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

Abstract

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.

Fig. 1. Clinical features and/or molecular characterization of Patients 1-4.

a Array-CGH results for patient 1 showing a hemizygous deletion involving exons 3–24 of KDM6A (arr[hg19] Xp11.3(44818602_44947539)×0). The reference sequence used for KDM6A is NM_021140.3. b Confirmation analysis of the deletion by duplex-PCR of exons 10 and 19 of KDM6A using a control amplicon in the MECP2 gene revealed the presence of a faint band corresponding to the KDM6A exons 10 and 19 in the patient’s DNA, suggesting the likely mosaic nature of the deletion. c Facial features of patient 1 at 9 months of age, showing long palpebral fissures, long eyelashes, and thin vermilion of the upper lip. d Array-CGH results for patient 2 providing evidence of a heterozygous deletion involving exons 7–17 of KDM6A (arr[hg19] Xp11.3(44892185_ 44935785)×1). e Patient 3 at 13 months old with the typical facial appearance and presence of persistent fingertip pads. f Patient 4 at 14 months old with the typical facial appearance of KS