Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 9 affected individuals

Genet Med. 2019 Jan;21(1):233-242. doi: 10.1038/s41436-018-0013-9. Epub 2018 Jun 15.


Purpose: Describe the clinical and molecular findings of patients with Kabuki syndrome (KS) who present with hypoglycemia due to congenital hyperinsulinism (HI), and assess the incidence of KS in patients with HI.

Methods: We documented the clinical features and molecular diagnoses of 9 infants with persistent HI and KS via a combination of sequencing and copy-number profiling methodologies. Subsequently, we retrospectively evaluated 100 infants with HI lacking a genetic diagnosis, for causative variants in KS genes.

Results: Molecular diagnoses of KS were established by identification of pathogenic variants in KMT2D (n = 5) and KDM6A (n = 4). Among the 100 infants with HI of unknown genetic etiology, a KS diagnosis was uncovered in one patient.

Conclusions: The incidence of HI among patients with KS may be higher than previously reported, and KS may account for as much as 1% of patients diagnosed with HI. As the recognition of dysmorphic features associated with KS is challenging in the neonatal period, we propose KS should be considered in the differential diagnosis of HI. Since HI in patients with KS is well managed medically, a timely recognition of hyperinsulinemic episodes will improve outcomes, and prevent aggravation of the preexisting mild to moderate intellectual disability in KS.

Keywords: Hypoglycemia; KDM6A; KMT2D; Kabuki syndrome; hyperinsulinism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / physiopathology
  • Child, Preschool
  • Congenital Hyperinsulinism / complications
  • Congenital Hyperinsulinism / diagnosis
  • Congenital Hyperinsulinism / genetics*
  • Congenital Hyperinsulinism / physiopathology
  • DNA-Binding Proteins / genetics*
  • Face / abnormalities*
  • Face / physiopathology
  • Female
  • Genetic Predisposition to Disease
  • Hematologic Diseases / complications
  • Hematologic Diseases / diagnosis
  • Hematologic Diseases / genetics*
  • Hematologic Diseases / physiopathology
  • Histone Demethylases / genetics*
  • Humans
  • Infant
  • Intellectual Disability / complications
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics
  • Intellectual Disability / physiopathology
  • Male
  • Mutation
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Pathology, Molecular
  • Retrospective Studies
  • Vestibular Diseases / complications
  • Vestibular Diseases / diagnosis
  • Vestibular Diseases / genetics*
  • Vestibular Diseases / physiopathology


  • DNA-Binding Proteins
  • KMT2D protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • Histone Demethylases
  • KDM6A protein, human

Supplementary concepts

  • Kabuki syndrome