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.

The Bihormonal Bionic Pancreas Improves Glycemic Control in Individuals With Hyperinsulinism and Postpancreatectomy Diabetes: A Pilot Study.

OBJECTIVE: To determine whether the bihormonal bionic pancreas (BHBP) improves glycemic control and reduces hypoglycemia in individuals with congenital hyperinsulinism (HI) and postpancreatectomy diabetes (PPD) compared with usual care (UC). RESEARCH DESIGN AND METHODS: Ten subjects with HI and PPD completed this open-label, crossover pilot study. Coprimary outcomes were mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration <3.3 mmol/L. RESULTS: Mean (SD) CGM glucose concentration was 8.3 (0.7) mmol/L in the BHBP period versus 9 (1.8) mmol/L in the UC period (P = 0.13). Mean (SD) time with CGM glucose concentration <3.3 mmol/L was 0% (0.002) in the BHBP period vs. 1.3% (0.018) in the UC period (P = 0.11). CONCLUSIONS: Relative to UC, the BHBP resulted in comparable glycemic control in our population.

Critical region within 22q11.2 linked to higher rate of autism spectrum disorder.

BACKGROUND: Previous studies have reported no clear critical region for medical comorbidities in children with deletions or duplications of 22q11.2. The purpose of this study was to evaluate whether individuals with small nested deletions or duplications of the LCR-A to B region of 22q11.2 show an elevated rate of autism spectrum disorder (ASD) compared to individuals with deletions or duplications that do not include this region. METHODS: We recruited 46 patients with nested deletions (n = 33) or duplications (n = 13) of 22q11.2, including LCR-A to B (ndel = 11), LCR-A to C (ndel = 4), LCR-B to D (ndel = 14; ndup = 8), LCR-C to D (ndel = 4; ndup = 2), and smaller nested regions (n = 3). Parent questionnaire, record review, and, for a subset, in-person evaluation were used for ASD diagnostic classification. Rates of ASD in individuals with involvement of LCR-B to LCR-D were compared with Fisher's exact test to LCR-A to LCR-B for deletions, and to a previously published sample of LCR-A to LCR-D for duplications. The rates of medical comorbidities and psychiatric diagnoses were determined from questionnaires and chart review. We also report group mean differences on psychiatric questionnaires. RESULTS: Individuals with deletions involving LCR-A to B showed a 39-44% rate of ASD compared to 0% in individuals whose deletions did not involve LCR-A to B. We observed similar rates of medical comorbidities in individuals with involvement of LCR-A to B and LCR-B to D for both duplications and deletions, consistent with prior studies. CONCLUSIONS: Children with nested deletions of 22q11.2 may be at greater risk for autism spectrum disorder if the region includes LCR-A to LCR-B. Replication is needed.