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.
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.
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.
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).
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.
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 (
= 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 (
= 0.11).
Relative to UC, the BHBP resulted in comparable glycemic control in our population.
Abstract 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 Measure(s) 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.
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.
We recruited 46 patients with nested deletions (
= 33) or duplications (
= 13) of 22q11.2, including LCR-A to B (
= 11), LCR-A to C (
= 4), LCR-B to D (
= 14;
= 8), LCR-C to D (
= 4;
= 2), and smaller nested regions (
= 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.
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.
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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.
Fluoro-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
mutation. These cases highlight the importance of a multidisciplinary and personalized approach to the management of infants with HI.
Diazoxide, the only U.S. Food and Drug Administration-approved drug to treat hyperinsulinemic hypoglycemia, has been associated with several adverse events, which has raised concerns about the safety ...of this drug. Existing reports are limited to small studies and case reports.
To determine prevalence of and clinical factors associated with adverse events in infants and children treated with diazoxide.
Retrospective cohort study of children with hyperinsulinism (HI) treated with diazoxide between 2003 and 2014.
The Congenital Hyperinsulinism Center at the Children's Hospital of Philadelphia.
Children and infants with laboratory-confirmed diagnosis of HI.
Prevalence of pulmonary hypertension (PH), edema, neutropenia, thrombocytopenia, and hyperuricemia was determined. Tests of association and logistic regression were used to identify potential risk factors.
A total of 295 patients (129 female) met inclusion criteria. The median age at diazoxide initiation was 29 days (interquartile range, 10 to 142 days; n = 226 available start dates); 2.4% of patients were diagnosed with PH after diazoxide initiation. Children with PH (P = 0.003) or edema (P = 0.002) were born at earlier gestational age and more frequently had potential PH risk factors, including respiratory failure and structural heart disease (P < 0.0001 and P = 0.005). Other adverse events included neutropenia (15.6%), thrombocytopenia (4.7%), and hyperuricemia (5.0%).
In this large cohort, PH occurred in infants with underlying risk factors, but no identifiable risk profile emerged for other adverse events. The relatively high prevalence of neutropenia, thrombocytopenia, and hyperuricemia suggests the value in proactively screening for these side effects in children treated with diazoxide.
Effective treatment and close monitoring in children with congenital hyperinsulinism (HI) are important to prevent hypoglycemic-associated brain damage. The current monitoring approach involves ...measuring plasma glucose intermittently, but this does not provide a comprehensive assessment of glycemic control and may fail to detect episodes of hypoglycemia.
To determine whether Dexcom G5®, a continuous glucose monitoring system (CGMS), is an accurate and effective method for monitoring glycemic control in children with HI.
Cross-sectional, observational study in 15 children with HI. Participants wore a blinded Dexcom G5® device for 2 weeks. At the end of 2 weeks, data from the Dexcom G5® and home glucose meter were downloaded and analyzed.
Fourteen children (15-67 months) completed the study. Using Bland-Altman analysis, the mean (SD) difference between 1,155 paired CGM and glucose meter readings was -8.09 (53.76). The sensitivity and specificity of CGM to detect hypoglycemia (<70 mg/dL) were 86 and 81.4%, respectively. The positive predictive values for hypoglycemia and severe hypoglycemia (<54 mg/dL) detected by CGM were low (50.3 and 14.8%, respectively), while the negative predictive values were high (96.4% for glucose <70 mg/dL and 99.1% for glucose <54 mg/dL).
Our study showed that CGM is not a reliable method to monitor for hypoglycemia, given the high number of false positive hypoglycemia readings. However, CGM can be useful in preventing unnecessary checks by glucose meter during times of normoglycemia. Therefore, the benefits of using CGM in patients with HI would be in guiding the need to check plasma glucose by glucose meter rather than point accuracy.
Congenital Hyperinsulinism (HI) is a disorder of beta-cell function that results in severe hypoglycemia. Near-total pancreatectomy (Ppx) is necessary for intractable hypoglycemia in the most severe ...cases, which results in diabetes later in life. The evolution of diabetes after Ppx is characterized by marked hypo- and hyper-glycemia due to residual dysregulated insulin secretion and glucagon deficiency. We aim to evaluate the safety and efficacy of a bihormonal bionic pancreas (BHBP) in individuals with HI and post-Ppx diabetes. Autonomously adaptive dosing algorithms in the BHBP use data from an integrated continuous glucose monitor (CGM) to control subcutaneous delivery of insulin and glucagon. Our hypothesis is that the BHBP will result in improved glycemic control compared to conventional insulin pump (CIP) therapy. This is an open-label, random-order, crossover, pilot study. Subjects with HI and post-Ppx diabetes are randomly assigned to BHBP therapy or CIP therapy during a 4-day inpatient stay, followed by the opposite intervention at least 1 week later. The BHBP was initialized with only the subject’s body weight. The coprimary outcomes are mean glucose and time with CGM glucose < 60 mg/dL analyzed over days 2-4. Seven subjects age 7-25 years (4 F) with mean A1C of 7.5% (SD 0.57) have completed the study to date. Mean CGM glucose was 148 mg/dL (SD 14) during the BHBP period vs. 156 mg/dL (SD 28) during the CIP period. All subjects had mean glucose during their BHBP period at or below 169 mg/dL (corresponding to A1C of 7.5%), whereas only 57% of subjects met this goal during their CIP period. Mean time with CGM glucose < 60 mg/dL was 0.07% (SD 0.60%) during the BHBP period vs. 1.71% (SD 3.48) during the CIP period. The BHBP was well tolerated. Relative to CIP therapy, the BHBP was able to produce, with greater ease of use, comparable, if not superior, results in terms of mean glucose and reduced frequency of hypoglycemia in individuals with HI and post-Ppx diabetes.
Disclosure
A. Rayannavar: None. L.M. Mitteer: None. K. Lord: None. C.P. Hawkes: None. C.A. Balliro: None. F. El-Khatib: Employee; Self; Beta Bionics. Stock/Shareholder; Self; Beta Bionics. E. Damiano: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Beta Bionics. Employee; Self; Beta Bionics. Stock/Shareholder; Self; Beta Bionics. Stock/Shareholder; Spouse/Partner; Beta Bionics. Other Relationship; Self; Ascensia Diabetes Care, Senseonics. S.J. Russell: Advisory Panel; Self; Companion Medical, Unomedical a/s. Consultant; Self; Flexion Therapeutics. Research Support; Self; Beta Bionics, MITRE Corporation, Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Self; ADOCIA, Ascensia Diabetes Care, Ascensia Diabetes Care, Lilly Diabetes, Roche Diabetes Care, Senseonics. D. De Leon: Consultant; Self; Crinetics, Novartis Pharmaceuticals Corporation, ProSciento, Soleno Therapeutics, Zealand Pharma A/S. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Crinetics, Dexcom, Inc., Zealand Pharma A/S. Stock/Shareholder; Self; Merck & Co., Inc.
Funding
Zealand Pharma A/S; Dexcom, Inc.; University of Pennsylvania; Children's Hospital of Philadelphia Women's Committee; National Institutes of Health (T32DK06368-14 to A.R.); Pediatric Endocrine Society
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