Diazoxide-Responsive Forms of Congenital Hyperinsulinism

Yau, Daphne; Stanley, Charles A.

doi:10.1007/978-3-030-02961-6_2

Cited by 3 publications

(2 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given the risk of diazoxide-associated fluid retention and pulmonary hypertension, our Center's practice is to concomitantly treat with diuretic and consult cardiology before initiating diazoxide in children with congenital heart disease. Diazoxide responsiveness was defined as the ability to maintain plasma glucose concentration >70 mg/dL (3.9 mmol/L) for at least 12 hours of fasting and/or generate appropriate hyperketonemia (plasma β-hydroxybutyrate >1.8 mmol/L) before development of plasma glucose <50-60 mg/dL (2.8-3.3 mmol/L) [ 22 , 23 ]. Resolution of HI was defined as demonstration of the development of hyperketonemia (β-hydroxybutyrate >1.8 mmol/L) before development of plasma glucose <50 mg/dL (2.8 mmol/L) during a controlled inpatient fast performed off treatment [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome

Rosenfeld,

Mitteer,

Boodhansingh

et al. 2024

Journal of the Endocrine Society

View full text Add to dashboard Cite

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, genotype Results Hypoglycemia was recognized on the first day of life in 25 children (76%). Median age at HI diagnosis was 1.8 months (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). Conclusions 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, as KS features may not be recognized in infancy, KMT2D and KDM6A should be included in the genetic evaluation of HI.

show abstract

Section: Methodsmentioning

confidence: 99%

Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome

Rosenfeld,

Mitteer,

Boodhansingh

et al. 2024

Journal of the Endocrine Society

View full text Add to dashboard Cite

show abstract

“…Responsiveness to diazoxide can be demonstrated by showing that the cardinal feature of HI, hypoketotic hypoglycemia, has been reversed. In practice, this means demonstrating that the infant or child can fast and generate hyperketonemia (BOHB levels >1.8 mmol/L) prior to developing hypoglycemia (plasma glucose levels below 50–60 mg/dL [<2.8–3.3 mmol/L]) [ 112 ]. In patients in whom the rate of dextrose infusion cannot be reduced after 5 days of treatment with diazoxide at a dose of 15 mg/kg/day or in whom unresponsiveness has been confirmed by a fasting test, diazoxide should be discontinued.…”

Section: Medical Managementmentioning

confidence: 99%

International Guidelines for the Diagnosis and Management of Hyperinsulinism

León¹,

Arnoux²,

Banerjee³

et al. 2023

Horm Res Paediatr

Self Cite

View full text Add to dashboard Cite

Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI, however; there have been almost no new therapeutic modalities since the development of diazoxide. Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in ‘developed’ countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an “essential medicine” by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.

show abstract

Hyperinsulinism–hyperammonemia syndrome in two Peruvian children with refractory epilepsy

Torre

Villar

Lama

et al. 2022

Journal of Pediatric Endocrinology and Metabolism

View full text Add to dashboard Cite

Objectives Congenital hyperinsulinism (HI) is a heterogeneous clinical disorder with great variability in its clinical phenotype, and to date, pathogenic variants in 23 genes have been recognized. Hyperinsulinism-hyperammonemia syndrome (HI/HA) is the second most frequent cause of this disease that shows an autosomal dominant pattern and is caused by an activating mutation of the GLUD1 gene, which responds favorably to the use of diazoxide. HI/HA syndrome presents with fasting hypoglycemia; postprandial hypoglycemia, especially in those with a high protein content (leucine); and persistent mild hyperammonemia. Neurological abnormalities, in the form of epilepsy or neurodevelopmental delay, are observed in a high percentage of patients; therefore, timely diagnosis is crucial for proper management. Case presentation We report the clinical presentation of two Peruvian children that presented with epilepsy whose genetic analysis revealed a missense mutation in the GLUD1 gene, one within exon 11, at 22% mosaicism; and another within exon 7, as well as their response to diazoxide therapy. To the best of our knowledge, these are the first two cases of HI/HA syndrome reported in Peru. Conclusion HI/HA syndrome went unnoticed, because hypoglycemia was missed and were considered partially controlled epilepsies. A failure to recognize hypoglycemic seizures will delay diagnosis and adequate treatment, so a proper investigation could avoid irreversible neurological damage.

show abstract

Diazoxide-Responsive Forms of Congenital Hyperinsulinism

Cited by 3 publications

References 73 publications

Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome

Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome

International Guidelines for the Diagnosis and Management of Hyperinsulinism

Hyperinsulinism–hyperammonemia syndrome in two Peruvian children with refractory epilepsy

Contact Info

Product

Resources

About