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Published on: November 16, 2011
Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome
Elizabeth Rosenfeld1,2, Lauren M Mitteer1, Kara Boodhansingh1
1Congenital Hyperinsulinism Center, Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Insights
Kabuki syndrome (KS) is often linked to congenital hyperinsulinism (HI), with most infants experiencing hypoglycemia at birth. Early evaluation for HI is crucial in KS patients, and genetic testing for KMT2D and KDM6A is recommended.
Area of Science:
- Genetics
- Pediatrics
- Endocrinology
Background:
- Kabuki syndrome (KS) is a rare genetic disorder associated with various clinical manifestations.
- Congenital hyperinsulinism (HI) is a significant condition characterized by persistent hypoglycemia in newborns.
- A known association exists between KS and HI, necessitating further investigation into their relationship.
Purpose of the Study:
- To elucidate the clinical and molecular characteristics of congenital hyperinsulinism (HI) in pediatric patients diagnosed with Kabuki syndrome (KS).
- To analyze the diagnostic timeline, treatment responses, and genetic underpinnings of HI in the context of KS.
Main Methods:
- A retrospective cohort study was conducted involving 33 children with both KS and HI.
- Data collected spanned from 1998 to 2023, focusing on HI presentation, management, clinical course, and genetic variants.
- Analysis included diagnostic ages, treatment outcomes with diazoxide, and discontinuation of therapy.
Main Results:
- Hypoglycemia was detected at birth in 76% of patients, though HI diagnosis was often delayed (median age 1.8 months).
- Pathogenic variants in KMT2D (73%) and KDM6A (15%) were identified as key genetic factors.
- Diazoxide effectively managed HI in 92% of cases, with treatment discontinuation possible in 46% by early childhood.
Conclusions:
- Most children with KS and HI present with neonatal hypoglycemia, highlighting the need for timely HI diagnosis.
- Diazoxide is an effective treatment for HI in this cohort, and many patients can discontinue therapy over time.
- Genetic evaluation for KMT2D and KDM6A is recommended for infants with HI, especially when KS is suspected or diagnosed.
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.
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