocrine disorders continue to face substantial and persistent barriers in diagnosis, treatment, and long-term care across Europe and worldwide. Diagnostic uncertainty remains common due to non-standardized criteria, limited validation of biomarkers, and unequal access to advanced testing. Fragmented care pathways and insufficient multidisciplinary coordination further undermine optimal management, particularly during the transition from pediatric to adult services. Pediatric drug development is constrained by small patient populations, ethical and regulatory challenges, and limited commercial incentives, resulting in therapeutic gaps. Families frequently shoulder considerable psychosocial and financial burdens, often without adequate educational, psychological, or social support. Addressing these inequalities requires strategic action to stimulate research innovation, harmonize diagnostic and training standards, improve equitable access to care and medicines, and strengthen patient and family empowerment through collaborative networks and advocacy. This document aimed to highlight these unmet medical needs and outline a path forward. By identifying key barriers and proposing strategic directions, ESPE seeks to foster collaboration among clinicians, researchers, policymakers, patient communities, and pharmaceutical partners. Only through coordinated action can we ensure that every child with an endocrine disorder receives equitable, timely, and high-quality care - regardless of where they live.

Congenital hyperinsulinism (HI) is a rare condition causing excessive insulin secretion, leading to severe hypoglycemia and high risk of neurological damage. Studies of neurodevelopmental outcomes in HI report prevalence ranging from less than one-quarter to about half of all people with HI. These studies largely focus on formal clinical assessments, but the real-world experiences of individuals with HI and their families are rarely published. The aim of this study was to describe the neurodevelopmental outcomes of a heterogenous cohort of individuals with HI directly from the perspective of the person with HI or their family, as shared through the HI Global Registry. 193 participants with HI from 34 countries were included in this analysis. Mean age at follow-up was 12.52 years (SD = 12.60). 66

A thyroid function test (TFT) is a common investigation, often undertaken by general paediatricians and general practitioners. TFT involves the measurement of serum free thyroxine (fT4) and thyroid stimulating hormone (TSH) to guide the diagnosis and management of hypothyroidism and hyperthyroidism, requiring treatment with medications such as levothyroxine (LT4) and carbimazole. Thyroid hormones play a crucial role in early life neurodevelopment; therefore, the correct interpretation of TFT is required to optimise treatment outcomes. TFT needs to be contextualised to influencing factors such as intercurrent illness, diet, presence of obesity, assay interference and non-adherence to treatment.

BACKGROUND:Plasma renin is measured in children with salt-wasting adrenal insufficiency (AI) as part of assessing the adequacy of mineralocorticoid (MC) replacement. It is recommended that plasma renin is used to monitor MC replacement. This can be measured as either plasma renin concentration (PRC) or activity (PRA); it is not known if one method is preferable over the other. METHODS:Samples from 129 patients less than 18-years old requested for PRC were selected randomly. PRC was measured using the IDS-iSYS chemiluminescence immunoassay, PRA was measured by LC-MS/MS. The PRC and PRA values for each sample were reviewed using published reference ranges and categorised as low, normal and high. Samples which showed disagreement between PRC and PRA results based on the reference ranges were divided into groups. Samples collected from patients attending the regional adrenal clinic were clinically reviewed in retrospect, using serum sodium and blood pressure as decision guides, to determine if MC replacement dosing would differ if PRA was used instead of PRC. RESULTS:Ninety-six (74%) of the samples analysed exhibited agreement between their PRC and PRA interpretation. Seventeen of 33 samples which displayed disagreement were collected from adrenal clinic patients. Of these, eight would have a different clinical decision concerning MC replacement based on PRA compared with PRC. In each of these instances, adjustments to MC dose based on PRA was strongly supported by serum sodium levels and blood pressure centiles. In one instance, PRC had been deliberately ignored by clinicians and MC dose had been adjusted according to other conventional parameters such as blood pressure and serum sodium. In this instance, PRA provided reassurance that MC replacement had been correctly assessed by clinicians. CONCLUSIONS:Our investigation found PRA performed superiorly to PRC for assessing MC replacement in paediatric patients, based on supporting biochemical and clinical parameters. Our results indicated that use of PRA may help to standardise practice when assessing MC replacement; this is likely to have patient benefit through improved blood-pressure and electrolyte control.

We recently reported non-coding variants in a cis-regulatory element of the beta-cell disallowed gene hexokinase 1 (HK1) as a novel cause of congenital hyperinsulinism. These variants lead to a loss of repression of HK1 in pancreatic beta-cells, causing insulin secretion during hypoglycaemia. In this study, we aimed to determine the prevalence, genetics, and phenotype of HK1-hyperinsulinism by screening a large international cohort of patients living with the condition. We screened the HK1 cis-regulatory region in 1761 probands with hyperinsulinism of unknown aetiology who had been referred to one of three large European genomics laboratories. We identified a HK1 variant in 89/1761 probands (5%) and 63 family members. Within the Exeter HI cohort, these variants accounted for 2.8% of all positive genetic diagnoses (n = 54/1913) establishing this as an important cause of HI. Individuals with a disease-causing variant were diagnosed with hyperinsulinism between birth and 26 years (median: 7 days) with variable response to treatment; 80% were medically managed and 20% underwent pancreatic surgery due to poor response to medical therapy. Glycaemic outcomes varied from spontaneous remission to hypoglycaemia persisting into adulthood. Eight probands had inherited the variant from a parent not reported to have hyperinsulinism (median current age: 39 years), confirming variable penetrance. Two of the 23 novel HK1 variants allowed us to extend the minimal cis-regulatory region from 42 to 46 bp. Non-coding variants within the HK1 cis-regulatory region cause hyperinsulinism of variable severity ranging from neonatal-onset, treatment-resistant disease to being asymptomatic into adulthood. Discovering variants in 89 families confirms HK1 as a major cause of hyperinsulinism and highlights the important role of the non-coding genome in human monogenic disease.

CONTEXT:Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia in childhood with a considerable risk of lifelong neurological sequelae. Available pharmacological therapies are limited. Dasiglucagon is a glucagon analog for the treatment of hypoglycemia. OBJECTIVE:To assess the efficacy and safety of dasiglucagon in children with CHI up to 1 year of age. METHODS:This study included a randomized, crossover, double-blind, placebo-controlled part 1 and an open-label, single-arm part 2 at 4 centers in Germany, the United Kingdom, and the United States. Participants comprised children with CHI aged 7 days to 12 months who were dependent on IV glucose. In part 1, participants were randomized to dasiglucagon or placebo for 48 hours, then crossed over to the other treatment for 48 hours. In part 2, all participants received dasiglucagon for 21 days. The primary outcome was mean IV glucose infusion rate (GIR) in the last 12 hours of part 1. RESULTS:Between June 19, 2020, and February 9, 2022, 12 eligible participants were randomized to dasiglucagon-placebo (n = 7) or placebo-dasiglucagon (n = 5). The IV GIR was significantly reduced with dasiglucagon compared with placebo (least-squares mean 4.3 mg/kg/min [95% confidence interval [CI], 1.04 to 7.60 mg/kg/min] and 9.5 mg/kg/min [95% CI, 6.24 to 12.81 mg/kg/min], respectively; P = .004). The most frequent adverse events in both treatment groups were gastrointestinal, dermatological, and metabolism and nutritional disorders. CONCLUSION:In infants with CHI, dasiglucagon significantly reduced the amount of IV glucose needed to maintain euglycemia compared with placebo. Dasiglucagon represents a promising treatment for the management of CHI.

IntroductionCongenital hyperinsulinism (HI) is a rare disease that causes severe hypoglycemia. Diazoxide is the first-line treatment; however, many individuals using diazoxide continue to experience hypoglycemia. Diazoxide is associated with side effects that impact life and well-being.MethodsThe study utilized a mixed-methods approach combining structured, survey-based cross-sectional quantitative data from the HI Global Registry (HIGR) (n=165, 89% were caregivers), of whom 75% reported current diazoxide use, with qualitative interviews with caregivers (n=12) and individuals with HI (n=6). This is the first mixed-methods study to focus on the experience of diazoxide treatment as reported by the individual taking the medicine and/or their caregiver.ResultsOf HIGR participants, 93% reported at least one side effect, including hypertrichosis (89%), loss of appetite (40%), facial changes (23%), and swelling (22%) with diazoxide use. In HIGR, 37% of people currently on diazoxide reported experiencing hypoglycemia up to several times per week. Interview participants described how these side effects, the drug’s taste, and feeding difficulties associated with HI and diazoxide adversely impacted daily life.DiscussionDiazoxide is commonly used by families living with HI, but a significant proportion reported hypoglycemia. Individuals who experienced better glycemic control with the drug were less critical of side effects. Combining HIGR data with in-depth interviews facilitated understanding of day-to-day life, which can help implement measures to better support families managing HI. This study prompts the need for improved treatment options and for clinicians to utilize the International HI Care Guideline to optimize diazoxide therapy.

Background:Virtual reality (VR) is increasingly used as a distraction tool for painful procedures in children. Studies have shown variable benefit but have not identified factors to maximize utility. Objective:This study aimed to undertake a feasibility study to investigate factors influencing virtual reality headset (VRH) utility for venipuncture and cannulation. Methods:Children admitted as inpatients were recruited and given a VRH during anticipated venipuncture or cannulation. Feedback from participants, parents, and operators was obtained through questionnaires and the Wong-Baker Faces Scale (WBFS). Results:Thirteen children of a target 32 (41%), aged a median of 7 (range 5-12) years, were recruited to the study; 9 (69%) parents and 7 (54%) participants reported a positive VR experience, found VRH comfortable, and wanted repeat application for future venisection or cannulation. However, patient recruitment was suboptimal at 41% (binomial 95% CI 24%-59%) of the target, as busy operators undertaking venisection or cannulation on eligible patients were unable to spare time for VRH use during the COVID-19 pandemic. The preprocedure time spent with VRH was associated with participants' positive experience of VR distraction (median 15, IQR 2.5-50 vs 180, IQR 120-450) seconds (P=.02). Five (38.4%) participants removed the VRH prior to procedure; these were relatively young compared to those who continued VRH (median 6, IQR 5.00-7.00 vs 10, IQR 6.75-12.00 years), suggesting better acceptance of VR in older children. There was no significant difference in WBFS pain ratings before (median 0, IQR 0-10) or after the procedure (median 0, IQR 0-6), with many children choosing 0 ("no hurt") at initial assessment. By contrast, parent and doctor or phlebotomist responses indicated that VR reduced pain and anxiety (n=9, 69%), in agreement with participant perception (n=7, 54%; Cohen κ=0.68). Conclusions:VR as a distraction tool in children is influenced by age and preprocedure familiarity, suggesting that the optimal use is in older children with greater cognitive and emotional maturity. Multidimensional feedback from participants, parents, and investigators should be obtained to test the true efficacy of VR in future studies.

Congenital hyperinsulinism (CHI) is a rare disorder causing persistent hypoglycaemia in infants due to excessive insulin secretion from pancreatic β-cells. It has genetic causes, primarily mutations in ATP-sensitive potassium channel genes (ABCC8, KCNJ11). CHI manifests in three forms-focal, diffuse, and atypical-distinguished by histology and genetics, influencing treatment strategies. Early diagnosis and tailored management are vital to prevent neurological damage. While transient CHI resolves spontaneously, permanent CHI often requires complex medical and/or surgical intervention. Despite advances, long-term neurodisability remains high, highlighting increased need to improve monitoring as well as better therapies with lesser side effects. Acute treatment aims to rapidly normalize glucose levels and long-term treatments include diazoxide (KATP channel agonist) to suppress insulin secretion, though its effectiveness depends on genetic mutation type. Other therapies include somatostatin analogues. Newer emerging therapies include novel glucagon analogues, monoclonal antibodies targeting insulin receptors, GLP-1 receptor antagonist, and selective somatostatin receptor agonist, currently under clinical trials. Along with medical treatment, children may require additional feeding support with carbohydrate supplementation using glucose polymers and special formulas. Continuous glucose monitoring aids detection but has limitations. Surgery is preferred for focal lesions to potentially cure CHI.